Clinical practice companion

CLINICAL PRACTICE COMPANION

An NEJM Special Collection

We are pleased to present you with a collection of recent articles relevant to today’s practicing physician. NEJM is committed to helping physicians improve patient care by providing the best current information in an understandable and clinically useful format . These regular features, Clinical Practice, Clinical Therapeutics, and Current Concepts, demonstrate how to diagnose and manage diseases, keep you up to date with the latest in clinical care, and highlight the best treatments and management options. This collection will only be available for a limited time, with free access available by clicking through from the Special Collections tab in My NEJM.

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CLINICAL PRACTICE

CLINICAL PRACTICE

Gout T. NeogiFebruary 3, 2011

CLINICAL PRACTICE

Calcium Kidney StonesE.M. Worcester and F.L. CoeSeptember 2, 2010

CLINICAL PRACTICE

Emergency Treatment of AsthmaS.C. LazarusAugust 19, 2010

CLINICAL PRACTICE

Early Alzheimer’s DiseaseR. MayeuxJune 10, 2010

CLINICAL PRACTICE

Helicobacter pylori InfectionK.E.L. McColApril 29, 2010

CLINICAL THERAPEUTICS


Iron-Chelating Therapy for Transfusional Iron OverloadG.M. BrittenhamJanuary 13, 2011


Bisphosphonates for OsteoporosisM.J. FavusNovember 18, 2010


Ranibizumab Therapy for Neovascular Age-Related Macular DegenerationJ.C. Folk and E.M. StoneOctober 21, 2010


Dietary Therapy in HypertensionF.M. Sacks and H. Campos June 3, 2010


Mitral-Valve Repair for Mitral-Valve ProlapseS. Verma and T.G. MesanaDecember 3, 2009

CURRENT CONCEPTS

REVIEW ARTICLE

Point-of-Care UltrasonographyC.L. Moore and J.A. CopelFebruary 24, 2011

REVIEW ARTICLE

Myocardial Infarction Due to Percutaneous Coronary InterventionA. Prasad and J. HerrmannFebruary 3, 2011

REVIEW ARTICLE

MDR Tuberculosis — Critical Steps for Prevention and ControlE. Nathanson and othersSeptember 9, 2010

OTHER CLINICAL RESOURCES

VIDEOS IN CLINICAL MEDICINE

Clinical Evaluation of the KneeT.L. Schraeder and others July 22, 2010

INTERACTIVE MEDICAL CASE

Lying LowJ.J. Ross and others February 10, 2011

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Table of Contents

Table of Contents

4

Clinical Practice

Clinical Practice articles begin with the presentation of a single case and continue to provide a complete description of diagnostic and treatment strategies, therapeutic options, areas of uncertainty, treatment guidelines — everything you need to know about the current state of knowledge about a common condition. These articles are also available in audio format, so you can listen at your computer or download articles for transfer to any iPod or MP3 player.

5

clinical practice

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;5 nejm.org february 3, 2011 443

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the author’s clinical recommendations.

An audio version of this article is available at NEJM.org

GoutTuhina Neogi, M.D., Ph.D.

From the Section of Clinical Epidemiolo-gy Research and Training Unit, Boston University School of Medicine; and the Department of Epidemiology, Boston University School of Public Health — both in Boston. Address reprint requests to Dr. Neogi at the Clinical Epidemiology Unit, Boston University School of Medi-cine, 650 Albany St., Suite X-200, Boston, MA 02118, or at [email protected].

N Engl J Med 2011;364:443-52.Copyright © 2011 Massachusetts Medical Society.

A 54-year-old man with crystal-proven gout has a history of four attacks during the previous year. Despite receiving 300 mg of allopurinol daily, his serum urate level is 7.2 mg per deciliter (428 μmol per liter). He is moderately obese and has hypertension, for which he receives hydrochlorothiazide, and his serum creatinine level is 1.0 mg per deciliter (88 μmol per liter). How should his case be managed?

The Clinic a l Problem

Symptoms and Prevalence

Gout is a type of inflammatory arthritis induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. It is associated with hyperurice-mia, which is defined as a serum urate level of 6.8 mg per deciliter (404 μmol per liter) or more, the limit of urate solubility at physiologic temperature and pH.1 Hu-mans lack uricase and thus cannot convert urate to soluble allantoin as the end prod-uct of purine metabolism. Hyperuricemia that is caused by the overproduction of urate or, more commonly, by renal urate underexcretion is necessary but not suffi-cient to cause gout. In one cohort study, gout developed in only 22% of subjects with urate levels of more than 9.0 mg per deciliter (535 μmol per liter) during a 5-year period.2

Gout has two clinical phases. The first phase is characterized by intermittent acute attacks that spontaneously resolve, typically over a period of 7 to 10 days, with asymptomatic periods between attacks. With inadequately treated hyperuricemia, transition to the second phase can occur, manifested as chronic tophaceous gout, which often involves polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. Although the prevalence of tophaceous gout varies among populations, in one study, tophi were detected in three quarters of patients who had had untreated gout for 20 years or more.3 Recurrent attacks are common. In one study, approximately two thirds of patients with at least one gout attack in the previous year had recurrent attacks.4

An estimated 6.1 million adults in the United States have had gout.5 The preva-lence increases with age and is higher among men than among women, with a ratio of 3 or 4 to 1 overall.5-7 However, this sex disparity decreases at older ages, at least in part because of declining levels of estrogen, which has uricosuric effects in women. The rising incidence and prevalence of gout are probably related to the aging of the population, increasing levels of obesity, and dietary changes.6,7

Risk Factors

The use of thiazide diuretics, cyclosporine, and low-dose aspirin (<1 g per day) can cause hyperuricemia, whereas high-dose aspirin (≥3 g per day) is uricosuric. Factors

Click here to access audio version.




6


n engl j med 364;5 nejm.org february 3, 2011444

that are associated with hyperuricemia and gout include insulin resistance, the metabolic syndrome, obesity, renal insufficiency, hypertension, conges-tive heart failure, and organ transplantation.8,9 The uricosuric effects of glycosuria in diabetes may re-duce the risk of gout.10 Rare X-linked inborn errors of metabolism can cause gout.8 Genomewide as-sociation studies have identified common poly-morphisms in several genes involved in renal urate transport that are associated with gout, includ-ing SLC2A9, ABCG2, SLC17A3, and SLC22A12.11,12 The risk of incident gout is increased in persons with an increased intake of dietary purines (par-ticularly meat and seafood), ethanol (particularly beer and spirits), soft drinks, and fructose13-16 and is decreased in those with an increased intake of coffee, dairy products, and vitamin C (which lower urate levels).15,17,18

Triggers for recurrent flares include recent di-uretic use, alcohol intake, hospitalization, and surgery.19,20 Urate-lowering therapy, which reduces the risk of gout attacks in the long term, can trigger attacks in the early period after its initia-tion, presumably as a result of mobilization of bodily urate stores.21,22

S tr ategies a nd E v idence

The diagnostic standard remains synovial fluid or tophus aspiration with identification of nega-tively birefringent monosodium urate crystals under polarizing microscopy. Crystals are detect-able during attacks and also potentially between attacks, primarily in previously inflamed joints in patients with hyperuricemia.23 However, crys-tal evaluation is not performed routinely in clini-cal practice.15 Hyperuricemia may not be present during acute gout attacks and therefore may not be a helpful criterion for diagnosis. A typical pre-sentation that is strongly suggestive of the diag-nosis includes rapid development of severe pain (i.e., within 24 hours), erythema, and swelling in a characteristic joint distribution — for example, in the first metatarsophalangeal joint (podagra). In a population with a 0.5% prevalence of gout overall, a patient with hyperuricemia and this pre-sentation has an 82% chance of having gout.23

The differential diagnosis of acute gout in-cludes other crystal-induced arthritides (e.g., cal-cium pyrophosphate dihydrate) and a septic joint. Joint aspiration with Gram’s staining and culture must be performed if a septic joint is suspected,

even if monosodium urate crystals are identified. Older adults, particularly women, may present with polyarticular involvement, which may be mis-taken for rheumatoid arthritis; a tophus may be mistaken for a rheumatoid nodule. Tophaceous deposits that are not clinically apparent may be visualized by plain radiography or another imag-ing method. A diagnosis of gout should prompt evaluation for potentially modifiable risk factors (e.g., dietary habits) and associated coexisting ill-nesses (e.g., hypertension and hyperlipidemia) that may require intervention.

Tr e atmen t Op tions

Acute Gout

The main aim of therapy for acute gout is rapid relief of pain and disability caused by intense in-flammation. Options for managing acute attacks include the use of nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, glucocorticoids, and possibly corticotropin.24 The choice of agent, dose, and duration of therapy is guided by consideration of coexisting illnesses that preclude the safe use of a particular regimen, as well as the severity of the gout. Adjunctive measures include applying ice to and resting the affected joint.25

NSAIDs and colchicine are first-line agents for acute attacks (Table 1).24 Oral colchicine has long been used, although it has only recently (in 2009) been approved by the Food and Drug Ad-ministration (FDA) for use in patients with acute gout. In a randomized trial, colchicine (at a dose of 1.2 mg at the onset of a f lare, followed by 0.6 mg 1 hour later) was significantly more likely than placebo to result in a reduction in pain of 50% or more 24 hours later (rates, 37.8% and 15.5%, respectively).26 This regimen had efficacy similar to that of a high-dose regimen (1.2 mg, then 0.6 mg per hour for 6 hours), with fewer gastrointestinal side effects. This study did not address treatment after the first 24 hours.

The relative efficacy of colchicine as compared with NSAIDs is unknown. In head-to-head studies, various NSAIDs have had similar benefits for acute gout, and a controlled trial showed the efficacy of tenoxicam over placebo.24,27

When the use of NSAIDs or colchicine is poor-ly tolerated or contraindicated, glucocorticoids or corticotropin may be used, although evidence for the use of intraarticular and intramuscular glu-cocorticoids and corticotropin is limited by a lack

7

clinical pr actice


Tabl

e 1.

Pha

rmac

olog

ic M

anag

emen

t Opt

ions

for

Acu

te G

out A

ttac

ks.

Dru

gEx

ampl

es o

f Reg

imen

s fr

om

Ran

dom

ized

Clin

ical

Tri

als

Alte

rnat

ive

Reg

imen

s fo

r C

ompl

ete

Att

ack

Res

olut

ion*

Prec

autio

ns

Non

ster

oida

l ant

iinfla

mm

ator

y dr

ug†

Avo

id in

pat

ient

s w

ith r

enal

or

hepa

tic in

suffi

cien

cy, b

leed

ing

dis-

orde

r, c

onge

stiv

e he

art f

ailu

re, o

r al

lerg

y; a

ssoc

iate

d w

ith a

n in

crea

sed

risk

of a

dver

se th

rom

botic

and

gas

troi

ntes

tinal

ev

ents

; may

be

adm

inis

tere

d w

ith a

pro

ton-

pum

p in

hibi

tor

in p

atie

nts

at r

isk

for

gast

roin

test

inal

eve

nts.

Nap

roxe

n50

0 m

g or

ally

twic

e da

ily fo

r 5

days

375–

500

mg

oral

ly tw

ice

daily

for

3 da

ys,

then

250

–375

mg

oral

ly tw

ice

daily

fo

r 4–

7 da

ys o

r un

til a

ttac

k re

solv

es

Indo

met

haci

n50

mg

oral

ly th

ree

times

dai

ly fo

r 2

days

, th

en 2

5 m

g or

ally

thre

e tim

es d

aily

fo

r 3

days

50 m

g or

ally

thre

e tim

es d

aily

for

3 da

ys,

then

25

mg

oral

ly th

ree

times

dai

ly

for

4–7

days

or

until

att

ack

reso

lves

Col

chic

ine

1.2

mg

oral

ly a

t fir

st s

ign

of g

out f

lare

, fo

llow

ed b

y 0.

6 m

g or

ally

1 h

r la

ter

Con

side

r ad

ditio

nal a

cute

gou

t reg

imen

to

con

tinue

man

agin

g at

tack

12

–24

hr a

fter

col

chic

ine

regi

men

(e

.g.,

0.6

mg

of c

olch

icin

e tw

ice

daily

, a

nons

tero

idal

ant

iinfla

mm

ator

y dr

ug r

egim

en, o

r an

ora

l glu

coco

rti-

coid

reg

imen

unt

il at

tack

res

olve

s)

Avo

id (

or u

se lo

wer

dos

e) in

old

er a

dults

and

thos

e w

ith r

enal

in

suffi

cien

cy, h

epat

ic d

ysfu

nctio

n, o

r kn

own

gast

roin

test

inal

sy

mpt

oms;

adj

ust d

ose

(and

avo

id in

pat

ient

s w

ith r

enal

or

hep

atic

impa

irm

ent)

if u

sed

in c

onju

nctio

n w

ith

P-gl

ycop

rote

in o

r C

YP3A

4 in

hibi

tors

(e.

g., c

yclo

spor

ine,

cla

r-ith

rom

ycin

, cer

tain

ant

iret

rovi

ral a

gent

s, c

erta

in a

ntifu

ngal

ag

ents

, cer

tain

cal

cium

-cha

nnel

blo

cker

s, a

nd g

rape

frui

t ju

ice)

; avo

id fo

r go

ut-fl

are

ther

apy

in p

atie

nts

with

ren

al o

r he

-pa

tic im

pair

men

t who

are

alr

eady

rec

eivi

ng c

olch

icin

e pr

o-ph

ylax

is; m

onito

r fo

r ga

stro

inte

stin

al s

ympt

oms,

myo

toxi

city

, an

d bl

ood

dysc

rasi

as (

deta

ils a

re a

vaila

ble

at w

ww

.fda.

gov)

.

Ora

l glu

coco

rtic

oids

(pre

dnis

one

orpr

edni

solo

ne)‡

Pred

niso

lone

, 30–

35 m

g da

ily fo

r 5

days

Pred

niso

ne, 3

0–60

mg

daily

for

2 da

ys

(dep

endi

ng o

n se

veri

ty o

f att

ack)

, th

en r

educ

e by

5–1

0 m

g ev

ery

2 da

ys

(dep

endi

ng o

n st

artin

g do

se)

in

10-d

ay ta

per

Use

cau

tion

in p

atie

nts

with

hyp

ergl

ycem

ia o

r co

nges

tive

hear

t fa

ilure

; may

be

used

in p

atie

nts

with

mod

erat

e-to

-sev

ere

rena

l im

pair

men

t.

* Lo

nger

dur

atio

ns o

f the

rapy

may

be

nece

ssar

y fo

r pa

tient

s w

ith lo

ng-s

tand

ing

dise

ase

and

seve

re fl

ares

.†

The

re a

re n

o pu

blis

hed

tria

ls e

stab

lishi

ng t

he e

ffica

cy o

f cel

ecox

ib, t

he o

nly

sele

ctiv

e cy

cloo

xyge

nase

-2 in

hibi

tor

avai

labl

e in

the

Uni

ted

Stat

es, f

or u

se in

acu

te g

out.

‡ A

lthou

gh t

here

are

insu

ffici

ent

data

to

reco

mm

end

the

use

of in

traa

rtic

ular

glu

coco

rtic

oid

inje

ctio

n, it

may

be

a us

eful

alte

rnat

ive

for

atta

cks

that

are

lim

ited

to o

ne o

r tw

o jo

ints

and

am

enab

le t

o as

pira

tion

and

in t

he a

bsen

ce o

f joi

nt s

epsi

s.

8



of data from blinded, randomized, placebo-controlled trials24,27-29 (Table 1). Monoarticular attacks are often managed with the use of intra-articular glucocorticoids. In two randomized, placebo-controlled trials of a 5-day course of oral prednisolone (one evaluating a dose of 30 mg daily and the other a dose of 35 mg daily), the efficacy of prednisolone was equivalent to that of standard regimens of indomethacin (vs. the 30-mg dose of prednisolone) and naproxen (vs. the 35-mg dose).30,31

The dose and duration of therapy for acute gout should be sufficient to eradicate the profound inflammatory response. Although randomized tri-als have generally studied the effects of short courses of treatment on pain reduction, clinical experience suggests that 7 to 10 days of treatment may be necessary to ensure the resolution of symptoms. Increased doses of antiinflammatory drugs are typically prescribed for the first few days, with a reduction in the dose once symptoms begin to improve.32 Flares should be treated without interruption of urate-lowering therapy. A “medications in the pocket” strategy should be considered for patients with established gout so that therapy can be started promptly at the onset of symptoms that are consistent with typical at-tacks.

There is evidence that attacks of gout are caused by the activation of the NLRP3 inflamma-some by urate crystals, leading to the release of interleukin-1β33 (Fig. 1). For this reason, inter-leukin-1 antagonists are being studied as poten-tial options for patients in whom other treatments are not feasible.34 In a randomized trial, the fully human monoclonal antibody canakinumab sig-nificantly reduced pain from acute gout, as com-pared with 40 mg of intramuscular triamcino-lone acetonide, 72 hours after administration of the study drug.35 Anakinra and rilonacept im-proved acute and chronic gout symptoms, respec-tively, in two small, uncontrolled pilot studies; however, rilonacept did not significantly reduce pain, as compared with indomethacin, in a ran-domized trial.34,36,37 More data are needed to as-sess the potential role of these agents.

Hyperuricemia

Pharmacologic ApproachesThe purpose of lowering serum urate levels is to prevent acute f lares and development of tophi. However, gout does not develop in all patients with

hyperuricemia, and antihyperuricemic therapies are not without risk. Recommendations that are based on both consensus and evidence support the consideration of urate-lowering therapy in pa-tients with hyperuricemia who have at least two gout attacks per year or tophi (as determined by either clinical or radiographic methods).38 How-ever, the severity and frequency of flares, the pres-ence of coexisting illnesses (including nephroli-thiasis), and patient preference are additional considerations.24 Urate-lowering therapy should not be initiated during acute attacks but rather started 2 to 4 weeks after flare resolution, with a low initial dose that is increased as needed over a period of weeks to months, and with close mon-itoring of urate levels, renal function, and adverse effects. The dose should be adjusted as necessary to maintain a serum urate level below 6 mg per deciliter (357 μmol per liter), which is associated with a reduced risk of recurrent attacks and to-phi.22,39,40 It is uncertain whether a more stringent target of less than 5 mg per deciliter (297 μmol per liter) results in greater disease control.41,42 Ther-apy is generally continued indefinitely.

Three classes of drugs are approved for low-ering urate levels: xanthine oxidase inhibitors, uricosuric agents, and uricase agents (Table 2 and Fig. 2). Xanthine oxidase inhibitors block the synthesis of uric acid and can be used regardless of whether there is overproduction of urate. In this class of drugs, the one most commonly pre-scribed to lower urate levels is allopurinol, which is effective in decreasing flares and tophi, particu-larly among patients in whom target urate levels are achieved.22,39 Although allopurinol has an ac-ceptable side-effect profile in most patients, a mild rash develops in approximately 2%.22,39,43 Severe allopurinol hypersensitivity is much less common but can be life-threatening. Allopurinol desensi-tization can be attempted in patients with mild cutaneous reactions, but its safety in those with more serious reactions is unknown.44 The major-ity of patients receive 300 mg of allopurinol daily, but this dose is often inadequate to achieve target urate levels. Daily doses up to 800 mg may be used in patients with normal renal function. The dose is typically reduced in patients with renal impair-ment, owing to concerns about an increased risk of hypersensitivity in such patients. However, stud-ies have not shown an association between dose and risk of hypersensitivity, and a reduced dose may contribute to suboptimal gout control.43

9

clinical pr actice


In 2009, another xanthine oxidase inhibitor, febuxostat, was approved by the FDA for the treatment of hyperuricemia in patients with gout. As compared with a daily dose of 300 mg of allopurinol, febuxostat at daily doses of 80 mg and 120 mg was 2.5 and 3 times as likely, re-spectively, to achieve serum urate levels of less than 6 mg per deciliter in a 52-week trial.22 Dur-ing the initial 8 weeks of the study, the fre-quency of gout attacks was higher among pa-tients receiving 120 mg of febuxostat than among those receiving either 80 mg of febuxo-stat or 300 mg of allopurinol, but there was no significant difference among the three groups for the remainder of the trial. In another study involving patients with renal impairment (de-fined as a creatinine clearance of 30 to 89 ml per minute), daily doses of 80 mg and 40 mg of febuxostat were superior to 300 mg of allopuri-nol (or 200 mg in patients with moderate renal impairment) for lowering serum urate to a level below 6 mg per deciliter.39 There was no in-crease in cardiovascular risk or hypersensitivity associated with the use of either dose of febuxo-stat, as compared with allopurinol, although the trial was not powered for such comparisons. Postmarketing surveillance is needed to better understand the risks and benefits of febuxostat. Its efficacy as compared with increased doses of al-lopurinol is not known, nor is its safety in per-sons with allopurinol hypersensitivity.

Uricosuric drugs (including probenecid, sulfin-pyrazone, and benzbromarone) block renal tubu-lar urate reabsorption. Although these drugs can be used in patients with underexcretion of urate (accounting for up to 90% of patients with gout), they are used less frequently than xanthine oxi-dase inhibitors and are contraindicated in pa-tients with a history of nephrolithiasis. Benzbro-marone (not available in the United States) may be used in patients with mild-to-moderate renal insufficiency but is potentially hepatotoxic, where-as the other two drugs are generally ineffective in patients with renal impairment. In two open-label, randomized trials, benzbromarone was equivalent to allopurinol (the latter at a daily dose of as much as 600 mg) and superior to probenecid (among patients in whom target urate levels were not achieved with 300 mg of allopurinol) in lower-ing serum urate to 5 mg per deciliter or less.41,45

Uricase converts uric acid into soluble allan-toin. Pegloticase, a polyethylene glycolated (peg-

y lated) modified porcine recombinant uricase, was approved by the FDA in 2010 for chronic gout that is refractory to conventional treatments. The approval was based on data from two double-blind, randomized, placebo-controlled, 6-month trials showing the drug’s urate-lowering and to-phus-reducing effects. However, pegloticase must be administered intravenously, and infusion reac-tions were common.46 Rasburicase, which is ap-proved for use in preventing the tumor lysis syn-

Residentmacrophage

lineagecells

Pro–interleukin-1β

NLRP3inflammasome

Interleukin-1receptor

Adhesion molecules,chemokines

C5b-9

Interleukin-1β

Monosodiumurate crystals

Endothelialor synovial cell Neutrophil recruitment,

activation, and releaseof additional

inflammatory mediators

+ +

Other mediators (e.g., TNF-α,interleukin-6 and 8,

leukotrienes, alarmins)

Figure 1. Mechanisms of Inflammation in Gout.

In acute gout, monosodium urate crystals that have undergone phagocyto-sis activate the NLRP3 inflammasome, leading to secretion of interleukin-1β. In turn, this secretion can induce further production of interleukin-1β and other inflammatory mediators and further the activation of synovial lin-ing cells and phagocytes. Monosodium urate crystals also induce many other inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α], inter-leukin-6 and 8, leukotrienes, and alarmins) by mechanisms that are both dependent on and independent of interleukin-1. Experimental models of gout have demonstrated a role for the activation of the terminal comple-ment pathway (C5b-9 membrane attack complex) induced by monosodium urate crystals. Binding of interleukin-1β to the interleukin-1 receptor results in signal transduction, leading to altered expression of adhesion molecules and chemokines, which together with the other inflammatory events re-sults in the neutrophil recruitment that is a major driver of the intense in-flammation in gout. In chronic gout, with low-grade synovitis and frequent-ly recurring or nonresolving flares, these inflammatory processes are probably ongoing with potentially continued release of inflammatory medi-ators, including interleukin-1β, in the presence of persistent monosodium urate crystals.

10



Tabl

e 2.

Pha

rmac

olog

ic O

ptio

ns fo

r H

yper

uric

emia

The

rapy

in G

out.*

Dru

gEx

ampl

e of

Reg

imen

Con

side

ratio

ns o

r Pr

ecau

tions

Ura

te-lo

wer

ing

ther

apy

Aim

to m

aint

ain

seru

m u

rate

leve

ls b

elow

6 m

g pe

r de

cilit

er, w

hich

req

uire

s re

gu-

lar

mon

itori

ng a

nd m

ay r

equi

re d

ose

adju

stm

ents

. Acc

ompa

ny th

e in

itiat

ion

of th

erap

y w

ith fl

are

prop

hyla

xis.

Xan

thin

e ox

idas

e in

hibi

tor

Use

in p

atie

nts

with

ura

te o

verp

rodu

ctio

n or

und

erex

cret

ion.

Avo

id u

se (

or m

oni-

tor

clos

ely)

in p

atie

nts

rece

ivin

g az

athi

opri

ne o

r 6-

mer

capt

opur

ine

beca

use

thes

e dr

ugs

are

met

abol

ized

by

xant

hine

oxi

dase

.

Allo

puri

nol

Star

ting

dose

: 50–

100

mg

oral

ly d

aily

; inc

reas

e do

se e

very

2–4

wk

to a

chie

ve s

erum

ura

te ta

rget

, with

dos

e ba

sed

on c

reat

inin

e cl

eara

nce;

ave

rage

dai

ly d

ose,

300

mg,

alth

ough

man

y pa

tient

s re

quir

e hi

gher

dos

es

Use

with

cau

tion

in p

atie

nts

with

ren

al in

suffi

cien

cy (

base

d on

cre

atin

ine

clea

r-an

ce).

The

max

imal

dos

e m

ay b

e as

hig

h as

800

mg

daily

, but

ther

e ar

e lim

ited

data

for

dose

s ab

ove

300

mg

daily

. A m

ild r

ash

occu

rs in

app

roxi

mat

ely

2% o

f pa

tient

s, a

nd th

e ri

sk is

pot

entia

lly in

crea

sed

by c

oadm

inis

trat

ion

of a

mpi

cilli

n,

amox

icill

in, t

hiaz

ide

diur

etic

s, o

r A

CE

inhi

bito

rs. A

llopu

rino

l hyp

erse

nsiti

vity

is

rare

, occ

urri

ng in

app

roxi

mat

ely

0.1%

of p

atie

nts,

but

can

be

fata

l (ra

te o

f de

ath,

20%

). If

the

targ

et s

erum

ura

te le

vel i

s no

t ach

ieve

d, c

onsi

der

dose

es-

cala

tion

beyo

nd th

e le

vel s

ugge

sted

by

guid

elin

es in

pat

ient

s w

ith r

enal

impa

ir-

men

t (w

ith c

lose

mon

itori

ng)

or c

onsi

der

the

use

of a

n al

tern

ativ

e th

erap

y (e

.g.,

febu

xost

at).

Allo

puri

nol c

an in

crea

se th

e an

ticoa

gula

nt e

ffect

of w

arfa

rin.

Febu

xost

atSt

artin

g do

se: 4

0 m

g or

ally

dai

ly; i

ncre

ase

to 8

0 m

g or

ally

dai

ly

afte

r 2–

4 w

k to

ach

ieve

ser

um u

rate

targ

et, i

f nec

essa

ry†

Use

as

a se

cond

-line

age

nt fo

r pa

tient

s w

ho h

ave

cont

rain

dica

tions

or

an in

ade-

quat

e re

spon

se to

allo

puri

nol o

r ur

icos

uric

ther

apy.

Alth

ough

no

dose

adj

ust-

men

t is

requ

ired

for

patie

nts

with

mild

-to-

mod

erat

e re

nal o

r he

patic

insu

ffi-

cien

cy, t

here

are

insu

ffici

ent d

ata

for

use

in p

atie

nts

with

a c

reat

inin

e cl

eara

nce

of <

30 m

l per

min

ute

or s

ever

e he

patic

impa

irm

ent.

Cur

rent

ly c

ontr

aind

icat

ed

for

use

with

theo

phyl

line.

Feb

uxos

tat h

as a

hig

her

cost

than

allo

puri

nol.

Uri

cosu

ric

agen

t (pr

oben

ecid

)‡St

artin

g do

se: 2

50 m

g or

ally

dai

ly; i

ncre

ase

by 5

00 m

g pe

r m

o to

a

max

imal

dos

e of

2–3

g p

er d

ay (

2 di

vide

d do

ses)

in p

atie

nts

with

nor

mal

ren

al fu

nctio

n to

ach

ieve

ser

um u

rate

targ

et

Avo

id in

pat

ient

s w

ith a

his

tory

of n

ephr

olith

iasi

s an

d a

crea

tinin

e cl

eara

nce

of<3

0 m

l per

min

ute.

Ade

quat

e hy

drat

ion

is r

equi

red

to r

educ

e ri

sk o

f nep

hrol

i-th

iasi

s. T

he u

se o

f thi

s dr

ug c

an in

crea

se s

erum

pen

icill

in le

vels

. Eva

luat

e fo

r re

nal u

ric

acid

exc

retio

n in

pat

ient

s w

ith a

fam

ily h

isto

ry o

f ear

ly o

nset

of g

out,

onse

t of g

out a

t <25

yr,

or

a hi

stor

y of

nep

hrol

ithia

sis,

sin

ce th

is m

ay id

entif

y pa

tient

s w

ith a

n ov

erpr

oduc

tion

of u

rate

in w

hom

uri

cosu

ric

ther

apy

shou

ld b

e av

oide

d be

caus

e of

the

risk

of n

ephr

olith

iasi

s.

11

clinical pr actice


drome, is not appropriate for use in patients with gout because of its immunogenicity and short half-life.

Lifestyle, Nutrition, and Adjunctive TherapiesObservational data indicate that nonpharmaco-logic approaches, such as avoiding alcohol or mod-ifying one’s diet, can reduce serum urate levels but may not be sufficient to control established gout.24 In one randomized trial involving persons without gout, 500 mg of vitamin C per day for 2 months resulted in serum urate levels that were 0.5 mg per deciliter (30 μmol per liter) lower than in those receiving placebo.47 The intake of dairy milk reduced serum urate levels by approximately 10% during a 3-hour period in a small, random-ized, crossover trial involving healthy volunteers.48 Whether these approaches would have similar ef-fects in persons with gout, or with a longer dura-tion of therapy, is not known. Losartan and feno-fibrate, which have uricosuric effects, may be considered in patients with gout who have hyper-tension or hypertriglyceridemia, respectively,49 al-though it is not known whether their use reduces the frequency of gout attacks.

Flare Prophylaxis during Initiation of Urate-Lowering TherapyBecause rapid lowering of urate levels is associat-ed with gout flares, with an increased risk asso-ciated with therapies that more effectively lower urate levels,22,46 prophylaxis against acute flares is advised during the initiation of urate-lowering therapy (Table 2).24 In a study of patients with nor-mal renal function who were starting allopurinol therapy, oral colchicine (at a dose of 0.6 mg twice daily for an average of 5.2 months) significantly reduced the likelihood of gout attacks and less-ened the severity of flares that did occur, as com-pared with placebo.21 Diarrhea was common, resulting in a once-daily regimen of colchicine for many patients. Thus, the general recommenda-tion for flare prophylaxis is to use colchicine at a dose of 0.6 mg once or twice daily, with dose ad-justments as needed for renal impairment, poten-tial drug interactions, or intolerance. Although NSAIDs are also used for prophylaxis, there are few studies that support their use.24 For patients without tophi, prophylaxis should be continued for 6 months. The optimal duration for those with tophi is uncertain; ongoing prophylaxis until to-phus resolution may be necessary.U

rica

se (

pegl

otic

ase)

Intr

aven

ous

infu

sion

of 8

mg

ever

y 2

wk;

req

uire

s pr

emed

icat

ion

with

ant

ihis

tam

ines

and

glu

coco

rtic

oids

; sta

rt g

out-

flare

pro

-ph

ylax

is ≥

7 da

ys b

efor

e in

itiat

ing

trea

tmen

t

Use

for

chro

nic

gout

in a

dults

who

se d

isea

se is

ref

ract

ory

to c

onve

ntio

nal t

hera

py

(e.g

., la

ck o

f nor

mal

izat

ion

of s

erum

ura

te, i

nade

quat

e co

ntro

l of s

igns

and

sy

mpt

oms

with

the

use

of a

xan

thin

e ox

idas

e in

hibi

tor

at m

axim

um m

edic

ally

ap

prop

riat

e do

se, o

r ot

her

cont

rain

dica

tion)

. The

re is

a r

isk

of in

fusi

on r

eac-

tions

(26

%, v

s. 5

% in

pla

cebo

gro

up)

even

with

pre

med

icat

ion,

par

ticul

arly

in

patie

nts

with

out a

ther

apeu

tic r

espo

nse

(in

who

m s

erum

ura

te le

vels

incr

ease

to

abo

ve 6

mg

per

deci

liter

, par

ticul

arly

on

two

cons

ecut

ive

occa

sion

s) o

r w

ith

antib

odie

s ag

ains

t peg

lotic

ase.

Ana

phyl

axis

occ

urs

in 5

% o

f pat

ient

s (v

s. 0

% in

pl

aceb

o gr

oup)

. No

data

are

ava

ilabl

e re

gard

ing

retr

eatm

ent a

fter

sto

ppin

g tr

eatm

ent f

or lo

nger

than

4 w

eeks

. Do

not u

se in

pat

ient

s w

ith G

6PD

def

icie

ncy,

an

d us

e ca

utio

n in

pat

ient

s w

ith c

onge

stiv

e he

art f

ailu

re (

insu

ffici

ent s

afet

y da

ta;

som

e ex

acer

batio

ns in

clin

ical

tria

ls).

Cos

t is

high

er th

an fo

r ot

her

ther

apie

s.

Flar

e pr

ophy

laxi

s du

ring

initi

atio

n of

ura

te-lo

wer

ing

ther

apy

Aim

to r

educ

e th

e ri

sk o

f fla

re d

urin

g in

itial

dec

reas

e in

ura

te le

vels

, pre

sum

ably

re

late

d to

rap

id m

obili

zatio

n of

bod

ily u

rate

sto

res.

The

dur

atio

n of

ther

apy

is n

ot w

ell d

efin

ed b

ut tr

eatm

ent f

or a

t lea

st 6

mo

or u

ntil

toph

i res

olve

is

reco

mm

ende

d.

Col

chic

ine

0.6

mg

oral

ly o

nce

or tw

ice

daily

as

tole

rate

dSe

e Ta

ble

1 fo

r pr

ecau

tions

, par

ticul

arly

taki

ng in

to a

ccou

nt p

oten

tial f

or in

crea

sed

toxi

c ef

fect

s w

ith p

rolo

nged

ther

apy.

NSA

IDN

apro

xen,

250

mg

twic

e da

ilySe

e Ta

ble

1 fo

r pr

ecau

tions

, par

ticul

arly

taki

ng in

to a

ccou

nt p

oten

tial f

or in

crea

sed

toxi

c ef

fect

s w

ith p

rolo

nged

ther

apy.

Thi

s dr

ug h

as n

ot b

een

form

ally

test

ed

but h

as b

een

used

for

prop

hyla

xis

in tr

ials

of u

rate

-low

erin

g th

erap

ies.

* A

CE

deno

tes

angi

oten

sin-

conv

ertin

g en

zym

e, a

nd N

SAID

non

ster

oida

l ant

iinfla

mm

ator

y dr

ug.

† F

ebux

osta

t at

a d

ose

of 1

20 m

g is

ava

ilabl

e in

Eur

ope.

‡ B

enzb

rom

aron

e an

d su

lfinp

yraz

one

are

avai

labl

e in

a li

mite

d nu

mbe

r of

cou

ntri

es b

ut n

ot in

the

Uni

ted

Stat

es.

12



A r e a s of Uncerta in t y

Data are limited regarding the safety and effica-cy of combination therapies for the treatment of gout (e.g., the use of a xanthine oxidase inhibitor and a uricosuric agent for hyperuricemia or the use of multiple drugs for acute gout attacks). The safety and cost-effectiveness of new agents for gout, including inhibitors of urate transporter 1 and purine nucleoside phosphorylase, which are under development, and interleukin-1 antagonists, require further study. Preliminary data have sug-gested the potential efficacy of the interleukin-1 antagonists canakinumab and rilonacept for flare prophylaxis.34

Risk factors for recurrent gout flares may differ from those that predispose patients to the initial attack. Whether factors that lower serum urate levels over the long term in persons without gout would have similar effects with short-term or episodic exposure in persons with gout requires clarification.

It is not known to what level urate can be safely lowered. Observational data have suggested associations between low urate levels and an in-creased risk of Parkinson’s disease,50 but it is unclear whether the low levels are a cause or consequence of disease. The optimal duration of urate-lowering therapy is also uncertain, and such therapy is recommended indefinitely at this time. In one study, the withdrawal of urate-lowering therapy was associated with prolonged symptom-free intervals (3 to 4 years) in a cohort of 89 pa-tients after long-term control of urate levels (<7 mg per deciliter), flares, and tophi resolution,51 but further study is needed.

Finally, the concept of asymptomatic hyperuri-cemia as a benign condition is being challenged. Experimental data suggest that urate may con-tribute to vascular remodeling and hypertension, although it remains uncertain whether urate plays a causal role in cardiovascular disease.9

Guidelines

The American College of Rheumatology is cur-rently developing guidelines for the management of gout. The European League against Rheumatism and the British Society for Rheumatology have published guidelines for the evaluation and man-agement of gout on the basis of trial data (when available) and expert consensus.23,24,42 The pres-ent recommendations are largely consistent with these guidelines.

Conclusions a nd R ecommendations

In patients presenting with suspected gout, the diagnosis should be confirmed by examination of synovial fluid or tophus aspirate for monosodium urate crystals. Management should be tailored to the stage of disease and coexisting illnesses. The patient who is described in the vignette has crystal-proven gout, with multiple attacks and a serum urate level of more than 6 mg per deciliter despite receipt of allopurinol at a dose of 300 mg per day.

Exogenouspurines

Xanthineoxidase

inhibitors

Dietaryrestriction

Recombinant uricase

Renalinsufficiency

or failureUricosuric

agents

Endogenouspurines

Body urate pool

Renaltubules

Figure 2. Management Strategies in Patients with Hyperuricemia.

Hyperuricemia can be targeted at many levels. Restric-tion of exogenous purine intake through dietary modi-fications or the use of xanthine oxidase inhibitors to block uric acid synthesis from endogenous purine me-tabolism can reduce the amount of urate that contrib-utes to the total-body urate pool. Modified uricase agents reduce the total-body urate pool by converting uric acid into soluble allantoin. In patients with normal renal function, uricosuric agents can promote renal elimination of urate, thereby reducing total-body urate pools. However, decreased renal urate excretion in pa-tients with renal impairment leads to increased total-body urate stores.

13

clinical pr actice


Since his renal function is normal, the allopuri-nol dose should be increased (e.g., 100-mg incre-ments every 2 to 4 weeks until the target urate level is reached), with monitoring of renal function and serum urate levels and assessment for potential adverse reactions. Colchicine prophylaxis (0.6 mg once or twice daily) is reasonable while the dose of allopurinol is escalated. If target serum urate levels cannot be achieved or if the patient has seri-ous side effects at higher allopurinol doses, the use of either febuxostat or a uricosuric agent is another option, given his normal renal function.

The patient should understand that the intake of alcohol and an excessive amount of meat or seafood and sugar-sweetened drinks may contrib-ute to elevated urate levels and should be mini-mized. He should be advised to keep well hydrated and to lose weight. Associated cardiovascular risk factors should be identified and treated. Although the use of hydrochlorothiazide may contribute to

the increased urate level, I would not necessarily change that medication if it is effectively con-trolling his blood pressure, and I would advise him to take the diuretic consistently, since inter-mittent use may precipitate flares. The addition of losartan for the hypertension might be considered. He should be advised to maintain his urate-low-ering regimen during flares, which can be man-aged with colchicine. Follow-up is necessary to ensure that appropriate serum urate levels are achieved and maintained and to monitor the pa-tient for adverse effects.

Dr. Neogi reports serving as a core expert panel leader for the American College of Rheumatology Gout Treatment Guidelines. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

I thank Drs. Saralynn Allaire, Hyon Choi, and Yuqing Zhang for their review of the first draft of the manuscript and Dr. Rob-ert Terkeltaub for his review of an earlier version of Figure 1.

References

1. Loeb JN. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum 1972;15:189-92.2. Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study. Am J Med 1987;82:421-6.3. Gutman AB. The past four decades of progress in the knowledge of gout, with an assessment of the present status. Ar-thritis Rheum 1973;16:431-45.4. Neogi T, Hunter DJ, Chaisson CE, Al-lensworth-Davies D, Zhang YQ. Frequency and predictors of inappropriate manage-ment of recurrent gout attacks in a longi-tudinal study. J Rheumatol 2006;33:104-9.5. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part II. Arthritis Rheum 2008;58:26-35.6. Arromdee E, Michet CJ, Crowson CS, O’Fallon WM, Gabriel SE. Epidemiology of gout: is the incidence rising? J Rheuma-tol 2002;29:2403-6.7. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 2004;31:1582-7.8. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499-516.9. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21. [Erratum, N Engl J Med 2010;362:2235.]10. Rodríguez G, Soriano LC, Choi HK. Impact of diabetes against the future risk

of developing gout. Ann Rheum Dis 2010;69:2090-4.11. Dehghan A, Kottgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a ge-nome-wide association study. Lancet 2008;372:1953-61.12. Taniguchi A, Urano W, Yamanaka M, et al. A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout. Arthritis Rheum 2005;52:2576-7.13. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004;363:1277-81.14. Choi HK, Willett W, Curhan G. Fruc-tose-rich beverages and risk of gout in women. JAMA 2010;304:2270-8.15. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093-103.16. Choi HK, Curhan G. Soft drinks, fruc-tose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008;336:309-12.17. Choi HK, Gao X, Curhan G. Vitamin C intake and the risk of gout in men: a pro-spective study. Arch Intern Med 2009;169:502-7.18. Choi HK, Willett W, Curhan G. Coffee consumption and risk of incident gout in men: a prospective study. Arthritis Rheum 2007;56:2049-55.19. Hunter DJ, York M, Chaisson CE, Woods R, Niu J, Zhang Y. Recent diuretic use and the risk of recurrent gout attacks:

the online case-crossover gout study. J Rheumatol 2006;33:1341-5. [Erratum, J Rheumatol 2006;33:1714.]20. Zhang Y, Woods R, Chaisson CE, et al. Alcohol consumption as a trigger of re-current gout attacks. Am J Med 2006;119(9):800.e13-800.e18.21. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Col-chicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31:2429-32.22. Becker MA, Schumacher HR Jr, Wort-mann RL, et al. Febuxostat compared with allopurinol in patients with hyperurice-mia and gout. N Engl J Med 2005;353:2450-61.23. Zhang W, Doherty M, Pascual E, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the EULAR Standing Com-mittee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1301-11.24. Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Com-mittee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2006;65:1312-24.25. Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 2002;29:331-4.26. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for

14


clinical pr actice

early acute gout flare: twenty-four-hour out-come of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060-8.27. Sutaria S, Katbamna R, Underwood M. Effectiveness of interventions for the treatment of acute and prevention of re-current gout — a systematic review. Rheu-matology (Oxford) 2006;45:1422-31.28. Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum 1988;31:803-5.29. Janssens HJ, Lucassen PL, Van de Laar FA, Janssen M, Van de Lisdonk EH. System-ic corticosteroids for acute gout. Cochrane Database Syst Rev 2008;2:CD005521.30. Janssens HJ, Janssen M, van de Lis-donk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lan-cet 2008;371:1854-60.31. Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral predniso-lone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled tri-al. Ann Emerg Med 2007;49:670-7.32. Mandell BF, Edwards NL, Sundy JS, Simkin PA, Pile JC. Preventing and treat-ing acute gout attacks across the clinical spectrum: a roundtable discussion. Cleve Clin J Med 2010;77:Suppl 2:S2-S25.33. Martinon F, Pétrilli V, Mayor A, Tardi-vel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflamma-some. Nature 2006;440:237-41.34. Neogi T. Interleukin-1 antagonism in acute gout: is targeting a single cytokine the answer? Arthritis Rheum 2010;62:2845-9.

35. So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty ar-thritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum 2010;62:3064-76.36. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakin-ra in acute gout. Arthritis Res Ther 2007;9:R28.37. Terkeltaub R, Sundy JS, Schumacher HR, et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann Rheum Dis 2009;68:1613-7.38. Mikuls TR, MacLean CH, Olivieri J, et al. Quality of care indicators for gout man-agement. Arthritis Rheum 2004;50:937-43.39. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63.40. Perez-Ruiz F, Lioté F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 2007;57:1324-8.41. Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escala-tion of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout. Ann Rheum Dis 2009;68:892-7.42. Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheuma-tology guideline for the management of gout. Rheumatology (Oxford) 2007;46:1372-4.43. Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in pa-

tients with gout. J Rheumatol 2006;33:1646-50.44. Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desensitization to allopurinol following cutaneous reac-tions. Arthritis Rheum 2001;44:231-8.45. Reinders MK, van Roon EN, Jansen TL, et al. Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis 2009;68:51-6.46. Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloti-case (polyethylene glycol-conjugated uri-case) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008;58:2882-91.47. Huang HY, Appel LJ, Choi MJ, et al. The effects of vitamin C supplementation on serum concentrations of uric acid: re-sults of a randomized controlled trial. Arthritis Rheum 2005;52:1843-7.48. Dalbeth N, Wong S, Gamble GD, et al. Acute effect of milk on serum urate con-centrations: a randomised controlled cross-over trial. Ann Rheum Dis 2010;69:1677-82.49. Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyper-uricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis 2003;62:572-5.50. Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Phar-macol Exp Ther 2008;324:1-7.51. Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla JM. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Rheum 2006;55:786-90.Copyright © 2011 Massachusetts Medical Society.

CLINICAL TRIAL REGISTRATION

The Journal requires investigators to register their clinical trials in a public trials registry. The members of the International Committee of Medical Journal Editors (ICMJE) will consider most reports of clinical

trials for publication only if the trials have been registered. Current information on requirements and appropriate registries

is available at www.icmje.org/faq_clinical.html.

15

clinical practice



when they exist. The article ends with the authors’ clinical recommendations.

n engl j med 363;10 nejm.org september 2, 2010954

An audio version of this article is available at

NEJM.org

Calcium Kidney StonesElaine M. Worcester, M.D., and Fredric L. Coe, M.D.

From the Nephrology Section, Depart-ment of Medicine, University of Chicago, Chicago. Address reprint requests to Dr. Worcester at the Nephrology Section, MC 5100, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, or at [email protected].


A 43-year-old man presents for evaluation of recurrent kidney stones. He passed his first stone 9 years earlier and has had two additional symptomatic stones. Analysis of the first and the last stones showed that they contained 80% calcium oxalate and 20% calcium phosphate. Analysis of a 24-hour urine collection while the patient was not receiving medications revealed a calcium level of 408 mg (10.2 mmol), an oxalate level of 33 mg (367 μmol), and a volume of 1.54 liters; the urine pH was 5.6. The patient had been treated with 20 to 40 mmol of potassium citrate daily since he passed his first stone. How should he be further evaluated and treated?


In the United States, the prevalence of kidney stones has risen over the past 30 years.1 By 70 years of age, 11.0% of men and 5.6% of women will have a symptom-atic kidney stone. The risk among white persons is approximately three times that among black persons. About 80% of stones are composed of calcium oxalate with variable amounts of calcium phosphate. Diagnosis of a calcium stone requires analysis after passage or removal of the stone. After passage of a first stone, the risk of recurrence is 40% at 5 years and 75% at 20 years. Among patients with recurrent calcium stones who have served as control subjects in randomized, controlled trials of interventions, new stones formed in 43 to 80% of subjects within 3 years.2-9 Hospitalizations, surgery, and lost work time that are associated with kidney stones cost more than $5 billion annually in the United States.10 Stone formation is associ-ated with increased rates of chronic kidney disease and hypertension,11,12 increases that are not completely explained by obesity, which is a risk factor for each of these conditions.13

Although many inherited and systemic diseases are associated with calcium kidney stones,14 most such stones are idiopathic. The majority of patients with idiopathic stones have at least one metabolic abnormality, as identified by 24-hour urine testing. Prevention requires evaluation to identify systemic disease and modi-fiable factors.

Patho genesis

Physicochemical Factors

Supersaturation, often expressed as the ratio of urinary calcium oxalate or calcium phosphate concentration to its solubility, is the driving force in stone formation. At levels of supersaturation below 1, crystals dissolve, whereas at supersaturation levels above 1, crystals can nucleate and grow, promoting stone formation. Supersatura-tion is generally higher in patients with recurrent kidney stones than in those without the condition, and the type of stone that is formed correlates with urinary





16

clinical pr actice

n engl j med 363;10 nejm.org september 2, 2010 955

supersaturation. Calcium oxalate supersaturation is independent of urine pH, but calcium phosphate supersaturation increases rapidly as urine pH rises from 6 to 7. Since calcium oxalate stones form over an initial calcium phosphate layer,15 treat-ment optimally should lower the supersaturation of both types. Most 24-hour analyses of kidney-stone risk that are performed at specialized labo-ratories include calculated supersaturation values.

Urine also contains substances that can ac-celerate or retard urinary crystallization.16 The only such substance that can be modified in practice at this time is citrate, which can slow the growth of calcium crystals.17

Anatomic abnormalities, in particular those that result in urinary stasis (such as ureteropelvic junction obstruction, horseshoe kidney, or poly-cystic kidney), may precipitate or worsen stone formation.18 Patients with a single functioning kidney are at particular risk, since stone passage with ureteral obstruction can result in acute kid-ney failure.

Metabolic Factors

Imbalances between excretions of calcium, oxa-late, and water create supersaturation. Hypercal-ciuria, the most common metabolic abnormality found in patients with recurrent calcium stones, is most often familial and idiopathic19 and is strongly influenced by diet. Gut calcium absorp-tion is increased in persons with idiopathic hyper-calciuria, but serum calcium values remain un-changed, since absorbed calcium is promptly excreted.20 On a low-calcium diet, such persons often excrete more calcium than they eat,21 and urinary calcium excretion also rises markedly af-ter the intake of calcium-free nutrients such as simple oral glucose; in such cases, the only source possible is bone. Although hypercalciuria is some-times divided into subtypes (absorptive, resorptive, and renal leak), this classification is not helpful in guiding treatment. However, measurement of serum calcium is indicated to identify patients with primary hyperparathyroidism.

The level of oxalate excretion is modestly higher among patients with recurrent calcium stones than among those without the condition, possibly because of increased oxalate absorption in the gut.22 The intake of ascorbic acid and a high level of protein may increase oxalate pro-duction.23 Because calcium binds with oxalate in the gut and hinders its absorption, oxalate is

more readily absorbed when dietary calcium is low.23 This may be why a low-calcium diet does not successfully prevent stone recurrence.24

Citrate chelates calcium in the urine, decreas-ing supersaturation and reducing the growth of crystals17; hypocitraturia is a risk factor for stone formation. Distal renal tubular acidosis, hypo-kalemia, and the use of carbonic anhydrase in-hibitors (e.g., topiramate) lead to hypocitraturia, but the cause of this condition in most patients with recurrent kidney stones is unknown.25 Hyperuricosuria, often from high dietary intake of purines, is thought to promote the formation of calcium stones by reducing the solubility of calcium oxalate.26

Histopathology

Intraoperative papillary biopsy specimens ob-tained from patients with recurrent kidney stones show that the pattern of crystal deposition differs according to the type of stone. Idiopathic calci-um oxalate stones form over regions of intersti-tial calcium phosphate deposits (Randall’s plaque) on the papillary surface,27 whereas idiopathic calcium phosphate stones are associated with crystal deposits in inner medullary collecting ducts that contain mainly apatite,28,29 sometimes mixed with other crystals. (For additional details, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)


Patients with recurrent calcium stones should be evaluated to rule out systemic disease and guide preventive therapy. Evaluation includes history taking directed at detecting potential causes of stones (Table 1). All stones should be analyzed to classify the type and to detect conversion from one stone type to another — for example, from calcium oxalate to struvite in the presence of in-fection or to calcium phosphate if the urinary pH rises in response to treatment.30

Computed tomography (CT) without the use of contrast material provides information regard-ing the presence, size, and location of stones, as well as ruling out anatomic abnormalities and providing a baseline for assessing whether sub-sequent stones that are passed are old or new (with the latter indicating a need for improved preventive treatment). Given the expense and radiation exposure of CT, renal ultrasonography

17



or abdominal plain radiography may be used in follow-up imaging of known stones, although these methods are less sensitive than CT.

Metabolic testing should be done after the resolution of the acute episode of stone passage, when patients have resumed their usual diet and activity. Evaluation includes a blood test to screen for hypercalcemia, chronic kidney disease, and renal tubular acidosis. Analysis of a 24-hour urine collection to detect metabolic abnormali-ties should preferably be performed twice, since mineral excretions may vary from day to day.31 Tables 2 and 3 provide a suggested framework

for testing and interpretation. Whether to evalu-ate patients after a single kidney-stone episode is controversial, although it seems prudent to rule out systemic disease, especially in patients with a first stone before adulthood.

Tr e atmen t

Management of Symptomatic Stones

Stones that have formed in kidneys do not re-quire removal or fragmentation unless they cause obstruction, infection, serious bleeding, or persis-tent pain. Ureteral stones of less than 10 mm in

Table 1. Key Coexisting Medical Conditions, Medication Use, Diet, and Other Factors Associated with Calcium Kidney Stones.

Variable Features Type of Kidney Stone

CalciumOxalate

CalciumPhosphate

Medical or surgical history

Bowel disease Chronic diarrhea, malabsorption Yes

Intestinal surgery Small-bowel resection, ileostomy Yes

Bariatric surgery Duodenal switch, Roux-en-Y gastric bypass Yes

Sarcoidosis Yes Yes

Gout Yes

Renal tubular acidosis Yes

Bone disease or fracture Primary hyperparathyroidism, idiopathic hypercalciuria, myeloma

Yes Yes

Immobilization Trauma, prolonged illness Yes Yes

Hyperthyroidism Untreated, iatrogenic Yes Yes

Renal anomaly Urinary stasis Yes Yes

Medications

Topiramate Seizures, migraine Yes

Calcium supplements Antacids, dietary supplement Yes Yes

Carbonic anhydrase inhibitor Glaucoma Yes

Alkali Bicarbonate, citrate Yes

Vitamin D Yes Yes

Occupational or recreational factor

Dehydration Hot environment, inability to drink Yes Yes

Dietary factor

Oxalate loads Nuts, spinach, ascorbic acid Yes

Excess salt Prepared foods, snack foods Yes Yes

Eating disorders Vomiting, use of laxatives Yes Yes

Strange diets* Protein powder, sugar loads Yes Yes

Family history

History of kidney stones in a first-degree relative

Idiopathic hypercalciuria, primary hyperoxaluria Yes Yes

* Strange diets include very restrictive choices of food or the use of a large number or amount of supplements.

18

clinical pr actice


Table 2. Diagnostic Testing for Patients with Recurrent Kidney Stones.*

Measurement Normal Value or Range for Adults Purpose

Blood testing

Calcium 8.8–10.3 mg/dl Detection of primary hyperparathyroidism, excessive vitamin D intake, sarcoidosis

Phosphate 2.5–5.0 mg/dl Detection of primary hyperparathyroidism

Creatinine 0.6–1.2 mg/dl Detection of chronic kidney disease

Bicarbonate 20–28 mmol/liter Detection of renal tubular acidosis

Chloride 95–105 mmol/liter Detection of renal tubular acidosis

Potassium 3.5–4.8 mmol/liter Detection of renal tubular acidosis, eating disorders, gastro-intestinal disease

Urine collection over 24-hour period

Volume >1.5 liter/day Detection of low volume as cause of stones

Calcium <300 mg/day for men, <250 mg/day for women; <140 mg/g creatinine/day

Detection of hypercalciuria

Oxalate <40 mg/day Detection of hyperoxaluria

pH 5.8–6.2 Calculation of calcium phosphate and uric acid supersatura-tion, diagnosis of renal tubular acidosis

Phosphate 500–1500 mg/day Calculation of calcium phosphate supersaturation

Citrate >450 mg/day for men, >550 mg/day for women Detection of low citrate level and diagnosis of renal tubular aci-dosis; calculation of calcium phosphate supersaturation

Uric acid <800 mg/day for men, <750 mg/day for women Detection of hyperuricosuria as cause of stones; calculation of uric acid supersaturation

Sodium 50–150 mmol/day Diet counseling; calculation of supersaturation

Potassium 20–100 mmol/day Use of potassium salts; calculation of supersaturation

Magnesium 50–150 mg/day Detection of malabsorption; calculation of supersaturation

Sulfate 20–80 mmol/day Calculation of supersaturation; measure of net acid production

Ammonium 15–60 mmol/day Calculation of supersaturation

Creatinine 20–24 mg/kg/day for men, 15–19 mg/kg/day for women

Comparison of actual with predicted creatinine to assess the completeness of the urine collection

Protein catabolic rate† 0.8–1.0 g/kg/day Estimation of protein intake

Calculated supersaturation‡

Calcium oxalate 6–10 Guidance of treatment

Calcium phosphate 0.5–2 Guidance of treatment

Other screening tests

Urinary cystine screening§ Negative Detection of cystinuria

Stone analysis Basic classification of condition

* Blood testing for renal tubular acidosis, chronic kidney disease, and hypercalcemia, along with urinary cystine screening and kidney-stone analysis, are appropriate for all patients with recurrent kidney stones. Collection of urine over a 24-hour period is appropriate if medical prevention of kidney-stone formation is planned. To convert the values for calcium to millimoles per day, multiply by 0.025. To convert the values for phosphate to millimoles per day, multiply by 0.0323. To convert the values for creatinine to micromoles per day multiply by 0.00884. To convert the values for urinary oxalate to micromoles per day, multiply by 11.11. To convert the values for urinary citrate to mmol per day, multiply by 0.0052. To convert the values for urinary uric acid to millimoles per day, multiply by 0.00595. To convert the values for urinary magnesium to mmol per day, multiply by 0.0411. To convert the values for urinary urea nitrogen to moles per day, multiply by 0.0357.

† The protein catabolic rate is calculated by multiplying the urea nitrogen excretion in grams per day by 6.25 and dividing by body weight in kilograms.

‡ Supersaturation is expressed as the ratio of urinary calcium oxalate or calcium phosphate concentration to its solubility.§ Urinary cystine was tested with the use of the cyanide nitroprusside test. A negative test means that the cystine concentration is less than

75 mg per liter.

19



diameter may be followed with conservative treat-ment in the absence of fever, infection, or renal failure, if pain is controlled. Opioid analgesics and nonsteroidal antiinflammatory agents are both effective for pain control in acute colic. Therapy with drugs that block α1-adrenergic re-ceptors or calcium-channel blockers may facili-tate passage of ureteral stones.32 In general, stones larger than 10 mm in diameter will not pass, and those smaller than 5 mm will; stones from 5 mm to 10 mm have variable outcomes. Stones in the distal ureter are more likely to pass than those located more proximally.

If stones do not pass, there are several surgi-cal options for removal.33 Data to guide surgical recommendations are derived largely from meta-analyses of small trials. For ureteral stones, the treatment of choice is either shock-wave litho-tripsy or ureteroscopy with laser lithotripsy. Stone-free rates are better with ureteroscopy, but com-plication rates are higher, including sepsis and ureteral injury. For stones lodged in the kidney, the size, location, and presumed composition play a role in determining treatment. Not all stone types fragment equally well; for example,

calcium oxalate monohydrate and brushite stones are more resistant to fragmentation than calci-um oxalate dihydrate or apatite stones. Shock-wave lithotripsy and ureteroscopy are frequently used for smaller stones. Percutaneous nephro-lithotomy may be used for single large stones (above 2 cm) or a large or obstructing stone bur-den. This procedure requires general anesthesia and hospitalization and carries more risk of com-plications, including bleeding and infection, than other techniques but can result in a stone-free kidney.34 Open or laparoscopic procedures are occasionally used for stone removal in challeng-ing cases.

Prevention of Idiopathic Calcium Oxalate Stones

Prevention of recurrent stones requires decreas-ing urinary supersaturation, which is generally achieved by raising urine volume and lowering calcium and oxalate excretion. It should be rec-ognized that urinary abnormalities are graded risk factors, and thresholds for the definition of normal urinary function are not absolute cut-offs.35 Table 4 summarizes treatment strategies.

Table 3. Primary Causes of Calcium Kidney Stones and Their Treatments.*

Cause Key Abnormality

SerumCalcium

Serum Parathyroid Hormone

UrineCalcium

UrinepH

UrineCitrate

UrineOxalate

Idiopathic calcium oxalate Normal Normal Normal or increased

Normal Normal or decreased

Normal or increased

Idiopathic calcium phosphate Normal Normal Normal or increased

Increased Normal or decreased

Normal

Primary hyperparathyroidism Increased Increased Increased Increased Normal Normal

Sarcoidosis Increased Decreased Increased Normal Normal Normal

Lithium use Increased Increased Increased Increased Normal Normal

Oral supplementation with calcium or vitamin D

Normal or increased

Normal Increased Normal Normal Normal

Ileostomy Normal or decreased

Normal Decreased Decreased Decreased Normal

Short-bowel syndrome Normal or decreased

Normal Decreased Decreased Decreased Increased

Bariatric surgery Normal or decreased

Normal Decreased Normal Decreased Increased

Renal tubular acidosis Normal Normal Normal or increased

Increased Decreased Normal

* NA denotes not available because histologic analyses have not been reported for patients with the listed conditions.

20

clinical pr actice


(For additional details regarding treatment trials, see Table 1 in the Supplementary Appendix.)

A randomized trial of increased fluid intake that was targeted to maintain a daily urine vol-ume of more than 2 liters showed a significant reduction in recurrent stone passage among pa-tients with first-time kidney stones.36 A target urine volume of 2 to 2.5 liters is reasonable and can be achieved by an increased intake of fluids, especially water, although most low-sodium, low-carbohydrate fluids are acceptable in moderation for this purpose.

In a randomized, controlled trial involving Italian men with hypercalciuria,24 a diet that was low in animal protein (52 g per day), sodium (50 mmol per day), and oxalate (200 mg per day) with normal calcium intake (1200 mg per day) was associated with a reduction in stone forma-tion of almost 50% over a period of 5 years, as compared with a diet that was low in calcium (400 mg per day) and oxalate. In contrast, in a U.S. trial, a low-protein diet did not reduce stone recurrence during a 4.5-year period, but compli-ance with the diet was poor and dietary sodium was not restricted.37 A low-sodium diet can sig-nificantly decrease excretion of both calcium and

oxalate,38 but data on the effect of a sodium-restricted diet alone on stone recurrence are lacking. Calcium restriction should be avoided in patients with hypercalciuria, since it may result in a reduction in bone mineral density39 and an increased rate of fracture.40

Thiazide-type diuretics decrease urine calcium excretion, and in randomized, controlled trials, these medications significantly reduced recur-rence rates of calcium stones by more than 50% during a 3-year period, as compared with place-bo.2,4,6,9 Long-acting agents like chlorthalidone and indapamide are effective with once-daily doses, whereas twice-daily doses are recom-mended for hydrochlorothiazide.

Hyperoxaluria may occur when dietary calci-um is low or oxalate intake is unusually high or (less commonly) when oxalate is overproduced. Dietary oxalate restriction to less than 100 mg per day and the avoidance of an intake of ascor-bic acid above 100 mg per day are prudent if hy-peroxaluria is present. Foods that are very high in oxalate include spinach, rhubarb, wheat bran, chocolate, beets, miso, tahini, and most nuts. (A list of the oxalate content of various foods is available at www.ohf.org under Resources.) Marked

Supersaturation Tissue Changes Treatment

UrineUric Acid

UrineVolume

Calcium Oxalate

Calcium Phosphate

UricAcid

Interstitial Plaque

Collecting-Duct Plugging

Normal or increased

Normal or decreased

High Normal or high

Normal or high

Increased Not present ��

Thiazide for idiopathic hypercalciuria; potassium citrate for calcium oxalate

Normal Normal High High Normal Normal Increased ��

(and perhaps calcium phosphate) stones; allopurinol for hyperuricosu-ria; sodium restriction and possible protein or oxalate restriction; in-creased fluid intake

Normal Normal High High Low Increased Increased Parathyroid surgery

Normal Normal High High Normal NA NA Glucocorticoids, possible ketoconazole

Normal Normal High High Normal NA NA Discontinuation of lithium

Normal Normal High High Low NA NA Discontinuation of supplements

Normal Decreased High Low High Increased Increased ��

Normal Decreased High Low High Normal Increased ��

Fluids, alkali; supplements to reduce urine oxalate excretion for the short-bowel syndrome and bariatric surgery

Normal Normal High Normal Normal Normal Increased��

Normal Increased Normal High Low Normal Increased Alkali, possible thiazides

21



hyperoxaluria should prompt consideration of malabsorption or one of the primary hyperox-aluria syndromes.41

Two randomized trials have shown substan-tial reductions in stone recurrence among patients with hypocitraturia who were treated with po-tassium alkali three times daily.3,7 One trial of sodium–potassium citrate had negative results.8 Potassium alkali may be safely combined with thiazide9,42 when indicated, but no trials have com-pared the combination against either agent alone for the prevention of stone recurrence.

Hyperuricosuria can decrease the solubility of calcium oxalate and increase the incidence of calcium oxalate stones. Allopurinol (at a dose of 300 mg daily) decreased stone recurrence in a randomized trial involving patients with idio-pathic calcium oxalate stones who had hyperuri-cosuria.5 A reduction in the intake of protein (and therefore purine) is also prudent but has not been explicitly tested among patients with hyperuricosuria and recurrent kidney stones.

In long-term clinical follow-up, preventive treatment resulted in persistent reductions in stone recurrence during a period of 20 years or more.43 However, compliance tended to wane over time, with rates of nonadherence approach-ing 20% per year.44

Prevention of Calcium Phosphate Stones

Most calcium stones consist of more than 90% calcium oxalate with trace amounts of calcium phosphate, but the proportion of calcium phos-phate in stones has increased over time.45,46 Idio-pathic calcium phosphate stones (more than 50% calcium phosphate) are more common among women and are associated with alkaline urine pH, a condition whose cause is not well under-stood. Mild abnormalities in urine acidification may be present, although metabolic acidosis is uncommon.46,47 Some patients convert from the formation of calcium oxalate stones to the forma-tion of calcium phosphate stones. In one study, such patients had a urine pH that was more alka-line (>6.2) at baseline than those who continued to produce calcium oxalate stones.30 Calcium phosphate stones are associated with poorer stone-free rates after percutaneous nephrolitho-tomy and with more shock-wave lithotripsy treat-ments than are calcium oxalate stones.46,48

Among patients with calcium phosphate stones, treatment is similar to that of patients with cal-cium oxalate stones except that potassium al-

Tabl

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ure

(may

be

desi

rabl

e); a

llerg

y an

d su

n se

nsiti

vity

Pota

ssiu

m a

lkal

iLo

wer

s su

pers

atur

atio

n by

che

latin

g ca

lciu

m; i

nhib

its g

row

th o

f cal

cium

cr

ysta

ls

Pota

ssiu

m c

itrat

e, 1

0–20

mm

ol tw

o or

thre

e tim

es d

aily

Patie

nts

with

hyp

ocitr

atur

iaN

eed

to m

onito

r ur

ine

pH a

nd c

alci

um

phos

phat

e su

pers

atur

atio

n; a

void

su

pers

atur

atio

n of

>1

Allo

puri

nol

Low

ers

urin

ary

uric

aci

d co

ncen

tra-

tion,

whi

ch m

ay im

prov

e so

lubi

lity

of c

alci

um s

alts

100–

300

mg/

day

(may

be

take

n on

ce

daily

)Pa

tient

s w

ith h

yper

uric

osur

ia a

nd

calc

ium

sto

nes

Alle

rgy

(may

be

seve

re)

22

clinical pr actice


kali should be used cautiously because it raises urine pH, potentially worsening calcium phos-phate supersaturation. Levels of urine pH and citrate and the degree of supersaturation should be assessed after starting therapy. If the citrate level does not rise and the degree of supersatura-tion worsens, the medication is unlikely to be of benefit.


Treatment trials for calcium stones have not looked specifically at outcomes in patients with calcium phosphate stones. Dietary recommenda-tions to increase fluids, lower salt and protein intake, and maintain a normal intake of calcium are supported by an Italian randomized trial,24 but no women were included in this study, and it is unclear whether many Americans can comply with the necessary dietary pattern sufficiently to successfully prevent stones. The Dietary Ap-proaches to Stop Hypertension (DASH)–Sodium diet, when modified to remove high-oxalate foods, replicates many of the features of the study diet and may provide a model to follow, but its effects on stone recurrence have not been explicitly stud-ied.49 Stone formation is associated with an in-creased risk of bone disease, chronic kidney disease, and hypertension, but it is not known whether effective stone prevention decreases these risks.

Guidelines

Guidelines of the American Urological Associa-tion (www.auanet.org) recommend that patients who require surgery for ureteral stones should be informed about benefits and risks of all current treatment approaches. Shock-wave lithotripsy and ureteroscopy with laser lithotripsy are both con-sidered acceptable first-line treatments, although ureteroscopy achieves greater stone-free rates. Percutaneous access and open or laparoscopic surgery are used as needed for selected cases. The guidelines do not address evaluation or treat-ment to prevent recurrent stones.


Preventive treatment to decrease stone recur-rence is indicated for patients with recurrent cal-cium stones, such as the patient in the vignette.

If systemic disease is not present, treatment should focus on metabolic abnormalities uncov-ered during the workup, such as hypercalciuria, hypo citraturia, hyperuricosuria, or hyperoxalu-ria. Although data comparing specific supersatu-ration targets are lacking, a logical strategy is to lower calcium oxalate and calcium phosphate supersaturation to the low end of the normal range.

Patients should be advised to increase fluid intake to at least 2 liters daily and reduce sodi-um intake to 2300 mg and protein intake to 0.8 to 1 g per kilogram of body weight per day, since these dietary interventions have reduced stone recurrence in randomized trials. Calcium intake should not be reduced below the recommended intake for sex and age and should be supplied by food rather than by supplements, which may in-crease the risk of stone formation. In many pa-tients, medication is also needed; the choice of medication is influenced by the metabolic ab-normalities identified, the type of stone, and the preference of patients.

The stones of the patient in the vignette con-tain 20% phosphate, despite a low urine pH while the patient was not receiving medications; the increased phosphate level may reflect his previous treatment with citrate. Both hypocitra-turia and hypercalciuria may contribute to his stone formation. In addition to the recommen-dations above, we would initiate therapy with a thiazide-type diuretic (e.g., 25 mg of chlorthali-done daily) to lower the urinary calcium level. A reduction in sodium intake will also reduce a thiazide-induced loss of potassium.

A follow-up 24-hour urine collection and se-rum chemical analysis should be performed in 4 to 6 weeks to assess the efficacy of treatment and possible side effects, particularly hypokale-mia, which can worsen hypocitraturia. If potas-sium supplementation is needed, it may be added as potassium alkali, but the urine pH level and the level of calcium phosphate supersaturation should be monitored. If the level of calcium phosphate supersaturation rises and is consistent-ly above 1, potassium chloride should be substi-tuted. Primary treatment with potassium alkali would be an alternative to a thiazide but may not lower the level of urinary calcium phosphate supersaturation as effectively. Ongoing attention is warranted at follow-up visits to monitor wheth-er the patient is adhering to preventive recom-mendations.

23



Drs. Worcester and Coe report receiving consulting fees from LabCorp. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Andrew Evan, Ph.D., for providing original versions of the figures in the Supplementary Appendix and guidance in the preparation of the manuscript.

References

1. Stamatelou KK, Francis ME, Jones CA, Nyberg LM, Curhan GC. Time trends in reported prevalence of kidney stones in the United States: 1976-1994. Kidney Int 2003;63:1817-23.2. Borghi L, Meschi T, Guerra A, No-varini A. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J Cardiovasc Pharmacol 1993;22:Suppl 6:S78-S86.3. Ettinger B, Pak CY, Citron JT, Thomas C, Adams-Huet B, Vangessel A. Potassium-magnesium citrate is an effective prophy-laxis against recurrent calcium oxalate nephrolithiasis. J Urol 1997;158:2069-73.4. Ettinger B, Citron JT, Livermore B, Dolman LI. Chlorthalidone reduces calci-um oxalate calculous recurrence but mag-nesium hydroxide does not. J Urol 1988;139:679-84.5. Ettinger B, Tang A, Citron JT, Liver-more B, Williams T. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med 1986;315:1386-9.6. Laerum E, Larsen S. Thiazide prophy-laxis of urolithiasis: a double-blind study in general practice. Acta Med Scand 1984;215:383-9.7. Barcelo P, Wuhl O, Servitge E, Rousaud A, Pak CYC. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol 1993;150:1761-4.8. Hofbauer J, Höbarth K, Szabo N, Mar-berger M. Alkali citrate prophylaxis in idiopathic recurrent calcium oxalate uro-lithiasis — a prospective randomized study. Br J Urol 1994;73:362-5.9. Fernández-Rodríguez A, Arrabal-Mar-tín M, García-Ruiz MJ, Arrabal-Polo MA, Pichardo-Pichardo S, Zuluaga-Gómez A. Papel de las tiazidas en la profilaxis de la litiasis calcica recidivante. Actas Urol Esp 2006;30:305-9.10. Saigal CS, Joyce G, Timilsina AR. Di-rect and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005;68:1808-14.11. Rule AD, Bergstralh EJ, Melton LJ III, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 2009;4:804-11.12. Madore F, Stampfer MJ, Rimm EB, Curhan GC. Nephrolithiasis and risk of hypertension. Am J Hypertens 1998;11:46-53.13. Taylor EN, Stampfer MJ, Curhan GC.

Obesity, weight gain, and the risk of kid-ney stones. JAMA 2005;293:455-62.14. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest 2005;115:2598-608.15. Evan AP, Coe FL, Lingeman JE, et al. Mechanism of formation of human cal-cium oxalate renal stones on Randall’s plaque. Anat Rec (Hoboken) 2007;290:1315-23.16. De Yoreo JJ, Qiu SR, Hoyer JR. Molec-ular modulation of calcium oxalate crys-tallization. Am J Physiol Renal Physiol 2006;291:F1123-F1131.17. Tiselius HG, Berg C, Fornander AM, Nilsson MA. Effects of citrate on the dif-ferent phases of calcium oxalate crystal-lization. Scanning Microsc 1993;7:381-9.18. Gambaro G, Fabris A, Puliatta D, Lupo A. Lithiasis in cystic kidney disease and malformations of the urinary tract. Urol Res 2006;34:102-7.19. Worcester EM, Coe FL. New insights into the pathogenesis of idiopathic hyper-calciuria. Semin Nephrol 2008;28:120-32.20. Worcester EM, Gillen DL, Evan AP, et al. Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis. Am J Physiol Renal Phys-iol 2007;292:F66-F75.21. Coe FL, Favus MJ, Crockett T, et al. Effects of low-calcium diet on urine cal-cium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in nor-mal subjects. Am J Med 1982;72:25-32.22. Voss S, Hesse A, Zimmermann DJ, Sauerbruch T, von Unruh GE. Intestinal oxalate absorption is higher in idiopathic calcium oxalate stone formers than in healthy controls: measurements with the [(13)C2]oxalate absorption test. J Urol 2006;175:1711-5.23. Taylor EN, Curhan GC. Determinants of 24-hour urinary oxalate excretion. Clin J Am Soc Nephrol 2008;3:1453-60.24. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the preven-tion of recurrent stones in idiopathic hy-percalciuria. N Engl J Med 2002;346:77-84.25. Hamm LL, Hering-Smith KS. Patho-physiology of hypocitraturic nephrolithia-sis. Endocrinol Metab Clin North Am 2002;31:885-93.26. Coe FL, Kavalach AG. Hypercalciuria and hyperuricosuria in patients with cal-cium nephrolithiasis. N Engl J Med 1974;291:1344-50.

27. Miller NL, Gillen DL, Williams JC Jr, et al. A formal test of the hypothesis that idiopathic calcium oxalate stones grow on Randall’s plaque. BJU Int 2009;103:966-71.28. Evan AP, Lingeman JE, Coe FL, et al. Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int 2005;67:576-91.29. Evan AE, Lingeman JE, Coe FL, et al. Histopathology and surgical anatomy of patients with primary hyperparathyroid-ism and calcium phosphate stones. Kid-ney Int 2008;74:223-9.30. Parks JH, Coe FL, Evan AP, Worcester EM. Urine pH in renal calcium stone formers who do and do not increase stone phosphate content with time. Nephrol Dial Transplant 2009;24:130-6.31. Parks JH, Goldfisher E, Asplin JR, Coe FL. A single 24-hour urine collection is inadequate for the medical evaluation of nephrolithiasis. J Urol 2002;167:1607-12.32. Hollingsworth JM, Rogers MA, Kauf-man SR, et al. Medical therapy to facili-tate urinary stone passage: a meta-analy-sis. Lancet 2006;368:1171-9.33. Wignall GR, Canales BK, Denstedt JD, Monga M. Minimally invasive approaches to upper urinary tract urolithiasis. Urol Clin North Am 2008;35:441-54.34. Keeley FX Jr, Assimos DG. Clinical tri-als of the surgical management of uro-lithiasis: current status and future needs. Adv Chronic Kidney Dis 2009;16:65-9.35. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int 2001;59:2290-8.36. Borghi L, Meschi T, Amato F, Briganti A, Novarini A, Giannini A. Urinary vol-ume, water and recurrences of idiopathic calcium nephrolithiasis: a 5-year random-ized prospective study. J Urol 1996;155:839-43.37. Hiatt RA, Ettinger B, Caan B, Quesen-berry CP Jr, Duncan D, Citron JT. Ran-domized controlled trial of low animal protein, high fiber diet in the prevention of recurrent calcium oxalate kidney stones. Am J Epidemiol 1996;144:25-33.38. Nouvenne A, Meschi T, Prati B, et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am J Clin Nutr 2010;91:565-70.39. Heilberg IP, Weisinger JR. Bone dis-ease in idiopathic hypercalciuria. Curr Opin Nephrol Hypertens 2006;15:394-402.

24

clinical pr actice


40. Lauderdale DS, Thisted RA, Wen M, Favus MJ. Bone mineral density and frac-ture among prevalent kidney stone cases in the Third National Health and Nutri-tion Examination Survey. J Bone Miner Res 2001;16:1893-8.41. Hoppe B, Beck BB, Milliner DS. The primary hyperoxalurias. Kidney Int 2009;75:1264-71.42. Odvina CV, Preminger GM, Lindberg JS, Moe OW, Pak CY. Long-term combined treatment with thiazide and potassium citrate in nephrolithiasis does not lead to hypokalemia or hypochloremic metabolic alkalosis. Kidney Int 2003;63:240-7.

43. Parks JH, Coe FL. Evidence for durable kidney stone prevention over several de-cades. BJU Int 2009;103:1238-46.44. Parks JH, Asplin JR, Coe FL. Patient adherence to long-term medical treatment of kidney stones. J Urol 2001;166:2057-60.45. Mandel N, Mandel I, Fryjoff K, Rej-niak T, Mandel G. Conversion of calcium oxalate to calcium phosphate with recur-rent stone episodes. J Urol 2003;169:2026-9.46. Parks JH, Worcester EM, Coe FL, Evan AP, Lingeman JE. Clinical implications of abundant calcium phosphate in routinely

analyzed kidney stones. Kidney Int 2004;66:777-85.47. Gault MH, Parfrey PS, Robertson WG. Idiopathic calcium phosphate nephro-lithiasis. Nephron 1988;48:265-73.48. Kacker R, Meeks JJ, Zhao L, Nadler RB. Decreased stone-free rates after per-cutaneous nephrolithotomy for high cal-cium phosphate composition kidney stones. J Urol 2008;180:958-60.49. Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol 2009;20:2253-9.Copyright © 2010 Massachusetts Medical Society.

Fox Robert Raichelson, M.D.

25

clinical practice


n engl j med 363;8 nejm.org august 19, 2010 755




Emergency Treatment of AsthmaStephen C. Lazarus, M.D.

From the Division of Pulmonary and Crit-ical Care Medicine and the Cardiovascu-lar Research Institute, University of Cali-fornia, San Francisco, San Francisco. Address reprint requests to Dr. Lazarus at the University of California, San Fran-cisco, 505 Parnassus Ave., San Francisco, CA 94143-0111, or at [email protected].


A 46-year-old woman who has had two admissions to the intensive care unit (ICU) for asthma during the past year presents with a 4-day history of upper respiratory illness and a 6-hour history of shortness of breath and wheezing. An inhaled corticosteroid has been prescribed, but she takes it only when she has symptoms, which is rarely. She generally uses albuterol twice per day but has increased its use to six to eight times per day for the past 3 days. How should this case be managed in the emergency de-partment?


Asthma is one of the most common diseases in developed countries and has a worldwide prevalence of 7 to 10%.1 It is also a common reason for urgent care and emergency department visits. From 2001 through 2003 in the United States, asthma accounted for an average 4210 deaths annually and an average annual total of ap-proximately 504,000 hospitalizations and 1.8 million emergency department visits.2 The average annual rate of emergency department visits for asthma was 8.8 per 100 persons with current asthma. Rates were higher among children than among adults (11.2 vs. 7.8 visits per 100 persons), among blacks than among whites (21 vs. 7 visits per 100 persons), and among Hispanics than among non-Hispanics (12.4 vs. 8.4 visits per 100 persons). Women made twice the number of emergency depart-ment visits as men.2 Approximately 10% of visits result in hospitalization.1

Asthma is a heterogeneous disease, with varied triggers, manifestations, and responsiveness to treatment. Some patients with acute severe asthma presenting to the emergency department have asthma that responds rapidly to aggressive therapy, and they can be discharged quickly; others require admission to the hospital for more prolonged treatment. The reasons for this difference in responsiveness to treatment include the degree of airway inflammation, presence or absence of mucus plugging, and individual responsiveness to β2-adrenergic and corticosteroid medi-cations. The major challenge in the emergency department is determining which patients can be discharged quickly and which need to be hospitalized.


Initial Assessment in the Emergency Department

Patients presenting to the emergency department with asthma should be evaluated and triaged quickly to assess the severity of the exacerbation and the need for urgent intervention (Fig. 1). A brief history should be obtained, and a limited physical ex-amination performed. This assessment should not delay treatment; it can be per-formed while patients receive initial treatment. Clinicians should search for signs





26


n engl j med 363;8 nejm.org august 19, 2010756

of life-threatening asthma (e.g., altered mental status, paradoxical chest or abdominal movement, or absence of wheezing), which necessitate ad-mission. Attention should be paid to factors that are associated with an increased risk of death from asthma, such as previous intubation or ad-

mission to an ICU, two or more hospitalizations for asthma during the past year, low socioeco-nomic status, and various coexisting illnesses.3 The measurement of lung function (e.g., forced expiratory volume in 1 second [FEV1] or peak ex-piratory flow [PEF]) can be helpful for assessing

Initiate treatment with oxygen toachieve SaO2 ≥90%

Reassess history, symptoms, vital signs, resultsof physical examination, PEF, and SaO2

after 60–90 min of treatment

Triage patient immediatelyTake brief history to ascertain risk factors

Previous intubation or ICU admission≥2 Hospitalizations or ≥3 emergency department visits in past yr>2 Canisters of short-acting β2-adrenergic agonist per moCoexisting conditions

Assess vital signs and perform brief physical examinationObserve for breathlessnessMeasure respiratory rate and heart rate, check for pulsus paradoxusNote whether accessory muscles of respiration usedPerform chest examination

Assess for mild-to-moderate exacerbationFEV1 or PEF ≥40%Patient talks in sentencesPulse ≤120 beats/minMinimal or no pulsus paradoxusSaO2 ≥90%

Assess for severe exacerbationFEV1 or PEF <40%Patient talks in words or phrases but

not sentencesPulse >120 beats/min, respiratory

rate >30 breaths per minPulsus paradoxus (decrease in systolic

arterial pressure by >25 mm Hg oninspiration)

Loud wheezes or silent chestSaO2 <90% or PaO2 <60 mm Hg

Initiate treatmentShort-acting β2-adrenergic agonist

administered by means of a metered-dose inhaler with valved holdingchamber or a nebulizer, up to 3 dosesin first hr

Oral corticosteroids if no immediateresponse or if patient recently receivedsystemic corticosteroids

Initiate treatmentHigh-dose short-acting β2-adrenergic

agonist plus ipratropium bromideadministered by means of a metered-dose inhaler with valved holdingchamber or a nebulizer every 20 minor continuously for 1 hr

Oral corticosteroids

Figure 1. Initial Assessment of a Patient Presenting to the Emergency Department with Asthma.

Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3.3 FEV1 denotes forced expiratory volume in 1 second, ICU intensive care unit, PaCO2 partial pressure of arterial carbon dioxide, PaO2 partial pressure of arterial oxygen, PEF peak expiratory flow, and SaO2 arterial oxygen saturation.

27

clinical pr actice


the severity of an exacerbation and the response to treatment but should not delay the initiation of treatment. Laboratory and imaging studies should be performed selectively, to assess patients for impending respiratory failure (e.g., by measuring the partial pressure of arterial carbon dioxide [PaCO2]), suspected pneumonia (e.g., by obtaining a complete blood count or a chest radiograph), or certain coexisting conditions such as heart dis-ease (e.g., by obtaining an electrocardiogram).

Treatment in the Emergency Department

All patients should be treated initially with sup-plementary oxygen to achieve an arterial oxygen saturation of 90% or greater, inhaled short-acting β2-adrenergic agonists, and systemic corticoste-roids (Fig. 1). The dose and timing of these agents and the use of additional pharmacologic therapy depend on the severity of the exacerbation.

β2-Adrenergic AgonistsInhaled short-acting β2-adrenergic agonists should be administered immediately on presentation, and administration can be repeated up to three times within the first hour after presentation. The use of a metered-dose inhaler with a valved holding chamber is as effective as the use of a pressurized nebulizer in randomized trials,4,5 but proper technique is often difficult to ensure in ill patients. Most guidelines recommend the use of nebulizers for patients with severe exacerba-tions; metered-dose inhalers with holding cham-bers can be used for patients with mild-to-mod-erate exacerbations, ideally with supervision from trained respiratory therapists or nursing person-nel (see the Supplementary Appendix and a Video, both available at NEJM.org, for descrip-tions of how to use inhalers with and inhalers without a holding chamber, respectively). The dose administered by means of metered-dose in-halers for exacerbations is substantially greater than that used for routine relief: four to eight puffs of albuterol can be administered every 20 minutes for up to 4 hours and then every 1 to 4 hours as needed (Table 1). Albuterol can be delivered by means of a nebulizer either inter-mittently or continuously. A meta-analysis of re-sults from six randomized trials indicated that intermittent administration and continuous ad-ministration have similar effects on both lung function and the overall rate of hospitalization,6

whereas a Cochrane review of findings from eight trials suggested that continuous adminis-tration resulted in greater improvement in PEF and FEV1 and a greater reduction in hospital ad-missions, particularly among patients with severe asthma.7

Albuterol is the inhaled β2-adrenergic agonist most widely used for emergency management. Levalbuterol, the R-enantiomer of albuterol, has been shown to be effective at half the dose of albuterol, but randomized trials conducted in the emergency department have not consistently shown a clinical advantage of levalbuterol over racemic albuterol.8,9 Pirbuterol and bitolterol are effective for mild or moderate exacerbations, but a higher dose is required than with albuterol or levalbuterol, and their use for severe exacerba-tions has not been studied.

Oral or parenteral administration of β2-adrenergic agonists is not recommended, since neither has been shown to be more effective than inhaled β2-adrenergic agonists, and both are associated with an increased frequency of side effects. The long-acting inhaled β2-adrenergic salmeterol has not been studied for the treat-ment of exacerbations, though trials with formot-erol (ClinicalTrials.gov numbers, NCT00819637 and NCT00900874) are under way.

Anticholinergic AgentsBecause of its relatively slow onset of action, in-haled ipratropium is not recommended as mono-therapy in the emergency department but can be added to a short-acting β2-adrenergic agonist for a greater and longer-lasting bronchodilator ef-fect.10,11 In patients with severe airflow obstruc-tion, the use of ipratropium together with a β2-adrenergic agonist in the emergency department, as compared with a β2-adrenergic agonist alone, has been shown to reduce rates of hospitaliza-tion by approximately 25%,12,13 although there is no apparent benefit of continuing ipratropium after hospitalization.

Systemic CorticosteroidsIn most patients with exacerbations that neces-sitate treatment in the emergency department, systemic corticosteroids are warranted. The ex-ception is the patient who has a rapid response to initial therapy with an inhaled β2-adrenergic agonist. Although most randomized, controlled

28



Tabl

e 1.

Med

icat

ions

for

Trea

tmen

t of A

sthm

a Ex

acer

batio

n in

the

Emer

genc

y D

epar

tmen

t.*

Dru

g an

d A

vaila

ble

Form

ulat

ion

Dos

eC

omm

ents

Shor

t-ac

ting

β2-

adre

nerg

ic a

goni

sts

Adv

erse

effe

cts

incl

ude

tach

ycar

dia,

pal

pita

tions

, tre

mor

, and

hyp

o-ka

lem

ia.

Alb

uter

ol

Met

ered

-dos

e in

hale

r (9

0 μg

/puf

f)4–

8 pu

ffs e

very

20

min

up

to 4

hr,

then

eve

ry 1

–4 h

r as

need

ed

Neb

uliz

er s

olut

ion

(0.6

3 m

g/3

ml,

1.25

m

g/3

ml,

2.5

mg/

3 m

l, or

5.0

mg/

ml)

2.5–

5 m

g ev

ery

20 m

in o

ver

the

first

hr,

then

2.5

–10

mg

ever

y 1–

4 hr

as

need

ed o

r 10

–15

mg/

hr c

ontin

uous

lyFo

r op

timal

del

iver

y, d

ilute

sol

utio

n to

a m

inim

um o

f 3 m

l at a

gas

flow

of

6–8

lite

rs/m

in. U

se la

rge-

volu

me

nebu

lizer

s fo

r con

tinuo

us a

dmin

-is

trat

ion.

Leva

lbut

erol

†

Met

ered

-dos

e in

hale

r (4

5 μg

/puf

f)Sa

me

as fo

r al

bute

rol,

met

ered

-dos

e in

hale

r; le

valb

uter

ol

adm

inis

tere

d in

hal

f the

mill

igra

m d

ose

of a

lbut

erol

has

si

mila

r ef

ficac

y an

d sa

fety

Neb

uliz

er s

olut

ion

(0.6

3 m

g/3

ml,

1.25

m

g/0.

5 m

l, or

1.2

5 m

g/3

ml)

1.25

–2.5

mg

ever

y 20

min

ove

r th

e fir

st h

r, th

en 1

.25–

5 m

g ev

ery

1–4

hr a

s ne

eded

; lev

albu

tero

l adm

inis

tere

d at

hal

f th

e m

illig

ram

dos

e of

alb

uter

ol h

as s

imila

r effi

cacy

and

sa

fety

; con

tinuo

us n

ebul

izat

ion

has

not b

een

eval

uate

d

Bito

ltero

lH

as n

ot b

een

stud

ied

in p

atie

nts

with

sev

ere

asth

ma

exac

erba

tions

. Not

av

aila

ble

in th

e U

nite

d St

ates

.

Met

ered

-dos

e in

hale

r (3

70 μ

g/pu

ff)Sa

me

as fo

r alb

uter

ol, m

eter

ed-d

ose

inha

ler;

bito

ltero

l tho

ught

to

be

half

as p

oten

t as

albu

tero

l on

a m

illig

ram

bas

is

Neb

uliz

er s

olut

ion

(2 m

g/m

l)Sa

me

as fo

r al

bute

rol,

nebu

lizer

sol

utio

n; b

itolte

rol t

houg

ht

to b

e ha

lf as

pot

ent a

s al

bute

rol o

n a

mill

igra

m b

asis

Pirb

uter

ol, m

eter

ed-d

ose

inha

ler

(200

μg/

puff)

Sam

e as

for a

lbut

erol

, met

ered

-dos

e in

hale

r; p

irbut

erol

th

ough

t to

be h

alf a

s po

tent

as

albu

tero

l on

a m

illig

ram

ba

sis

Has

not

bee

n st

udie

d in

pat

ient

s w

ith s

ever

e as

thm

a ex

acer

batio

ns.

Ant

icho

liner

gic

agen

tsA

dver

se e

ffect

s in

clud

e dr

y m

outh

, cou

gh, a

nd b

lurr

ed v

isio

n.

Ipra

trop

ium

bro

mid

eSh

ould

not

be

used

as

first

-line

ther

apy;

sho

uld

be a

dded

to s

hort

-act

ing

β2-a

dren

ergi

c ag

onis

t the

rapy

for

seve

re e

xace

rbat

ions

. The

add

ition

of

ipra

trop

ium

to a

sho

rt-a

ctin

g β

2-a

dren

ergi

c ag

onis

t has

not

bee

n sh

own

to p

rovi

de fu

rthe

r be

nefit

onc

e th

e pa

tient

is h

ospi

taliz

ed.

Met

ered

-dos

e in

hale

r (1

8 μg

/puf

f)8

puffs

eve

ry 2

0 m

in a

s ne

eded

, for

up

to 3

hr

Neb

uliz

er s

olut

ion

(0.2

5 m

g/m

l)0.

5 m

g ev

ery

20 m

in fo

r 1

hr (

thre

e do

ses)

, the

n as

nee

ded;

ca

n be

use

d w

ith a

lbut

erol

in o

ne n

ebul

izer

29

clinical pr actice


trials of corticosteroids in patients seen in the emergency department and those admitted to the hospital have been small, these studies individu-ally14,15 and collectively16-18 show that the use, as compared with nonuse, of systemic corticoste-roids is associated with a more rapid improvement in lung function, fewer hospitalizations, and a lower rate of relapse after discharge from the emergency department. Because comparisons of oral prednisone and intravenous corticosteroids have not shown differences in the rate of im-provement of lung function or in the length of the hospital stay,19-21 the oral route is preferred for patients with normal mental status and without conditions expected to interfere with gastrointes-tinal absorption. Although the optimal dose of corticosteroid is not known, pooled data from controlled trials involving patients seen in the emergency department or admitted to the hospi-tal have shown no significant advantage of doses greater than 100 mg per day of prednisone equiv-alent.19,20,22-25 The most recent guidelines from the National Asthma Education and Prevention Program (NAEPP) (Expert Panel Report 3) recom-mend the use of 40 to 80 mg per day in one dose or two divided doses.3

Inhaled CorticosteroidsAlthough high-dose inhaled corticosteroids are often used to treat worsening of asthma control and to try to prevent exacerbations, the evidence does not support the use of inhaled corticoster-oids as a substitute for systemic corticosteroids in the emergency department.26 Inhaled cortico-steroids are, however, preferred for long-term asthma control. At the time of discharge from the emergency department, these agents should be continued in patients who have been taking them for long-term control and should be pre-scribed for patients who have not previously taken them. In a randomized, controlled trial of 1006 consecutively enrolled patients with acute asthma treated in a Canadian emergency department, the addition at discharge of inhaled budesonide (for 21 days) to treatment with oral corticoste-roids (for 5 to 10 days) was associated with a 48% reduction in the rate of relapse at 21 days and with improvement in the quality of life with re-spect to asthma (as measured by the Asthma Quality of Life Questionnaire) and symptoms, as compared with treatment with oral corticoste-roids alone.27Ip

ratr

opiu

m b

rom

ide

and

albu

tero

lM

ay b

e us

ed fo

r up

to 3

hr d

urin

g in

itial

man

agem

ent o

f sev

ere

exac

erba

-tio

ns. T

he a

dditi

on o

f ipr

atro

pium

to a

lbut

erol

has

not

bee

n sh

own

to p

rovi

de fu

rthe

r be

nefit

onc

e th

e pa

tient

is h

ospi

taliz

ed.

Met

ered

-dos

e in

hale

r (e

ach

puff

cont

ain-

ing

18 μ

g of

ipra

trop

ium

and

90

μg

of a

lbut

erol

)

8 pu

ffs e

very

20

min

as

need

ed, u

p to

3 h

r

Neb

uliz

er s

olut

ion

(eac

h 3-

ml v

ial c

onta

ins

0.5

mg

of ip

ratr

opiu

m b

rom

ide

and

2.5

mg

of a

lbut

erol

)

3 m

l eve

ry 2

0 m

in fo

r 3

dose

s, th

en a

s ne

eded

Syst

emic

cor

ticos

tero

ids:

pre

dnis

one,

pre

d-ni

solo

ne, a

nd m

ethy

lpre

dnis

olon

e40

–80

mg/

day

in o

ne d

ose

or tw

o di

vide

d do

ses,

giv

en u

ntil

peak

exp

irat

ory

flow

rea

ches

70%

of p

redi

cted

val

ue o

r a

pers

onal

bes

t val

ue

Ther

e is

no

know

n ad

vant

age

of h

ighe

r dos

es o

f cor

ticos

tero

ids

to tr

eat

seve

re a

sthm

a ex

acer

batio

ns o

r of i

ntra

veno

us a

dmin

istr

atio

n ov

er

oral

ther

apy,

pro

vide

d th

at g

astr

oint

estin

al a

bsor

ptio

n is

not

im-

pair

ed. T

he to

tal c

ours

e of

sys

tem

ic c

ortic

oste

roid

s fo

r an

ast

hma

ex-

acer

batio

n ne

cess

itatin

g an

em

erge

ncy

depa

rtm

ent v

isit

or h

ospi

tal-

izat

ion

may

be

3 to

10

days

. For

cor

ticos

tero

id c

ours

es o

f <1

wk,

th

ere

is n

o ne

ed to

tape

r th

e do

se; f

or c

ours

es o

f 7–1

0 da

ys, t

here

pr

obab

ly is

no

need

to ta

per,

esp

ecia

lly if

pat

ient

s ar

e co

ncur

rent

ly

rece

ivin

g in

hale

d co

rtic

oste

roid

s.

Adv

erse

effe

cts

incl

ude

adre

nal s

uppr

essi

on, g

row

th s

uppr

essi

on, o

steo

-po

rosi

s, m

uscl

e w

eakn

ess,

hyp

erte

nsio

n, w

eigh

t gai

n, d

iabe

tes,

cat

a-ra

cts,

Cus

hing

’s s

yndr

ome,

and

der

mal

thin

ning

.

* A

dapt

ed fr

om t

he N

atio

nal A

sthm

a Ed

ucat

ion

and

Prev

entio

n Pr

ogra

m E

xper

t Pa

nel R

epor

t 3.

3

† L

eval

bute

rol i

s th

e R

-ena

ntio

mer

of a

lbut

erol

.

30



Treatments That Are Not RecommendedAlthough methylxanthines were once a standard treatment for asthma in the emergency depart-ment, it is now clear that their use increases the risk of adverse events without improving out-comes.28 Antibiotics should not be used routinely but rather should be reserved for patients in whom bacterial infection (e.g., pneumonia or sinusitis) seems likely. Similarly, neither aggressive hydra-tion nor administration of mucolytic agents is recommended for acute exacerbations.3

Assessment of Response to Treatment

Patients should be reassessed after the first treat-ment with an inhaled bronchodilator and again at 60 to 90 minutes (i.e., after three treatments).3 This assessment should include a survey of symp-toms, a physical examination, and measurement of FEV1 or PEF (Fig. 2). For the most severe exac-erbations, this repeat assessment should prob-ably include the measurement of arterial blood gases. Most patients will have clinically signifi-cant improvement after one dose of an inhaled

Reassess history, symptoms, vital signs, resultsof physical examination, PEF, and SaO2 after

60–90 min of treatment

Within <4 hr, make decision to admit or discharge

Discharge or admit, on the basisof risk factors, likelihood of ad-

herence, and home environment

AdmitDischarge

Patient has good responseFEV1 or PEF ≥70% sus-

tained for 60 minNo distressNormal examination

Patient has continued mild-to-moderateexacerbation

Patient has continued severeexacerbation

Continue treatmentOxygen to achieve SaO2 ≥90%Short-acting β2-adrenergic agonist

administered by means of ametered-dose inhaler with valvedholding chamber or a nebulizer,every 60 min

Oral corticosteroidsContinue treatment 1–3 hr, provided

there is improvement

Continue treatmentOxygen to achieve SaO2 ≥90%Short-acting β2-adrenergic agonist plus

ipratropium bromide administeredby means of a metered-dose inhalerwith valved holding chamber or anebulizer, every hr or continuously

Oral corticosteroidsConsider magnesium sulfate or heliox

Patient has poor responseFEV1 or PEF <40%PaCO2 ≥42 mm HgSevere symptomsDrowsiness, confusion

Patient has incomplete responseFEV1 or PEF 40–69%Mild-to-moderate symptoms

Figure 2. Continued Management of Asthma in the Emergency Department.

Adapted from the National Asthma Education and Prevention Program Expert Panel Report 3.3 Heliox is a mixture of helium and oxygen, usually 79% and 21%, respectively, whose density is about one third that of air. FEV1 denotes forced expiratory volume in 1 second, PaCO2 partial pressure of arterial carbon dioxide, PEF peak expiratory flow, and SaO2 arterial oxygen saturation.

31

clinical pr actice


bronchodilator, and 60 to 70% will meet the cri-teria for discharge from the emergency depart-ment (see below) after three doses.29-31 The de-gree of subjective and objective improvement that occurs in response to treatment predicts the need for hospitalization.32-38 In a study of 720 patients treated in 36 Australian emergency departments, the need for hospital admission among patients assessed as having moderate asthma, as well as the need for ICU care of patients assessed as hav-ing severe asthma, was better predicted by the assessment of asthma severity after 1 hour of treatment than by the initial assessment in the emergency department.38

Indications for Admission

After treatment in the emergency department for 1 to 3 hours, patients who have an incomplete or poor response, defined as an FEV1 or PEF of less than 70% of the personal best or predicted value, should be evaluated for admission to the hospi-tal. Patients who have an FEV1 of less than 40%, persistent moderate-to-severe symptoms, drows-iness, confusion, or a PaCO2 of 42 mm Hg or greater should be admitted. Patients who have an FEV1 of 40 to 69% and mild symptoms should be assessed individually for risk factors for death, ability to adhere to a prescribed regimen, and the presence of asthma triggers in the home. The NAEPP Expert Panel Report 3 suggests that the decision to admit or discharge a patient should be made within 4 hours after presentation to the emergency department.3

Management of Respiratory Insufficiency

Patients with altered mental status, exhaustion, or hypercapnia should be considered for immedi-ate intubation and ventilatory support. Because of high positive intrathoracic pressures, intubation and ventilation may lead to hypotension and barotrauma. Care should be taken to ensure ade-quate intravascular volume, and to avoid high airway pressures. A strategy of “permissive hyper-capnia,” achieved by adjusting the ventilator to correct hypoxemia while avoiding high airway pressures, was associated in an observational study with decreased mortality among patients with status asthmaticus,39 and this approach has become standard.

Guidelines suggest that once a decision has been made in the emergency department to in-tubate a patient, the procedure should be semi-elective and performed under controlled condi-

tions (vs. performed as an emergency procedure by the first available staff). Randomized trials have shown a benefit from noninvasive positive-pressure ventilation for acute exacerbations of chronic obstructive pulmonary disease, but most information used to guide the ventilation strategy for treating acute asthma comes from case re-ports or noncontrolled studies. A randomized crossover study that compared the use of bilevel positive airway pressure for 2 hours with stan-dard care in children with acute asthma showed a significantly lower respiratory rate and improved scores on a questionnaire regarding asthma symptoms with bilevel positive airway pressure but no significant difference in arterial oxygen saturation, transcutaneous carbon dioxide levels, or other outcomes.40 In a randomized, sham-controlled trial of the use of bilevel positive air-way pressure in 30 adults with acute asthma, bilevel positive airway pressure was associated with a higher FEV1 value at 4 hours and a lower rate of hospitalization (17.6%, vs. 62.5% with sham treatment).41 These data suggest that non-invasive positive-pressure ventilation could be considered for patients who decline intubation and for selected patients who are likely to co-operate with mask therapy, but more data are needed to recommend this approach.

Discharge from the Emergency Department

Patients may be discharged if the FEV1 or PEF after treatment is 70% or more of the personal best or predicted value and if the improvements in lung function and symptoms are sustained for at least 60 minutes.3 After discharge, patients should continue to use inhaled short-acting β2-adrenergic agonists as needed and should be given oral corticosteroids for 3 to 10 days3 (Table 2). Inhaled corticosteroids can be started at any time during treatment of the exacerbation, but initia-tion at the time of discharge, if not before, is prudent to reduce the risk of relapse.27,42,43

Education of Patients

The need for treatment in the emergency depart-ment often reflects inadequate maintenance ther-apy and insufficient knowledge of how to deal with a worsening of asthma control. Presenta-tion to the emergency department provides a unique opportunity to educate patients about medications, inhaler technique, and steps that can reduce exposure to household triggers of allergic reaction and to ensure that discharged

32



patients have an asthma action plan and instruc-tions for monitoring their symptoms and imple-menting their plan. A follow-up appointment should be scheduled with the patient’s primary care provider or with an asthma specialist to oc-cur 1 to 4 weeks after discharge. Guidelines also recommend that patients be encouraged to con-tact their asthma care provider within 3 to 5 days after discharge, when the risk of relapse is great-est,3 although data are lacking to show that this action improves outcomes.


In patients with severe asthma that is refractory to standard treatment, intravenous magnesium sulfate is widely used,44 but there is controversy regarding its efficacy. A meta-analysis of 1669 patients in 24 studies who received either intra-venous magnesium sulfate (used in 15 studies) or nebulized magnesium sulfate (used in 9 studies) showed that intravenous treatment was weakly associated with improved lung function in adults but had no significant effect on hospital admis-sions; in children, the use of intravenous magne-sium sulfate significantly improved lung func-tion and reduced rates of hospital admission. The effect of nebulized magnesium sulfate is less

substantiated.45 Expert opinion46 and guidelines3 suggest that clinicians consider the use of intra-venous magnesium sulfate in patients who have severe exacerbations and whose FEV1 or PEF re-mains less than 40% of the personal best or predicted value after initial treatments. The re-sults of a large multicenter trial in the United Kingdom47 (Current Controlled Trials number, ISRCTN04417063) comparing treatment with in-travenous or nebulized magnesium sulfate and standard treatment in patients with severe asthma are expected in 2011.

Heliox is a mixture of helium and oxygen, usually 79% and 21%, respectively, with a den-sity about one third that of air, that reduces airflow resistance within regions of the bron-chial tree where turbulent flow predominates. It is thought to reduce the work of breathing and to improve delivery of aerosolized medications. However, its role in the management of acute severe asthma is unclear. A Cochrane analysis of 544 patients in 10 trials led to the conclusion that heliox might be bene ficial in patients with severe airflow obstruction who have not had a response to initial treatment,48 and current guidelines reflect this conclusion.3

Since the administration of oral leukotriene inhibitors results in increases in the FEV1 within 1 to 2 hours,49,50 there has been interest in using these agents in the emergency department, but their usefulness in that setting is unclear. In a randomized, placebo-controlled trial of intrave-nous montelukast in 583 adults whose FEV1 re-mained at 50% or less of the predicted value after 60 minutes of standard care, the use of montelu-kast significantly improved the FEV1 at 60 minutes but did not reduce the rate of hospitalization.51

Guidelines

The NAEPP and the Global Initiative for Asthma have developed and updated evidence-based guide-lines for the diagnosis and management of asth-ma.3,52 The recommendations in this article are consistent with these guidelines.


The patient described in the vignette has chronic uncontrolled asthma necessitating daily rescue use of albuterol, but she has not been receiving

Table 2. Recommendations for Discharge from the Emergency Department.*

Medications

Continue inhaled short-acting β2-adrenergic agonists every 1–2 hr, as needed

Continue oral corticosteroids at a dose of 40–80 mg/day for 3–10 days

If course is <1 wk, no need to taper the dose

If course is 7–10 days, probably no need to taper, especially if patients are concurrently receiving inhaled corticosteroids

Continue or start an inhaled corticosteroid at a “medium dose” (e.g., beclo-methasone [HFA], 240–480 μg/day; budesonide [DPI], 600–1200 μg/day; or fluticasone [DPI], 300–500 μg/day)

Education

Review purposes and doses of asthma medications with patient

Review inhaler technique with patient

Teach patient to monitor for signs and symptoms of poor asthma control

Provide patient with an asthma action plan

Follow-up

Advise patient to call primary care provider within 3–5 days after discharge

Schedule a follow-up appointment with provider to occur within 1–4 wk

* DPI denotes dry-powder inhaler, and HFA hydrofluoroalkane formulation.

33

clinical pr actice


daily controller therapy. Her history of ICU admis-sions and excessive albuterol use indicate that she is at increased risk for death related to asthma.

Treatment with oxygen, aerosolized albuterol and ipratropium, and systemic corticosteroids should be initiated. The patient should be moni-tored closely and her signs and symptoms re-assessed frequently, and a decision to admit or discharge her should be made within 4 hours after presentation. If she is discharged from the emergency department, she should be educated about medications, inhaler technique, and steps

for monitoring symptoms and for managing ex-acerbations. Emergency department staff should provide her with a discharge plan, schedule a follow-up appointment, and ensure that she has adequate medications or prescriptions to last un-til that appointment. Because of her previous ad-missions to the ICU and her history of consis-tently poor asthma control, referral to an asthma specialist would be prudent.

No potential conflict of interest relevant to this article was reported.


References

1. Rowe BH, Voaklander DC, Wang D, et al. Asthma presentations by adults to emergency departments in Alberta, Can-ada: a large population-based study. Chest 2009;135:57-65.2. Moorman JE, Rudd RA, Johnson CA, et al. National surveillance for asthma — United States, 1980–2004. MMWR Sur-veill Summ 2007;56:1-54.3. National Heart, Lung, and Blood In-stitute, National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and man-agement of asthma: full report 2007. (Ac-cessed July 23, 2010, at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.)4. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2006;2:CD000052.5. Dhuper S, Chandra A, Ahmed A, et al. Efficacy and cost comparisons of bron-chodilatator administration between me-tered dose inhalers with disposable spac-ers and nebulizers for acute asthma in an inner-city adult population. J Emerg Med 2008 December 10 (Epub ahead of print).6. Rodrigo GJ, Rodrigo C. Continuous vs intermittent beta-agonists in the treatment of acute adult asthma: a systematic review with meta-analysis. Chest 2002;122:160-5.7. Camargo CA Jr, Spooner CH, Rowe BH. Continuous versus intermittent beta-agonists in the treatment of acute asth-ma. Cochrane Database Syst Rev 2003;4:CD001115.8. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003;143:731-6.9. Qureshi F, Zaritsky A, Welch C, Mead-ows T, Burke BL. Clinical efficacy of race-mic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46:29-36.10. Rodrigo GJ, Rodrigo C. First-line ther-apy for adult patients with acute asthma receiving a multiple-dose protocol of ipra-tropium bromide plus albuterol in the

emergency department. Am J Respir Crit Care Med 2000;161:1862-8.11. Gelb AF, Karpel J, Wise RA, Cassino C, Johnson P, Conoscenti CS. Bronchodilator efficacy of the fixed combination of ipra-tropium and albuterol compared to albu-terol alone in moderate-to-severe persis-tent asthma. Pulm Pharmacol Ther 2008;21:630-6.12. Plotnick LH, Ducharme FM. Com-bined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev 2000;4:CD000060.13. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of chil-dren and adults with acute asthma: a sys-tematic review with meta-analysis. Thorax 2005;60:740-6. [Errata, Thorax 2008;63:1029, 2006;61:274, 458.]14. Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in acute asthma: a criti-cal controlled trial. Am J Med 1983;74:845-51.15. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emer-gency treatment of acute asthma. N Engl J Med 1986;314:150-2.16. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: an evidence-based evaluation. Chest 1999;116:285-95.17. Rowe BH, Edmonds ML, Spooner CH, Diner B, Camargo CA Jr. Corticosteroid therapy for acute asthma. Respir Med 2004;98:275-84.18. Krishnan JA, Davis SQ, Naureckas ET, Gibson P, Rowe BH. An umbrella review: corticosteroid therapy for adults with acute asthma. Am J Med 2009;122:977-91.19. Harrison BD, Stokes TC, Hart GJ, Vaughan DA, Ali NJ, Robinson AA. Need for intravenous hydrocortisone in addition to oral prednisolone in patients admitted to hospital with severe asthma without ventilatory failure. Lancet 1986;1:181-4.20. Ratto D, Alfaro C, Sipsey J, Glovsky MM, Sharma OP. Are intravenous corti-costeroids required in status asthmaticus? JAMA 1988;260:527-9.

21. Jónsson S, Kjartansson G, Gíslason D, Helgason H. Comparison of the oral and intravenous routes for treating asthma with methylprednisolone and theophyl-line. Chest 1988;94:723-6.22. Engel T, Dirksen A, Frølund L, et al. Methylprednisolone pulse therapy in acute severe asthma: a randomized, double-blind study. Allergy 1990;45:224-30.23. Bowler SD, Mitchell CA, Armstrong JG. Corticosteroids in acute severe asthma: effectiveness of low doses. Thorax 1992;47:584-7.24. Emerman CL, Cydulka RK. A random-ized comparison of 100-mg vs 500-mg dose of methylprednisolone in the treat-ment of acute asthma. Chest 1995;107:1559-63.25. Marquette CH, Stach B, Cardot E, et al. High-dose and low-dose systemic cortico-steroids are equally efficient in acute severe asthma. Eur Respir J 1995;8:22-7. [Erratum, Eur Respir J 1995;8:1435.]26. Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH. Early use of inhaled corticosteroids in the emergency depart-ment treatment of acute asthma. Cochrane Database Syst Rev 2003;3:CD002308.27. Rowe BH, Bota GW, Fabris L, Ther-rien SA, Milner RA, Jacono J. Inhaled budesonide in addition to oral corticoste-roids to prevent asthma relapse following discharge from the emergency depart-ment: a randomized controlled trial. JAMA 1999;281:2119-26.28. Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to beta2-agonists in adults with acute asth-ma. Cochrane Database Syst Rev 2000;4:CD002742.29. Karpel JP, Aldrich TK, Prezant DJ, Guguchev K, Gaitan-Salas A, Pathiparti R. Emergency treatment of acute asthma with albuterol metered-dose inhaler plus holding chamber: how often should treat-ments be administered? Chest 1997;112:348-56.30. Strauss L, Hejal R, Galan G, Dixon L, McFadden ER Jr. Observations on the ef-fects of aerosolized albuterol in acute

34


clinical pr actice

asthma. Am J Respir Crit Care Med 1997;155:454-8.31. Rodrigo C, Rodrigo G. Therapeutic response patterns to high and cumulative doses of salbutamol in acute severe asth-ma. Chest 1998;113:593-8.32. Rodrigo G, Rodrigo C. Early predic-tion of poor response in acute asthma patients in the emergency department. Chest 1998;114:1016-21.33. Chey T, Jalaludin B, Hanson R, Leeder S. Validation of a predictive model for asthma admission in children: how accu-rate is it for predicting admissions? J Clin Epidemiol 1999;52:1157-63.34. McCarren M, Zalenski RJ, McDermott M, Kaur K. Predicting recovery from acute asthma in an emergency diagnostic and treatment unit. Acad Emerg Med 2000;7:28-35.35. Karras DJ, Sammon ME, Terregino CA, Lopez BL, Griswold SK, Arnold GK. Clini-cally meaningful changes in quantitative measures of asthma severity. Acad Emerg Med 2000;7:327-34.36. Smith SR, Baty JD, Hodge D III. Vali-dation of the pulmonary score: an asthma severity score for children. Acad Emerg Med 2002;9:99-104.37. Gorelick MH, Stevens MW, Schultz TR, Scribano PV. Performance of a novel clinical score, the Pediatric Asthma Se-verity Score (PASS), in the evaluation of acute asthma. Acad Emerg Med 2004;11:10-8.38. Kelly AM, Kerr D, Powell C. Is severity

assessment after one hour of treatment better for predicting the need for admis-sion in acute asthma? Respir Med 2004;98:777-81.39. Darioli R, Perret C. Mechanical con-trolled hypoventilation in status asthmati-cus. Am Rev Respir Dis 1984;129:385-7.40. Thill PJ, McGuire JK, Baden HP, Green TP, Checchia PA. Noninvasive positive-pressure ventilation in children with lower airway obstruction. Pediatr Crit Care Med 2004;5:337-42. [Erratum, Pediatr Crit Care Med 2004;5:590.]41. Soroksky A, Stav D, Shpirer I. A pilot prospective, randomized, placebo-con-trolled trial of bilevel positive airway pres-sure in acute asthmatic attack. Chest 2003;123:1018-25.42. Blais L, Ernst P, Boivin JF, Suissa S. Inhaled corticosteroids and the prevention of readmission to hospital for asthma. Am J Respir Crit Care Med 1998;158:126-32.43. Sin DD, Man SF. Low-dose inhaled corticosteroid therapy and risk of emer-gency department visits for asthma. Arch Intern Med 2002;162:1591-5.44. Jones LA, Goodacre S. Magnesium sul-phate in the treatment of acute asthma: evaluation of current practice in adult emergency departments. Emerg Med J 2009;26:783-5.45. Mohammed S, Goodacre S. Intrave-nous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J 2007;24:823-30.

46. Rowe BH, Camargo CA Jr. The role of magnesium sulfate in the acute and chron-ic management of asthma. Curr Opin Pulm Med 2008;14:70-6.47. NIHR Health Technology Assessment Program. The 3Mg Trial: randomised con-trolled trial of intravenous or nebulised magnesium sulphate or standard therapy for acute severe asthma. 2010. (Accessed July 23, 2010, at http://www.hta.ac.uk/project/1619.asp.)48. Rodrigo G, Pollack C, Rodrigo C, Rowe BH. Heliox for nonintubated acute asthma patients. Cochrane Database Syst Rev 2006;4:CD002884.49. Liu MC, Dubé LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month random-ized multicenter trial. J Allergy Clin Im-munol 1996;98:859-71.50. Dockhorn RJ, Baumgartner RA, Leff JA, et al. Comparison of the effects of in-travenous and oral montelukast on airway function: a double blind, placebo con-trolled, three period, crossover study in asthmatic patients. Thorax 2000;55:260-5.51. Camargo CA Jr, Gurner DM, Smith-line HA, et al. A randomized placebo-controlled study of intravenous montelu-kast for the treatment of acute asthma. J Allergy Clin Immunol 2010;125:374-80.52. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008;31:143-78.Copyright © 2010 Massachusetts Medical Society.

COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITE

The Journal’s Web site (NEJM.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient

entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.

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n engl j med 362;23 nejm.org june 10, 20102194

Early Alzheimer’s DiseaseRichard Mayeux, M.D.

From the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University, New York. Address reprint requests to Dr. Mayeux at the Taub Institute for Research on Alzhei mer’s Disease and the Aging Brain and the Ger-trude H. Sergievsky Center, Columbia University, 630 W. 168th St., New York, NY 10032, or at [email protected].

This article (10.1056/NEJMcp0910236) was updated on September 15, 2010, at NEJM.org.


A 72-year-old man who is still managing investments at a brokerage firm seeks consul-tation at the urging of his wife for increasing difficulty with memory over the past 2 years. Clients have expressed concern about his occasional lapses in memory. His wife reports that he frequently repeats questions about social appointments and be-comes angry when she points this out. The physical examination is normal, but the patient has difficulty remembering elements of a brief story and adding a small amount of change. He has a score of 28 out of 30 on the Mini–Mental State Examina-tion, indicating slightly impaired cognitive function.1 Early Alzheimer’s disease is suspected. How should the patient be further evaluated and treated?


Alzheimer’s disease is the most frequent cause of dementia in Western societies, affecting an estimated 5 million people in the United States and 17 million world-wide.2 The annual incidence worldwide increases from 1% between the ages of 60 and 70 years to 6 to 8% at the age of 85 years or older.3 In countries in which sur-vival to the age of 80 years or older is not uncommon, the proportion of persons in this age group with Alzheimer’s disease now approaches 30% and is expected to continue to increase substantially.4 The disease onset is insidious, and manifesta-tions evolve over a period of years from mildly impaired memory to severe cognitive loss. A transitional state, referred to as mild cognitive impairment, often precedes the earliest manifestations of Alzheimer’s disease.5 The course of Alzheimer’s dis-ease is inevitably progressive and terminates in mental and functional incapacity and death. Plateaus sometimes occur in which the degree of cognitive impairment is stable for 1 or 2 years, but progression usually resumes thereafter.

An inability to retain recently acquired information is typically the initial symp-tom, whereas memory for remote events is relatively spared until later. With disease progression, impairment in other areas of cognition (e.g., language, abstract rea-soning, and executive function or decision making) occurs to varying degrees and typically coincides with difficulty at work or in social situations or household ac-tivities. Changes in mood and affect often accompany the decline in memory.6 Delu-sions and psychotic behavior are not typically presenting signs but can occur at any time during the disease course.7 The occurrence of psychosis during the initial stages of dementia suggests other diagnoses, such as dementia with Lewy bodies.

At autopsy, the most frequent pathological features in the brains of patients with Alzheimer’s disease include extracellular beta-amyloid protein in diffuse plaques and in plaques containing elements of degenerating neurons, termed neuritic plaques.8 Intracellular changes include deposits of hyperphosphorylated tau pro-tein, a microtubule assembly protein, in the form of neurofibrillary tangles. These pathological lesions first appear in the entorhinal regions of the hippocampus and



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n engl j med 362;23 nejm.org june 10, 2010 2195

then become widespread. Over time, there is wide-spread loss of neurons and synapses. The patho-genic mechanisms that are responsible for the development of these changes are unknown.

A family history of dementia is one of the most consistently reported risk factors for Alzheimer’s disease.3 There are rare cases of families with autosomal dominant inheritance of Alzheimer’s disease that develops between the ages of 30 and 50 years; about half these cases result from mu-tations in genes encoding amyloid precursor pro-tein, presenilin 1, or presenilin 2.9 Studies of these mutated genes have led to the assertion that Alz-heimer’s disease is caused by the generation and aggregation of beta-amyloid peptide, which then forms neuritic plaques. Although several hundred families carry these mutations, they account for less than 1% of cases.

First-degree relatives of patients with late-onset disease have approximately twice the expected lifetime risk of the disease. The disease is also more often concordant among monozygotic twins than among dizygotic twins.10 Individuals from families that have many members with late-onset Alzheimer’s disease are at increased risk for de-mentia, but the distribution of cases is rarely con-sistent with mendelian inheritance.

The genetic variant encoding apolipoprotein (APOE) ε4 is the only well-established mutation associated with the late-onset form of Alzhei-mer’s disease.11 Risks that are associated with the APOE ε4 allele peak between the ages of 60 and 80 years. As compared with the absence of the APOE ε4 allele, the presence of one such al-lele is associated with a doubling or tripling of the lifetime risk of disease, and the presence of two copies is associated with an increase in risk by a factor of five or more. Associations between Alz-heimer’s disease and variants in sortilin-related receptor 1 (SORL1),12 clusterin, phosphatidylinos-itol-binding clathrin assembly protein, and a com-plement component (3b/4b) receptor have been reported,13,14 but mechanisms underlying these associations remain uncertain.


Impaired memory is typically one of the first signs of Alzheimer’s disease, but difficulty recalling the names of friends or recent events is also common among normal elderly persons. The clinician is thus faced with the difficulty of distinguishing between normal aging and the early stages of

Alzheimer’s disease. Mild cognitive impairment is an intermediate state in which persons have more memory problems than would be considered nor-mal for their age, but their symptoms are not as severe as the symptoms of Alzheimer disease and they do not have functional impairment.5 Alz-heimer’s disease develops at a much higher fre-quency among persons with mild cognitive im-pairment than among those with normal aging. Determining when patients have reached the very early stage of Alzheimer’s disease is not easy, par-ticularly because it is likely that a preclinical stage of Alzheimer’s disease exists in which senile plaques, neuritic plaques, and neurofibrillary tan-gles occur in sufficient numbers to meet standard neuropathological criteria for Alzheimer’s disease in the absence of overt symptoms or signs of de-mentia.15 Other causes of memory impairment must also be considered, such as cerebrovascular disease, hydrocephalus, hypothyroidism, vitamin B12 deficiency, central nervous system infection, a cognitive disorder related to human immuno-deficiency virus infection, adverse effects of pre-scribed medications, substance abuse, and cancer.

A substantial decline in verbal memory and executive function (e.g., the ability to perform se-quential tasks) typically occurs at the onset of Alz-heimer’s disease but may be difficult to document without formal neuropsychological testing (Fig. 1). Reduced independence in daily activities (often recognized by the patient’s family) is one of the strongest predictors of disease.16 Functional sta-tus can be measured by the Clinical Dementia Rating (CDR) scale, which evaluates cognitive and functional performance on a scale ranging from 0 to 3, with higher scores indicating a greater se-verity of impairment.17 This assessment requires a collateral source of information gathering con-cerning the patient’s ability to function indepen-dently but can be performed in the primary care setting and is particularly useful for clinicians who do not have ready access to formal neuropsycho-logical testing. The assessment requires 30 to 45 minutes to administer, and training is provided online. (Additional details are available in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The CDR score was the strongest predictor of Alzheimer’s disease in a study involving community volunteers without dementia, and scores on a functional rating scale that is based on the CDR effectively identified patients in the early stages of Alzheimer’s disease in a clinical setting.18 Formal neuro psychological

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testing that shows a substantial decline in verbal memory and executive function supports the di-agnosis of Alzheimer’s disease18,19 but requires a trained professional for administration and inter-pretation.

Occasionally, patients with early Alzheimer’s disease present with impaired language or per-ceptual dysfunction rather than memory loss.20

Over time, both memory impairment and func-tional decline become apparent in such patients.

Patients with early disease are at increased risk for motor vehicle accidents. The American Acad-emy of Neurology21 recommends that clinicians perform a careful assessment of driving ability, including asking the caregiver to rate the patient’s driving ability and reviewing any traffic citations and accidents. Cognitive assessments that include visual perception and sequential-task performance may also be helpful in assessing the capacity to

drive.22 Many state motor vehicle agencies have simulated driving laboratories or are willing to assess driving ability for a nominal fee. Informa-tion regarding resources for evaluating poten-tially impaired drivers is available through the National Highway Traffic Safety Administration (www.nhtsa.dot.gov).

Tr e atmen t Op tions

Drug Therapies

Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-d-aspartate receptor antagonist memantine are the only treat-ments for Alzheimer’s disease that have been ap-proved by the Food and Drug Administration23

(Table 1). Randomized, placebo-controlled clini-cal trials of cholinesterase inhibitors have includ-ed patients with mainly mild-to-moderate Alz-

Increasingamyloid plaques and

neurofibrillary tanglesamyloid plaques and

neurofibrillary tangles

Increasingl id l d

Normal Aging

CDR = 0 CDR = 0.5 CDR = 1.0

Early Alzheimer’s Disease

Time

CSF tau andphosphorylated tau

Dependence onassistance indaily activities

FDG-PET parietalmetabolism

Hippocampal sizeon MRI

Neuropsychologicaltest performance

CSF beta-amyloidpeptide

Preclinical Alzheimer’s DiseaseMIld Cognitive Impairment

Increases with time

Decreases with time

Figure 1. Sequence of Pathological, Clinical, Physiological, and Radiologic Changes from Normal Aging to Early Alzheimer’s Disease.

Changes from normal aging to preclinical Alzheimer’s disease to early Alzheimer’s disease (yellow to green) are shown. The most frequent pathological feature of Alzheimer’s disease is the presence of extracellular beta-amyloid protein in diffuse plaques, along with intracellular changes that include deposits of hyperphosphorylated tau protein in the form of neurofibrillary tangles. These changes correspond to scores on the Clinical Dementia Rating (CDR) scale, which ranges from 0 to 3, with 0 indicating no impairment, 0.5 very mild impairment, 1.0 mild impairment, 2.0 moderate impairment, and 3.0 severe impairment. CSF denotes cerebrospinal fluid, FDG-PET 18F-fluorodeoxy-glucose–positron-emission tomography, and MRI magnetic resonance imaging.

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heimer’s disease and have shown significant but clinically marginal benefits with respect to cog-nition, daily function, and behavior.24-26 The con-dition of patients who are taking these drugs re-mains stable for a year or more and then may decline, though at a rate that is slower than that among untreated patients.

Although there are few studies directly compar-ing the three cholinesterase inhibitors, a system-atic review and meta-analysis of data from 27 randomized trials concluded that there were no significant differences in effects on cognitive per-formance among these medications.27 During the study period (usually, 3 to 6 months), the use of each of these drugs as prescribed at a standard dose resulted in a mean improvement of 2 to 3 points on the Alzheimer’s Disease Assessment Scale for cognition (a scale ranging from 0 to 70, with higher scores indicating worse cognition) or a decreased rate of decline, as compared with the placebo group (approximately a 3-point differ-ence, with a minimal clinically important differ-ence of 4 points).

On the basis of 14 studies that measured daily function, donepezil was modestly but significantly more effective than rivastigmine. Donepezil was likewise modestly but significantly better than rivastigmine and galantamine with regard to be-havior, as measured by the Neuropsychiatric In-

ventory (on a scale ranging from 1 to 144, with higher scores indicating a greater severity of dis-ease). Patients receiving donepezil had a mean reduction of 4.3 points in the baseline score, as compared with a reduction of 1.4 for those re-ceiving the other agents. The likelihood of an overall improvement in score was 1.9 times as great with donepezil as with placebo, 1.2 times as great with rivastigmine as with placebo, and 1.6 times as great with galantamine as with pla-cebo. Adverse effects (including nausea, vomiting, diarrhea, dizziness, and weight loss) were frequent with all three medications, although slightly less frequent with donepezil than with the other medi-cations.

Initial randomized trials of memantine in-volving patients with moderate-to-severe disease showed a small but significant reduction in cog-nitive deterioration.28 Subsequent randomized tri-als involving patients with mild-to-moderate dis-ease showed that memantine resulted in marginal benefits over a period of 6 months, with absolute changes in cognitive and functional measures of 1 percentage point.29 However, studies that were limited to patients with mild or early-stage dis-ease have shown no significant benefit of meman-tine therapy.30 Memantine has also been used in patients with late-stage disease in combination with cholinesterase inhibitors, such as donepezil,

Table 1. Drug Therapy for Alzheimer’s Disease.

Medication DoseCommon Adverse

Side Effects Comments

Donepezil (Aricept) 5 mg/day at bedtime with or without food for 4 to 6 weeks; 10 mg/day there-after, if tolerated

Nausea, vomiting, loss of appetite, weight loss, diarrhea, dizziness, muscle cramps, insomnia and vivid dreams

Available in a single daily dose

Rivastigmine (Exelon) 3 mg daily, split into morning and evening doses with meals; dose increased by 3 mg/day every 4 weeks as tolerated, with a max-imum daily dose of 12 mg

Nausea, vomiting, loss of appetite, weight loss, diarrhea, indiges-tion, dizziness, drowsiness, headache, diaphoresis, weakness

Available as a patch

Galantamine (Razadyne) 8 mg daily, split into morning and evening doses with meals; dose increased by 4 mg every 4 weeks, as tolerated, with a maximum daily dose of 16 to 24 mg

Nausea, vomiting, loss of appetite, weight loss, diarrhea, dizziness, headache, fatigue

Available as an extended-release capsule

Memantine (Namenda) 5 mg/day with or without food; dose increased by 5 mg every week, with a maximum daily dose of 20 mg

Constipation, dizziness, headache, pain (nonspecific)

Often used as an adjunct to cholinesterase inhibitors; not recommended alone for treatment of early disease

39



with modest improvements (a relative change in score of 2 to 5%) on the Severe Impairment Bat-tery and the activities of daily living inventory of the Alzheimer’s Disease Cooperative Study.31

More data are needed to guide the optimal timing of treatment of early Alzheimer’s disease. In a small, randomized, placebo-controlled trial of donepezil, patients in whom Alzheimer’s dis-ease had been diagnosed within the preceding year showed improvement in cognitive perfor-mance over a period of 24 weeks.32 In an open-label study, patients who were treated early in the disease course had improvement that was only slightly greater than that of patients who began treatment later.26 In another observational study, a duration of treatment with cholinesterase inhibi-tors or memantine of at least 3 years was associ-ated with a significantly slower rate of decline in cognitive ability and daily function.33

In practice, subjective reports of improvement in patients receiving cholinesterase inhibitors or memantine are common, but objective improve-ments are modest, if detectable at all. A rational approach is to try a cholinesterase inhibitor first, switching to another agent in the same class if the initial agent is ineffective or if intolerable side effects emerge.23 Memantine may be added to any of the cholinesterase inhibitors in patients who have little or no improvement with cholinesterase inhibitor monotherapy.

Other Strategies

The use of nonsteroidal antiinflammatory drugs, estrogen therapy, antioxidant vitamins, or statins has been proposed for the prevention of Alzhei-mer’s disease, but the results of randomized trials have been inconsistent or negative.34-37 Similarly, the efficacy of commonly used complementary therapies (e.g., ginkgo biloba, acetyl-L-carnitine, lecithin, huperzine A, piracetam, curcumin, peri-winkle, and phosphatidylserine) has not been shown in randomized trials.38 A review of nine randomized clinical trials of cognitive training and rehabilitation therapies that were used to ad-dress loss of memory and other intellectual func-tions showed no significant effects.39

Management of Psychiatric Symptoms

Behavioral and psychiatric symptoms typically in-crease with disease progression. However, depres-sion and anxiety are frequent even in the early

stage of Alzheimer’s disease. In one study, 25% of patients with Alzheimer’s disease were reported to have received the diagnosis of depression at the time of or just before the onset of symptoms of the disease.40 In patients in whom pharmaco-therapy is considered appropriate, selective sero-tonin-reuptake inhibitors are commonly used; tri-cyclic antidepressants are generally avoided, since their anticholinergic effects can cause or exacer-bate confusion.41

Psychosis that is characterized by hallucina-tions and delusions may occur infrequently in pa-tients with early Alzheimer’s disease. The occur-rence of agitation, delusions, hallucinations, and irritability early in the disease course also raises the possibility of an alternative diagnosis, such as dementia with Lewy bodies. Treatment with con-ventional or atypical antipsychotic agents may be helpful, but such drugs should be used with cau-tion because of the potential adverse effects (e.g., parkinsonism, extrapyramidal signs, sedation, and confusion).42

Caregiver Support

Persons who live with and provide care for pa-tients with Alzheimer’s disease, even in the early phases of the disease, often report emotional stress, in part related to the need to give up vaca-tions, hobbies, or even work to care for the pa-tient. Caregivers should routinely be offered coun-seling and support. Resources for caregivers and patients are available through the Alzheimer’s As-sociation (www.alz.org).


Further study of brain-imaging methods and bio-markers that may facilitate the identification of patients with early Alzheimer’s disease is needed. Focal atrophy on magnetic resonance imaging (MRI) of the inferior temporal region, particularly the hippocampus, has been shown to predict the conversion from mild cognitive impairment to Alzheimer’s disease.43 However, there is no stan-dard technique to quantify atrophy in the clinical setting, and the diagnostic sensitivity and speci-ficity of MRI are unclear.

Studies have shown that evidence of decreased metabolism and perfusion in the parietal lobes on 18F-fluorodeoxyglucose–positron-emission to-mography (FDG–PET) is as accurate as evidence

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of focal atrophy on MRI in predicting progression from mild cognitive impairment to Alzheimer’s disease.43,44 However, PET scanning is costly and not widely available at present, and its role in di-agnosis remains uncertain. PET imaging with the use of amyloid-binding compounds, such as car-bon 11–labeled Pittsburgh compound B (PIB),45 has been reported to identify patients with early Alzheimer’s disease.46 Some normal elderly per-sons without dementia have PIB retention simi-lar to that observed in patients with Alzheimer’s disease, but progression to Alzheimer’s disease occurs more rapidly in persons with mild cogni-tive impairment who have PIB retention than in those without retention, indicating that amyloid deposition may be an early biomarker of incipi-ent disease.47,48

Measurement of markers in cerebrospinal fluid has also been proposed to identify early Alzheim-er’s disease. Among persons with mild cognitive impairment, reduced levels of beta-amyloid pep-tide and increased levels of total tau and tau phosphorylated at threonine 181 have predicted the diagnosis of Alzheimer’s disease.49,50 Assess-ment requires lumbar puncture, and the thresh-old diagnostic levels of these markers have var-ied across studies.51,52 These measures are now commercially available with clinical interpreta-tion, but their role in practice remains unclear.

Guidelines

The European Federation of Neurological Socie-ties has published recommendations for the di-agnosis and management of Alzheimer’s disease.53 On the basis of available randomized trials, treat-ment with cholinesterase inhibitors is recom-mended even for mild or early disease; no spe-cific cholinesterase inhibitor is recommended over another. The American Academy of Neurology pub-lished practice recommendations in 200154 that have not yet been updated. In 2006, the American Association for Geriatric Psychiatry published

practice recommendations that also emphasize treatment with approved medications for cogni-tive symptoms, as well as symptomatic treatment for neuropsychiatric manifestations, such as de-pression and psychosis, and attention to issues related to safety, such as driving, living alone, and medication administration.55


The 72-year-old patient who is described in the vignette has a history of memory and functional impairment, with a relatively high Mini–Mental State Examination1 score and a normal neurologic examination. Basic blood chemical analysis and measures of thyrotropin should be performed, along with additional laboratory studies as deemed clinically relevant. Brain MRI to rule out other brain diseases and assess atrophy and a detailed neuropsychological assessment are warranted to make a preliminary diagnosis. If the diagnosis of Alzheimer’s disease is established, I would discuss with the patient and caregiver potential safety is-sues, including the current living situation and driving, and I would initiate treatment with one of the cholinesterase inhibitors, probably donepe-zil (starting at 5 mg each night at bedtime). I would plan a follow-up visit in 4 to 6 weeks to assess the side effects and efficacy of the medication (both subjective and objective) by repeating the Mini–Mental State Examination. At that time, the dose of the cholinesterase inhibitor could be increased to 10 mg daily if the drug has been well toler-ated. The patient should be closely followed clin-ically, with repeated neuropsychological assess-ment within 2 years.

Dr. Mayeux reports receiving an honorarium from Quintiles for serving on a data and safety monitoring board for a trial of a product manufactured by Eli Lilly. No other potential conflict of interest relevant to this article was reported.


References

1. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98.2. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7.

3. Mayeux R. Epidemiology of neurode-generation. Annu Rev Neurosci 2003;26:81-104.4. Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi HM. Worldwide varia-tion in the doubling time of Alzheimer’s disease incidence rates. Alzheimers De-ment 2008;4:316-23.

5. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical character-ization and outcome. Arch Neurol 1999;56:303-8. [Erratum, Arch Neurol 1999;56:760.]6. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for

41



Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006;63:530-8.7. Lopez OL, Becker JT, Sweet RA, et al. Psychiatric symptoms vary with the sever-ity of dementia in probable Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 2003;15:346-53.8. Duyckaerts C, Delatour B, Potier MC. Classification and basic pathology of Alz-heimer disease. Acta Neuropathol 2009;118:5-36.9. Rogaeva E, Kawarai T, George-Hyslop PS. Genetic complexity of Alzheimer’s disease: successes and challenges. J Alz-heimers Dis 2006;9:Suppl:381-7.10. Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168-74.11. Mucke L. Neuroscience: Alzheimer’s disease. Nature 2009;461:895-7.12. Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;39:168-77.13. Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM as-sociated with Alzheimer’s disease. Nat Genet 2009;41:1088-93.14. Lambert JC, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 2009;41:1094-9.15. Price JL, McKeel DW Jr, Buckles VD, et al. Neuropathology of nondemented ag-ing: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging 2009;30:1026-36.16. Hsiung GY, Alipour S, Jacova C, et al. Transition from cognitively impaired not demented to Alzheimer’s disease: an analy-sis of changes in functional abilities in a dementia clinic cohort. Dement Geriatr Cogn Disord 2008;25:483-90.17. Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 1997;9:Suppl 1:173-8.18. Dickerson BC, Sperling RA, Hyman BT, Albert MS, Blacker D. Clinical predic-tion of Alzheimer disease dementia across the spectrum of mild cognitive impairment. Arch Gen Psychiatry 2007;64:1443-50.19. Aggarwal NT, Wilson RS, Beck TL, Bienias JL, Bennett DA. Mild cognitive im-pairment in different functional domains and incident Alzheimer’s disease. J Neu-rol Neurosurg Psychiatry 2005;76:1479-84.20. Alladi S, Xuereb J, Bak T, et al. Focal cortical presentations of Alzheimer’s dis-ease. Brain 2007;130:2636-45.21. Iverson DJ, Gronseth GS, Reger MA, Classen S, Dubinsky RM, Rizzo M. Prac-

tice parameter update: evaluation and management of driving risk in dementia: report of the Quality Standards Subcom-mittee of the American Academy of Neu-rology. Neurology 2010;74:1316-24.22. Dawson JD, Anderson SW, Uc EY, Dastrup E, Rizzo M. Predictors of driving safety in early Alzheimer disease. Neurol-ogy 2009;72:521-7.23. Farlow MR, Cummings JL. Effective pharmacologic management of Alzhei-mer’s disease. Am J Med 2007;120:388-97.24. Rösler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: inter-national randomised controlled trial. BMJ 1999;318:633-8.25. Wilcock GK, Lilienfeld S, Gaens E. Ef-ficacy and safety of galantamine in pa-tients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ 2000;321:1445-9.26. Winblad B, Wimo A, Engedal K, et al. 3-Year study of donepezil therapy in Alz-heimer’s disease: effects of early and con-tinuous therapy. Dement Geriatr Cogn Disord 2006;21:353-63.27. Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alz-heimer’s disease: a systematic review and meta-analysis. Clin Interv Aging 2008;3:211-25.28. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Meman-tine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333-41.29. McShane R, Areosa Sastre A, Mina-karan N. Memantine for dementia. Co-chrane Database Syst Rev 2006;2:CD003154.30. Bakchine S, Loft H. Memantine treat-ment in patients with mild to moderate Alzheimer’s disease: results of a ran-domised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2008;13:97-107.31. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Me-mantine treatment in patients with mod-erate to severe Alzheimer disease already receiving donepezil: a randomized con-trolled trial. JAMA 2004;291:317-24.32. Seltzer B, Zolnouni P, Nunez M, et al. Efficacy of donepezil in early-stage Alz-heimer disease: a randomized placebo-con-trolled trial. Arch Neurol 2004;61:1852-6.33. Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progres-sion of Alzheimer disease. Alzheimers Res Ther 2009;1:7.34. Aisen PS, Thal LJ, Ferris SH, et al. Ro-fecoxib in patients with mild cognitive impairment: further analyses of data

from a randomized, double-blind, trial. Curr Alzheimer Res 2008;5:73-82.35. Feldman HH, Doody RS, Kivipelto M, et al. Randomized controlled trial of ator-vastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010;74:956-64.36. Hogervorst E, Yaffe K, Richards M, Huppert FA. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev 2009;1:CD003799.37. Isaac MG, Quinn R, Tabet N. Vitamin E for Alzheimer’s disease and mild cogni-tive impairment. Cochrane Database Syst Rev 2008;3:CD002854.38. Kelley BJ, Knopman DS. Alternative medicine and Alzheimer disease. Neurol-ogist 2008;14:299-306.39. Clare L, Woods RT, Moniz Cook ED, Orrell M, Spector A. Cognitive rehabilita-tion and cognitive training for early-stage Alzheimer’s disease and vascular demen-tia. Cochrane Database Syst Rev 2003;4:CD003260.40. Panza F, Frisardi V, Capurso C, et al. Late-life depression, mild cognitive im-pairment, and dementia: possible contin-uum? Am J Geriatr Psychiatry 2010;18:98-116.41. Starkstein SE, Mizrahi R, Power BD. Depression in Alzheimer’s disease: phe-nomenology, clinical correlates and treat-ment. Int Rev Psychiatry 2008;20:382-8.42. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsy-chotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355:1525-38.43. Schroeter ML, Stein T, Maslowski N, Neumann J. Neural correlates of Alz-heimer’s disease and mild cognitive im-pairment: a systematic and quantitative meta-analysis involving 1351 patients. Neuroimage 2009;47:1196-206.44. Yuan Y, Gu ZX, Wei WS. Fluorodeoxy-glucose-positron-emission tomography, single-photon emission tomography, and structural MR imaging for prediction of rapid conversion to Alzheimer disease in patients with mild cognitive impairment: a meta-analysis. AJNR Am J Neuroradiol 2009;30:404-10.45. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-19.46. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature 2009;461:916-22.47. Fripp J, Bourgeat P, Acosta O, et al. Appearance modeling of 11C PiB PET im-ages: characterizing amyloid deposition in Alzheimer’s disease, mild cognitive im-pairment and healthy aging. Neuroimage 2008;43:430-9.48. Okello A, Koivunen J, Edison P, et al. Conversion of amyloid positive and nega-

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clinical pr actice


tive MCI to AD over 3 years: an 11C-PIB PET study. Neurology 2009;73:754-60.49. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Asso-ciation between CSF biomarkers and in-cipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228-34.50. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alz-heimer disease in patients with mild cog-nitive impairment. JAMA 2009;302:385-93.51. Smach MA, Charfeddine B, Ben Oth-man L, et al. Evaluation of cerebrospinal

fluid tau/beta-amyloid(42) ratio as diag-nostic markers for Alzheimer disease. Eur Neurol 2009;62:349-55.52. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimina-tion and cognitive correlations. Neurolo-gy 2009;73:287-93.53. Waldemar G, Dubois B, Emre M, et al. Recommendations for the diagnosis and management of Alzheimer’s disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007;14(1):e1-e26.

54. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review): re-port of the Quality Standards Subcommit-tee of the American Academy of Neurology. Neurology 2001;56:1143-53.55. Lyketsos CG, Colenda CC, Beck C, et al. Position statement of the American As-sociation for Geriatric Psychiatry regard-ing principles of care for patients with de-mentia resulting from Alzheimer disease. Am J Geriatr Psychiatry 2006;14:561-72.Copyright © 2010 Massachusetts Medical Society.

POSTING PRESENTATIONS AT MEDICAL MEETINGS ON THE INTERNET

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n engl j med 362;17 nejm.org april 29, 2010 1597



Helicobacter pylori InfectionKenneth E.L. McColl, M.D.

From the Division of Cardiovascular and Medical Sciences, University of Glasgow, Gardiner Institute, Glasgow, United King-dom. Address reprint requests to Dr. Mc-Coll at the Division of Cardiovascular and Medical Sciences, University of Glasgow, Gardiner Institute, 44 Church St., Glas-gow G11 6NT, United Kingdom, or at [email protected].

This article (10.1056/NEJMcp1001110) was updated on August 4, 2010, at NEJM.org.


A 29-year-old man presents with intermittent epigastric discomfort, without weight loss or evidence of gastrointestinal bleeding. He reports no use of aspirin or non-steroidal antiinflammatory drugs (NSAIDs). Abdominal examination reveals epi-gastric tenderness. A serologic test for Helicobacter pylori is positive, and he receives a 10-day course of triple therapy (omeprazole, amoxicillin, and clarithromycin). Six weeks later, he returns with the same symptoms. How should his case be further evaluated and managed?


Helicobacter pylori, a gram-negative bacterium found on the luminal surface of the gastric epithelium, was first isolated by Warren and Marshall in 19831 (Fig. 1). It induces chronic inflammation of the underlying mucosa (Fig. 2). The infection is usually contracted in the first few years of life and tends to persist indefinitely un-less treated.2 Its prevalence increases with older age and with lower socioeconomic status during childhood and thus varies markedly around the world.3 The higher prevalence in older age groups is thought to reflect a cohort effect related to poorer living conditions of children in previous decades. At least 50% of the world’s human population has H. pylori infection.2 The organism can survive in the acidic environ-ment of the stomach partly owing to its remarkably high urease activity; urease converts the urea present in gastric juice to alkaline ammonia and carbon dioxide.4

Infection with H. pylori is a cofactor in the development of three important upper gastrointestinal diseases: duodenal or gastric ulcers (reported to develop in 1 to 10% of infected patients), gastric cancer (in 0.1 to 3%), and gastric mucosa-associated lymphoid-tissue (MALT) lymphoma (in <0.01%). The risk of these disease outcomes in infected patients varies widely among populations. The great majority of patients with H. pylori infection will not have any clinically significant complications.

Gastric and Duodenal Ulcers

In patients with duodenal ulcers, the inflammation of the gastric mucosa induced by the infection is most pronounced in the non–acid-secreting antral region of the stomach and stimulates the increased release of gastrin.5 The increased gastrin levels in turn stimulate excess acid secretion from the more proximal acid-secreting fundic mucosa, which is relatively free of inflammation.5,6 The increased duodenal acid load damages the duodenal mucosa, causing ulceration and gastric metaplasia. The metaplastic mucosa can then become colonized by H. pylori, which may contrib-ute to the ulcerative process. Eradication of the infection provides a long-term cure of duodenal ulcers in more than 80% of patients whose ulcers are not associated with the use of NSAIDs.7 NSAIDs are the main cause of H. pylori–negative ulcers.






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n engl j med 362;17 nejm.org april 29, 20101598

Ulceration of the gastric mucosa is believed to be due to the damage to the mucosa caused by H. pylori. As with duodenal ulcers, eradicating the infection usually cures the disease, provided that the gastric ulcer is not due to NSAIDs.8

Gastric Cancer

Extensive epidemiologic data suggest strong asso-ciations between H. pylori infection and noncar-dia gastric cancers (i.e., those distal to the gastro-esophageal junction).9 The infection is classified as a human carcinogen by the World Health Or-ganization.10 The risk of cancer is highest among patients in whom the infection induces inflam-mation of both the antral and fundic mucosa and causes mucosal atrophy and intestinal metapla-sia.11 Eradication of H. pylori infection reduces the progression of atrophic gastritis, but there is little evidence of reversal of atrophy or intestinal meta-plasia,12 and it remains unclear whether eradica-tion reduces the risk of gastric cancer.13

Gastric MALT Lymphoma

Epidemiologic studies have also shown strong as-sociations between H. pylori infection and the pres-ence of gastric MALT lymphomas.14 Furthermore, eradication of the infection causes regression of most localized gastric MALT lymphomas.15

Other Gastrointestinal Conditions

At least 50% of persons who undergo endoscopy for upper gastrointestinal symptoms have no evi-dence of esophagitis or gastric or duodenal ulcer-ation and are considered to have nonulcer or functional dyspepsia. In such patients, biopsy

specimens of the gastric mucosa often reveal the presence of H. pylori and associated inflammation, although this finding is also common in persons without upper gastrointestinal symptoms. Most randomized trials of therapy for H. pylori eradica-tion in patients with nonulcer dyspepsia have shown no significant benefit regarding symp-toms; a few have shown a marginal benefit,16,17 but this can be explained by the presence of un-recognized ulceration.18 There is thus little evi-dence that chronic H. pylori infection in the ab-sence of gastric or duodenal ulceration causes upper gastrointestinal symptoms.

The prevalence of H. pylori infection is lower among patients with gastroesophageal reflux dis-ease (GERD)19 and those with esophageal adeno-carcinoma (which may arise as a complication of GERD) than among healthy controls.20 H. pylori–associated atrophic gastritis, which reduces acid secretion, may provide protection against these diseases. A recent meta-analysis showed no sig-nificant association between H. pylori eradication and an increased risk of GERD.21


Candidates for Testing for H. pylori Infection

Since the vast majority of patients with H. pylori infection do not have any related clinical disease, routine testing is not considered appropriate.22,23 Definite indications for identifying and treating

Figure 1. Helicobacter pylori.

H. pylori is a gram-negative bacterium with a helical rod shape. It has prominent flagellae, facilitating its penetration of the thick mucous layer in the stomach.

Figure 2. Gastric-Biopsy Specimen Showing Helico-bacter pylori Adhering to Gastric Epithelium and Underlying Inflammation.

H. pylori is visible as small black rods (arrows) on the epithelial surface and within the glands. The underly-ing mucosa shows inflammatory-cell infiltrates.

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the infection are confirmed gastric or duodenal ulcers and gastric MALT lymphoma.22,23 Testing for infection, and subsequent eradication, also seems prudent after resection of early gastric can-cers.24 In addition, European guidelines recom-mend eradicating H. pylori infection in first-degree relatives of patients with gastric cancer and in patients with atrophic gastritis, unexplained iron-deficiency anemia, or chronic idiopathic thrombo-cytopenic purpura, although the data in support of these recommendations are scant.23

Patients with uninvestigated, uncomplicated dyspepsia may also undergo testing for H. pylori infection by means of a nonendoscopic (noninva-sive) method22,23,25; eradication therapy is pre-scribed for patients with positive test results. The rationale for this strategy is that in some pa-tients with dyspepsia, underlying H. pylori–induced ulcer disease is causing their symptoms. This nonendoscopic strategy is not appropriate for patients with accompanying alarm symptoms (e.g., weight loss, persistent vomiting, or gastro-intestinal bleeding) or for older patients (≥45 or ≥55 years of age, depending on the specific set of guidelines) with new-onset dyspepsia, in whom endoscopy is warranted.22,23,25 The nonendoscopic strategy is also not generally recommended for patients with NSAID-associated dyspepsia, since NSAIDs can cause ulcers in the absence of H. py-lori infection.

An attraction of the test-and-treat strategy is that it avoids the discomfort and costs of endos-copy. However, because only a minority of pa-tients with dyspepsia who have a positive H. pylori test have underlying ulcer disease,26,27 most pa-tients treated by means of the test-and-treat strat-egy incur the inconvenience, costs, and potential side effects of therapy without a benefit. In a placebo-controlled trial of empirical treatment involving 294 patients with uninvestigated dys-pepsia and a positive H. pylori breath test, the 1-year rate of symptom resolution was 50% in those receiving H. pylori–eradication therapy, as compared with 36% of those receiving placebo (P = 0.02)28; 7 patients would need to receive eradication therapy for 1 patient to have a benefit. A greater benefit would be expected if treatment were limited to patients with an increased prob-ability of having an ulcer. However, neither the characteristics of the symptoms nor the presence of other risk factors for ulcer (e.g., male sex, smoking, and family history of ulcer disease) are

particularly useful in clinical practice for identi-fying patients with ulcer dyspepsia and those with nonulcer dyspepsia.29

In randomized trials comparing a noninvasive test-and-treat strategy with early endoscopy26,27 or with proton-pump–inhibitor therapy,30,31 the three strategies resulted in a similar degree of symptom improvement, but early endoscopy was more expensive than the other two strategies.32 However, the test-and-treat strategy is unlikely to be cost-effective in populations with a preva-lence of H. pylori infection below 20%.33 Infor-mation is lacking on the longer-term outcomes of these strategies.

Tests for H. pylori Infection

Table 1 summarizes the various tests for H. pylori infection.

Nonendoscopic TestsSerologic testing for IgG antibodies to H. pylori is often used to detect infection. However, a meta-analysis of studies of several commercially avail-able quantitative serologic assays showed an overall sensitivity and specificity of only 85% and 79%, respectively.34 The appropriate cutoff values vary among populations, and the test results are often reported as positive, negative, or equivocal. Also, this test has little value in confirming erad-ication of the infection, because the antibodies persist for many months, if not longer, after eradication.

The urea breath test involves drinking 13C-labeled or 14C-labeled urea, which is converted to labeled carbon dioxide by the urease in H. py-lori. The labeled gas is measured in a breath sample. The test has a sensitivity and a specific-ity of 95%.35 The infection can also be detected by identifying H. pylori–specific antigens in a stool sample with the use of polyclonal or mono-clonal antibodies (the fecal antigen test).36 The monoclonal-antibody test (which also has a specificity and a sensitivity of 95%36) is more accurate than the polyclonal-antibody test. For both the breath test and the fecal antigen test, the patient should stop taking proton-pump in-hibitors 2 weeks before testing, should stop tak-ing H2 receptor antagonists for 24 hours before testing, and should avoid taking antimicrobial agents for 4 weeks before testing, since these medications may suppress the infection and re-duce the sensitivity of testing.

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Endoscopic TestsH. pylori infection can be detected on endoscopic biopsy of the gastric mucosa, by means of several techniques. The biopsy specimens are usually taken from the prepyloric region, but an addi-tional biopsy specimen obtained from the fundic mucosa may increase the test’s sensitivity, espe-cially if the patient has recently been treated with a proton-pump inhibitor.

The urease-based method involves placement of the endoscopic biopsy specimen in a solution of urea and pH-sensitive dye. If H. pylori is pres-ent, its urease converts the urea to ammonia, in-creasing the pH and changing the color of the dye. Recommendations for avoiding proton-pump inhibitors, H2 receptor antagonists, and anti-microbial therapy before testing apply to this test as well, to minimize the chance of false negative results.37 The test has a sensitivity of more than 90% and a specificity of more than 95%.35

Another means of diagnosis involves routine histologic testing of a biopsy specimen; if there is H. pylori infection, the organism and associ-ated gastritis are apparent on sections stained with hematoxylin and eosin or Giemsa. Although culturing of the organism is also possible and permits testing for sensitivity to antimicrobial agents, facilities for the culture of H. pylori are not widely available and the method is relatively insensitive.

Treatment of H. pylori Infection

Various drug regimens are used to treat H. pylori infection (Table 2). Most include two antibiotics plus a proton-pump inhibitor or a bismuth prep-aration (or both). The most commonly used ini-tial treatment is triple therapy consisting of a proton-pump inhibitor plus clarithromycin and amoxicillin, each given twice per day for 7 to 14 days. Metronidazole is used in place of amoxicil-lin in patients with a penicillin allergy.

The recommended duration of triple therapy is typically 10 to 14 days in the United States and 7 days in Europe.22,23 A recent meta-analysis of 21 randomized trials showed that the rate of eradication was increased by 4 percentage points with the use of triple therapy for 10 days as com-pared with 7 days and by 5 percentage points with the use of triple therapy for 14 days as com-pared with 7 days38 — absolute differences that are statistically significant but of marginal clin-ical significance.

Another possible initial therapy in areas with a high prevalence of clarithromycin-resistant H. pylori infection (i.e., >20%) is quadruple ther-apy comprising the use of a proton-pump inhibi-tor, tetracycline, metronidazole, and a bismuth salt for 10 to 14 days23; however, bismuth salts are not available in some countries. A recent meta-analysis of 93 studies showed a higher rate of eradication with quadruple therapy that included

Table 1. Tests for Helicobacter pylori Infection.*

Test Advantages Disadvantages

Nonendoscopic

Serologic test Widely available; the least expensive of available tests

Positive result may reflect previous rather than current in-fection; not recommended for confirming eradication

Urea breath test High negative and positive predictive values; useful before and after treatment

False negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations; consid-erable resources and personnel required to perform test

Fecal antigen test High negative and positive predictive values with monoclonal-antibody test; useful before and after treatment

Process of stool collection may be distasteful to patient; false negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations

Endoscopic

Urease-based tests Rapid, inexpensive, and accurate in selected patients

False negative results possible in the presence of PPIs or with recent use of antibiotics or bismuth preparations

Histologic assessment Good sensitivity and specificity Requires trained personnel

Culture Excellent specificity; provides opportunity to test for antibiotic sensitivity

Variable sensitivity; requires trained staff and properly equipped facilities

* PPI denotes proton-pump inhibitor.

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both clarithromycin and metronidazole than with triple therapy that included both these agents in populations with either clarithromy-cin or metronidazole resistance.39

An alternative initial regimen is 10-day se-quential therapy, involving a proton-pump inhibi-tor plus amoxicillin for 5 days followed by a proton-pump inhibitor plus clarithromycin and tinidazole for 5 more days. This regimen was reported to achieve an eradication rate of 93%, as compared with a rate of 77% with standard triple therapy, in a meta-analysis of 10 random-ized trials in Italy.40 However, in a trial in Spain, the eradication rate among patients randomly assigned to receive sequential therapy was only 84%, indicating a need to confirm its efficacy before it is used widely.41

Confirmation of Eradication

It is important to confirm the eradication of H. pylori infection in patients who have had an H. pylori–associated ulcer or gastric MALT lym-phoma or who have undergone resection for early gastric cancer.22,23 In addition, to avoid repeated treatment of patients whose symptoms are not attributable to H. pylori, follow-up testing is indi-cated in patients whose symptoms persist after H. pylori eradication treatment for dyspepsia. Eradi-cation may be confirmed by means of a urea breath test or fecal antigen test; these are per-formed 4 weeks or longer after completion of ther-apy, to avoid false negative results due to suppres-sion of H. pylori.22 Eradication can also be confirmed by testing during repeat endoscopy (Table 1) for patients in whom endoscopy is required.

Management of Persistent Infection after Treatment

Before prescribing a second course of therapy, it is important to confirm that the infection is still pres-ent and consider whether additional antimicrobial treatment is appropriate. Further attempts at erad-ication are indicated in patients with confirmed ulcer or gastric MALT lymphoma or after resec-tion for early gastric cancer. However, if the ini-tial therapy was for uninvestigated dyspepsia, which is associated with a low likelihood of un-derlying ulcer and symptomatic benefit from erad-ication, the appropriateness of further eradication therapy is unclear; data from studies designed to determine the optimal management of such cases are lacking. Options for treatment include em-

pirical acid-inhibitory therapy, endoscopy to check for underlying ulcer or another cause of symp-toms, and repeat use of the noninvasive test-and-treat strategy. The possibility that symptoms may be due to a different cause (e.g., biliary tract, pancreatic, musculoskeletal, or cardiac disease or psychosocial stress) should routinely be consid-ered. If another course of therapy is administered to eradicate H. pylori infection, the importance of adherence to the treatment regimen should be

Table 2. Regimens Used to Treat Helicobacter pylori Infection.

Standard initial treatment (use one of the following three options)

Triple therapy for 7–14 days

PPI, healing dose twice/day*

Amoxicillin, 1 g twice/day†

Clarithromycin, 500 mg twice/day

Quadruple therapy for 10–14 days‡


Tripotassium dicitratobismuthate, 120 mg four times/day

Tetracycline, 500 mg four times/day

Metronidazole, 250 mg four times/day§

Sequential therapy

Days 1–5


Amoxicillin, 1 g twice/day

Days 6–10


Clarithromycin, 500 mg twice/day

Tinidazole, 500 mg twice/day§

Second-line therapy, if triple therapy involving clarithromycin was used initially (use one or the other)

Triple therapy for 7–14 days

PPI, healing dose once/day*

Amoxicillin, 1 g twice/day

Metronidazole, 500 mg (or 400 mg) twice/day§

Quadruple therapy, as recommended for initial therapy

* Examples of healing doses of proton-pump inhibitors (PPIs) include the follow-ing regimens, all twice per day: omeprazole at a dose of 20 mg, esomeprazole at a dose of 20 mg, rabeprazole at a dose of 20 mg, pantoprazole at a dose of 40 mg, and lansoprazole at a dose of 30 mg. In some studies, esomeprazole has been given at a dose of 40 mg once per day.

† If the patient has an allergy to amoxicillin, substitute metronidazole (at a dose of 500 mg or 400 mg) twice per day and (in initial triple therapy only) use clarithromycin at reduced dose of 250 mg twice per day.

‡ Quadruple therapy is appropriate as first-line treatment in areas in which the prevalence of resistance to clarithromycin or metronidazole is high (>20%) or in patients with recent or repeated exposure to clarithromycin or metronidazole.

§ Alcohol should be avoided during treatment with metronidazole or tinidazole, owing to the potential for a reaction resembling the reaction to disulfiram with alcohol use.

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emphasized, since poor adherence may underlie the failure of initial therapy.

The choice of second-line treatment is influ-enced by the initial treatment (Table 2). Treatment failure is often related to H. pylori resistance to clarithromycin or metronidazole (or both agents). If initial therapy did not include a bismuth salt, bismuth-based quadruple therapy is commonly used as second-line therapy, with eradication rates in case series ranging from 57 to 95%.42 Triple therapies have also been tested as second-line therapies in patients in whom initial therapy failed. A proton-pump inhibitor used in combina-tion with metronidazole and either amoxicillin or tetracycline is recommended in patients previ-ously treated with a proton-pump inhibitor, amoxicillin, and clarithromycin.23,43 Clarithro-mycin should be avoided as part of second-line therapy unless resistance testing confirms that the H. pylori strain is susceptible to the drug.44

Patients in whom H. pylori infection persists after a second course of treatment and for whom eradication is considered appropriate should be referred to a specialist with access to facilities

for culturing H. pylori and performing sensitivity testing and experience with alternative treatments for the infection. Several regimens have been re-ported to be effective as salvage therapy in case series. For example, retreatment after treatment failure with a triple regimen consisting of levo-floxacin or rifabutin, along with a proton-pump inhibitor and amoxicillin, has been associated with high rates of eradication.45-47 However, cau-tion is warranted in the use of rifabutin, which may lead to resistance of mycobacteria in pa-tients with preexisting mycobacterial infection.


Data from randomized trials are lacking to guide the care of patients whose symptoms persist after completion of H. pylori eradication therapy for uninvestigated dyspepsia. The effect of eradica-tion of H. pylori infection on the risk of gastric cancer is unclear but is currently under study.

Guidelines

The American College of Gastroenterology guide-lines22 and the Maastricht guidelines23 differ slightly in their recommendations for testing and treatment of H. pylori infection (Table 3).


The noninvasive test-and-treat strategy for H. py-lori infection is reasonable for younger patients who have upper gastrointestinal symptoms but not alarm symptoms, like the patient in the vi-gnette. Noninvasive testing can be performed with the use of the urea breath test, fecal antigen test, or serologic test; the serologic test is the least accurate. Triple therapy with a proton-pump inhibitor, clarithromycin, and amoxicillin or metronidazole remains an appropriate first-line therapy, provided that there is not a high local rate of clarithromycin resistance. Recurrence or persistence of symptoms after eradication therapy for uninvestigated dyspepsia is much less likely to indicate that treatment has failed than to indi-cate that the symptoms are unrelated to H. pylori infection. Further eradication therapy should not be considered unless persistent H. pylori infection is confirmed. Data are lacking to inform the op-

Table 3. Guidelines for Evaluation and Management of Helicobacter pylori Infection.*

American College of Gastroenterology

Maastricht III Consensus Report

Criteria for testing

Active gastric or duodenal ulcer, his-tory of active gastric or duodenal ulcer not previously treated for H. pylori infection, gastric MALT lymphoma, history of endoscop-ic resection of early gastric can-cer, or uninvestigated dyspepsia

Same as American College of Gastro-enterology criteria, with the follow-ing additional criteria: gastric can-cer in first-degree relative, atrophic gastritis, unexplained iron-deficien-cy anemia, or chronic idiopathic thrombocytopenic purpura†

Criteria for test-and-treat strategy

Age <55 yr and no alarm symptoms§ Age <45 yr and no alarm symptoms‡§

Duration of therapy

10–14 Days 7 Days

* The American College of Gastroenterology guidelines are reported by Chey, Wong, and the Practice Parameters Committee of the American College of Gastroenterology22; the Maastricht III consensus report guidelines are reported by Malfertheiner and colleagues.23 MALT denotes mucosa-associated lymphoid tissue.

† Eradication of H. pylori in patients with chronic idiopathic thrombocytopenic purpura has been reported to increase the platelet count, although the data are limited.

‡ The age cutoff varies among countries, depending on the prevalence of upper gastrointestinal cancer.

§ Alarm symptoms include dysphagia, weight loss, evidence of gastrointestinal bleeding, and persistent vomiting.

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timal management of recurrent or persistent dys-pepsia after noninvasive testing and treatment of H. pylori infection. Options include symptomatic acid-inhibitory therapy, endoscopy to check for underlying ulcer or another cause of symptoms, and repeat of the H. pylori test-and-treat strategy;

other potential reasons for the symptoms should also be reconsidered.

Dr. McColl reports receiving lecture fees from AstraZeneca and Nycomed and consulting fees from Sacoor. No other poten-tial conflict of interest relevant to this article was reported.


References

1. Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in ac-tive chronic gastritis. Lancet 1983;1:1273-5.2. Everhart JE. Recent developments in the epidemiology of Helicobacter pylori. Gastroenterol Clin North Am 2000;29:559-79.3. Woodward M, Morrison C, McColl K. An investigation into factors associated with Helicobacter pylori infection. J Clin Epidemiol 2000;53:175-81.4. Marshall BJ, Barrett LJ, Prakash C, McCallum RW, Guerrant RL. Urea pro-tects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid. Gas-troenterology 1990;99:697-702.5. el-Omar EM, Penman ID, Ardill JES, Chittajallu RS, Howie C, McColl KEL. Helicobacter pylori infection and abnor-malities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995;109:681-91.6. Gillen D, el-Omar EM, Wirz AA, Ar-dill JES, McColl KEL. The acid response to gastrin distinguishes duodenal ulcer pa-tients from Helicobacter pylori-infected healthy subjects. Gastroenterology 1998;114:50-7.7. Hentschel E, Brandstätter G, Drag-osics B, et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the re-currence of duodenal ulcer. N Engl J Med 1993;328:308-12.8. Axon ATR, O’Moráin CA, Bardhan KD, et al. Randomised double blind con-trolled study of recurrence of gastric ulcer after treatment for eradication of Helico-bacter pylori infection. BMJ 1997;314:565-8.9. Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer: a nested case-control study. Scand J Gastroenterol 1999;34:353-60.10. Infection with Helicobacter pylori. In: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC monographs on the evaluation of carcino-genic risks to humans. Vol. 61. Schisto-somes, liver flukes and Helicobacter pylori. Lyon, France: International Agency for Research on Cancer, 1994:177-240.11. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784-9.

12. Leung WK, Lin SR, Ching JY, et al. Factors predicting progression of gastric intestinal metaplasia: results of a ran-domised trial on Helicobacter pylori eradi-cation. Gut 2004;53:1244-9.13. Malfertheiner P, Sipponen P, Naumann M, et al. Helicobacter pylori eradication has the potential to prevent gastric can-cer: a state-of-the-art critique. Am J Gas-troenterol 2005;100:2100-15.14. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori and gastric lym-phoma. N Engl J Med 1994;330:1267-71.15. Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long term outcome of patients with gastric marginal zone B cell lymphoma of mu-cosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series. Gut 2004;53:34-7.16. Moayyedi P, Soo S, Deeks J, et al. Sys-tematic review and economic evaluation of Helicobacter pylori eradication treat-ment for non-ulcer dyspepsia. BMJ 2000;321:659-64.17. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann In-tern Med 2001;134:361-9.18. McColl KEL. Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med 2000;342:589.19. Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter py-lori in patients with gastro-oesophageal ref lux disease: systematic review. BMJ 2003;326:737-9.20. de Martel C, Llosa AE, Farr SM, et al. Helicobacter pylori infection and the risk of development of esophageal adenocarci-noma. J Infect Dis 2005;191:761-7.21. Yaghoobi M, Farrokhyar F, Yuan Y, Hunt RH. Is there an increased risk of GERD after Helicobacter pylori eradica-tion? A meta-analysis. Am J Gastroenterol 2010 January 19 (Epub ahead of print).22. Chey WD, Wong BCY, Practice Param-eters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the man-agement of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808-25.23. Malfertheiner P, Megraud F, O’Morain

C, et al. Current concepts in the manage-ment of Helicobacter pylori infection: the Maastricht III consensus report. Gut 2007;56:772-81.24. Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter py-lori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, ran-domised controlled trial. Lancet 2008;372:392-7.25. Talley NJ, Vakil N, Practice Parame-ters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastro-enterol 2005;100:2324-37.26. McColl KEL, Murray LS, Gillen D, et al. Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia. BMJ 2002;324:999-1002. [Errata, BMJ 2002;325:479, 580.]27. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helico-bacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.28. Chiba N, Van Zanten SJO, Sinclair P, Ferguson RA, Escobedo S, Grace E. Treat-ing Helicobacter pylori infection in pri-mary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment–Helicobacter pylori pos-itive (CADET-Hp) randomised controlled trial. BMJ 2002;324:1012-6.29. The Danish Dyspepsia Study Group. Value of the unaided clinical diagnosis in dyspepsia patients in primary care. Am J Gastroenterol 2001;96:1417-21.30. Jarbol DE, Kragstrup J, Stovring H, Havelund T, Schaffalitzky de Muckadell OB. Proton pump inhibitor or testing for Helicobacter pylori as the first step for pa-tients presenting with dyspepsia? A cluster-randomized trial. Am J Gastroenterol 2006;101:1200-8.31. Manes G, Menchise A, de Nucci C, Balzano A. Empirical prescribing for dys-pepsia: randomised controlled trial of test and treat versus omeprazole treatment. BMJ 2003;326:1118.32. Delaney BC, Innes MA, Deeks J, et al. Initial management strategies for dyspep-sia. Cochrane Database Syst Rev 2001;3:CD001961.

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33. Delaney BC, Moayyedi P, Forman D. Initial management strategies for dyspep-sia. Cochrane Database Syst Rev 2003;2:CD001961.34. Loy CT, Irwig LM, Katelaris PH, Talley NJ. Do commercial serological kits for Helicobacter pylori infection differ in ac-curacy? A meta-analysis. Am J Gastroen-terol 1996;91:1138-44.35. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-9.36. Gisbert JP, Pajares JM. Stool antigen test for the diagnosis of Helicobacter py-lori infection: a systematic review. Helico-bacter 2004;9:347-68.37. Midolo P, Marshall BJ. Accurate diag-nosis of Helicobacter pylori: urease tests. Gastroenterol Clin North Am 2000;29:871-8.38. Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analy-sis: duration of first-line proton-pump inhibitor based triple therapy for Helico-bacter pylori eradication. Ann Intern Med 2007;147:553-62.

39. Fischbach L, Evans EL. Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment Pharmacol Ther 2007;26:343-57.40. Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helico-bacter pylori infection in patients naive to treatment. Ann Intern Med 2008;148:923-31. [Erratum, Ann Intern Med 2008;149:439.]41. Sánchez-Delgade J, Calvet X, Bujanda L, Gisbert JP, Titó L, Castro M. Ten-day se-quential treatment for Helicobacter pylori eradication in clinical practice. Am J Gas-troenterol 2008;103:2220-3.42. Gisbert JP, Pajares JM. Helicobacter pylori “rescue” regimen when proton pump inhibitor-based triple therapies fail. Ali-ment Pharmacol Ther 2002;16:1047-57.43. Realdi G, Dore MP, Piana A, et al. Pre-treatment antibiotic resistance in Helico-bacter pylori infection: results of three randomized controlled studies. Helico-bacter 1999;4:106-12.

44. Lamouliatte H, Mégraud F, Delchier JC, et al. Second-line treatment for failure to eradicate Helicobacter pylori: a random-ized trial comparing four treatment strat-egies. Aliment Pharmacol Ther 2003;18:791-7.45. Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based res-cue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther 2006;23:35-44.46. Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infec-tion: a meta-analysis. Am J Gastroenterol 2006;101:488-96.47. Qasim A, Sebastian S, Thornton O, et al. Rifabutin- and furazolidone-based Helicobacter pylori eradication therapies after failure on standard first- and second-line eradication attempts in dyspepsia pa-tients. Aliment Pharmacol Ther 2005;21:91-6.Copyright © 2010 Massachusetts Medical Society.

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51

Clinical Therapeutics articles provide practical guidance for the use of specific medications, devices, and procedures in patient care. Topics include: how the therapy is used, evidence that supports (or fails to support) its use, adverse effects and areas of uncertainty, guidelines from major professional societies, and author recommendations.

Clinical Therapeutics

52

clinical therapeutics


n engl j med 364;2 nejm.org january 13, 2011146

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,

the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

Iron-Chelating Therapy for Transfusional Iron Overload

Gary M. Brittenham, M.D.

From the Division of Pediatric Hematol-ogy, Department of Pediatrics, Columbia University College of Physicians and Sur-geons, New York. Address reprint re-quests to Dr. Brittenham at the Division of Pediatric Hematology, Department of Pediatrics, Columbia University Medical Center, Rm. CHN 10-08, 3959 Broadway, New York, NY 10032, or at [email protected].


A 16-year-old boy with sickle cell anemia undergoes routine screening with transcra-nial Doppler ultrasonography to assess the risk of stroke. This examination shows an abnormally elevated blood-flow velocity in the middle cerebral artery. The hemoglo-bin level is 7.2 g per deciliter, the reticulocyte count is 12.5%, and the fetal hemoglo-bin level is 8.0%. Long-term treatment with red-cell transfusion is initiated to prevent stroke. A hematologist recommends prophylactic iron-chelating therapy.


Long-term treatment with red-cell transfusion effectively prevents stroke and other complications of sickle cell anemia1 and can sustain patients with chronic con-genital and acquired refractory anemia, including thalassemia major, Diamond–Blackfan anemia, myelodysplastic syndromes, myelofibrosis, aplastic anemia, and other disorders. In the United States, 10,000 to 20,000 patients with sickling disor-ders receive repeated transfusions. An estimated 4000 to 5000 patients with myelo-dysplastic syndromes and other forms of acquired refractory anemia require red-cell transfusions. The number of patients with transfusion-dependent thalassemia in the United States is smaller — probably less than 1000.2 However, globally, al-most 100,000 patients with thalassemia syndromes undergo transfusions. The ma-jority of these patients are in low- and middle-income countries.3

Because humans lack any effective means to excrete excess iron, long-term trans-fusion alone inexorably produces the clinical problem of iron overload. In patients with thalassemia who undergo transfusion from infancy, iron-induced liver dis-ease and endocrine disorders develop during childhood and are almost inevitably followed in adolescence by death from iron-induced cardiomyopathy.4 In patients with sickle cell anemia, although iron-induced complications appear to develop later, eventually, liver disease with cirrhosis as well as cardiac and pancreatic iron deposi-tion can develop.5,6 The annual per-patient costs of care for complications of iron overload are estimated at $15,000 to $20,000.7,8

PATHOPH YSIOL OGY A ND EFFEC T OF THER A PY

At the end of their life span, transfused red cells are phagocytosed by reticuloendo-thelial macrophages in the liver, bone marrow, and spleen (Fig. 1). Their hemoglobin is digested, and the iron is freed from heme and released into the cytosol. Early in the course of long-term transfusion, most of this additional iron can be stored within reticuloendothelial macrophages. Gradually, limits on the capacity of macro-phages to retain iron result in the release of excess iron into plasma.9 Transferrin

53

clinical ther apeutics

n engl j med 364;2 nejm.org january 13, 2011 147

binds the released iron, with an increase in the plasma iron concentration and transferrin satu-ration. As the transferrin saturation increases, hepatocytes are recruited to serve as storage sites for the excess iron.

With continued transfusion, macrophages and hepatocytes can no longer retain all the surplus iron. Iron then enters plasma in amounts that exceed the transport capacity of circulating trans-ferrin. As a consequence, non–transferrin-bound iron appears in the plasma (Fig. 1) as a hetero-geneous assortment of iron complexes that ap-pear to be the major mediators of extrahepatic tissue damage in transfusional iron overload.10 Non–transferrin-bound plasma iron enters spe-cific cells, particularly hepatocytes, cardiomyo-cytes, anterior pituitary cells, and pancreatic beta-cells. In these cells, iron accumulation leads to the generation of reactive oxygen species, result-ing in damage to lipids, proteins, DNA, and subcellular organelles, including lysosomes and mito chondria. This injury may result in cellular dysfunction, apoptosis, and necrosis.

Therapy with chelating agents that form a complex with iron and promote its excretion can clear plasma non–transferrin-bound iron, remove excess iron from cells, and maintain or return body iron to safe levels (Fig. 1). (An interactive graphic depicting iron supply and storage in sickle cell anemia with long-term red-cell trans-fusion and iron-chelating therapy is available with the full text of this article at NEJM.org.) Two iron-chelating agents are approved for use in North America (Table 1): parenteral deferox-amine mesylate (Desferal, Novartis) and oral deferasirox (Exjade, Novartis).

Deferoxamine is a siderophore (an iron-bind-ing compound) produced by the bacterium Strep-tomyces pilosus. It is poorly absorbed after oral ad-ministration and is rapidly cleared; consequently, subcutaneous or intravenous administration is necessary. One molecule of deferoxamine binds a single atom of iron, forming a feroxamine com-plex that is virtually inert metabolically. Plasma iron chelated with deferoxamine is eliminated pre-dominantly by the kidneys. Hepatocytes efficiently take up deferoxamine, which then chelates hepato-cellular iron, with the feroxamine excreted in the bile. Within cells, deferoxamine is localized to ly-sosomes, where it induces autophagy of cytosolic ferritin. Lysosomal degradation of cytosolic ferritin releases iron that is bound by deferoxamine, and the chelated iron is then cleared from the cell.14

In contrast to deferoxamine, the synthetic che-lator deferasirox is well absorbed from the gastro-intestinal tract and is cleared from the circulation slowly.13,15 Two molecules of deferasirox are need-ed to bind a single atom of iron. Like deferox-amine, deferasirox forms complexes with plasma iron, but deferasirox–iron complexes are elimi-nated predominantly through a hepatobiliary route. Hepatocytes readily take up deferasirox, which chelates hepatocellular iron. The defera-sirox–iron complexes are then excreted in the bile.15 Within cells, deferasirox chelates cyto-solic iron, leading to ferritin degradation by the proteasome.14

A third iron chelator, the synthetic oral agent deferiprone (Ferriprox, Apotex; Kelfer, Cipla), is not approved for use in the United States or Canada. In the European Union and some other countries, it is approved specifically for patients with thalassemia major when deferoxamine is contraindicated or inadequate (Table 1).

CLINIC A L E V IDENCE

The use of deferoxamine therapy antedates the common use of randomized, controlled trials to establish the efficacy of medical treatments. Only one small, randomized trial has compared chela-tion plus deferoxamine with no therapy; this trial enrolled 20 children with β-thalassemia. After a mean of 5.8 years of treatment with intramuscu-

Figure 1 (see next two pages). Iron Supply and Storage in Sickle Cell Anemia with Long-Term Red-Cell Transfusion and Iron-Chelating Therapy.

In all four panels, the area of the red and blue circles is roughly proportional to the amount of iron in each pool, and the width of the arrows is roughly proportional to the daily magnitude of the iron flux. Panel A shows normal iron supply and storage in a healthy person without sickle cell disease (i.e., with hemoglobin A). The major pathway of internal iron exchange is a unidi-rectional flow from plasma transferrin to the erythroid marrow to circulating red cells to reticuloendothelial macrophages and back to plasma transferrin (orange arrows). In the circulating plasma, virtually all iron is bound to trans-ferrin. Panel B shows that in sickle cell anemia, hemolysis shortens the aver-age life span of the red cell from about 4 months to 5 or 6 weeks, increasing red-cell catabolism by reticuloendothelial macrophages and increasing iron delivery to the erythroid marrow by 6 to 8 times the normal rate. There is lit-tle ineffective erythropoiesis, and iron absorption from the gastrointestinal tract is not increased. Panel C shows that long-term red-cell transfusion de-creases erythroid marrow activity to 2 to 3 times the normal rate but results in accumulation of iron in reticuloendothelial macrophages and hepatocytes. Eventually, the capacity for safe storage is exceeded, with the appearance of plasma non–transferrin-bound iron (dashed arrow) and its progressive depo-sition in the heart and endocrine organs. In Panel D, the green arrows show that iron-chelating therapy with deferasirox can clear plasma non–transferrin-bound iron and remove excess iron from the liver, heart, and other organs, with subsequent excretion through the bile into the stool.

An interactive graphic is available at NEJM.org

Click here to access interactive graphic.





54



Erythroid marrow

Transferrin-bound iron

Muscle and other parenchymal cells

Hepatocytes

Reticuloendothelial macrophages


Erythroid marrow


Gastrointestinaltract

Hepatocytes

A Normal Iron Supply and Storage

B Sickle Cell Anemia

Functional iron

Storage iron Heart andendocrine organs


Heart andendocrine organs


Circulatingred cells

Circulatingred cells

l tiiCi

55



C

Circulating red cells

Erythroid marrow


Hepatocytes

D Sickle Cell Anemia with Transfusionand Iron-Chelating Therapy

Sickle Cell Anemia with Long-TermRed-Cell Transfusion

Circulating red cells



Non–transferrin-bound iron

Erythroid marrow


Hepatocytes

Transfusion

Transfusion


Heart andendocrine organs

Muscle and other parenchymal cellsHeart and

endocrine organs



Chelator-bound iron

Circullatingti

Circulatingti

56



lar deferoxamine, the mean hepatic iron concen-tration was 25.9 mg per gram of liver tissue (dry weight) in the deferoxamine group and 42.2 mg per gram in the control group.16 At 14 years, one death had occurred in the deferoxamine group and six deaths had occurred in the control group.17

In lieu of randomized trials, observational studies have investigated the effects of deferox-amine in the management of transfusion-related iron overload. One study involved 977 children with transfusion-dependent thalassemia major who survived beyond the first decade of life.18 Subsequent survival was examined according to 5-year birth cohorts beginning in 1960; deferox-amine was introduced in 1975. The survival rate increased progressively in each 5-year cohort (see Fig. 1 in the Supplementary Appendix, avail-able at NEJM.org). The survival rate was signifi-cantly higher among children born after 1975 than among those in previous cohorts.

Deferasirox has been compared with deferox-amine in a few short-term trials sponsored by Novartis.19-23 In the largest of these trials, 586 children with β-thalassemia were randomly as-signed to either agent, with dosing according to the baseline hepatic iron concentration.19 The pri-mary end point was the percentage of subjects with either a maintained or reduced hepatic iron concentration at 1 year; this end point was reached in 52.9% of patients assigned to de-ferasirox and in 66.4% of patients assigned to deferoxamine. This result, which did not meet a prespecified noninferiority target, was attributed to the relative underdosing of deferasirox. The total hepatic iron concentration decreased by a mean of 2.4 mg per gram (dry weight) in the deferasirox group and by 2.9 mg per gram in the deferoxamine group. No trial has established the long-term effectiveness of deferasirox in prevent-ing organ toxicity or improving survival.

Deferiprone has also been compared with de-feroxamine in several small, randomized trials.24 As is the case with deferasirox, no long-term trials have been performed to evaluate the effect of deferiprone on organ function or survival.

CLINIC A L USE

Iron-chelating therapy should be considered in all patients who require long-term red-cell trans-fusion. Such patients include those with sickle cell disease, myelodysplastic syndromes, thalas-semia major, Diamond–Blackfan anemia, aplastic

Tabl

e 1.

Iron

-Che

latin

g A

gent

s in

Clin

ical

Use

.

Var

iabl

eD

efer

oxam

ine

Def

eras

irox

Def

erip

rone

Che

lato

r-ir

on c

ompl

exH

exad

enta

te, 1

:1 c

ompl

exTr

iden

tate

, 2:1

com

plex

Bid

enta

te, 3

:1 c

ompl

ex

Usu

al d

ose

25–5

0 m

g/kg

/day

20–4

0 m

g/kg

/day

75–1

00 m

g/kg

/day

Adm

inis

trat

ion

Subc

utan

eous

or

intr

aven

ous,

8–1

0 hr

/day

, 5–

7 da

ys/w

kO

ral,

once

dai

lyO

ral,

thre

e tim

es d

aily

Plas

ma

half-

life

20–3

0 m

in8–

16 h

r2–

3 hr

Rou

te o

f elim

inat

ion

Bili

ary

and

urin

ary

Pred

omin

antly

bili

ary

Pred

omin

antly

uri

nary

Reg

ulat

ory

appr

oval

App

rove

d in

Uni

ted

Stat

es, C

anad

a, E

urop

e,

and

othe

r co

untr

ies

App

rove

d in

Uni

ted

Stat

es, C

anad

a, E

urop

e,

and

othe

r co

untr

ies

Not

app

rove

d in

Uni

ted

Stat

es o

r C

anad

a; a

ppro

ved

in

Euro

pe11 a

nd o

ther

cou

ntri

es

Indi

catio

nTr

ansf

usio

nal i

ron

over

load

Tran

sfus

iona

l iro

n ov

erlo

adTr

ansf

usio

nal i

ron

over

load

in p

atie

nts

with

thal

asse

mia

m

ajor

, whe

n de

fero

xam

ine

ther

apy

is c

ontr

aind

icat

ed

or in

adeq

uate

Adv

erse

effe

cts

Irri

tatio

n at

the

infu

sion

site

, ocu

lar

and

audi

tory

di

stur

banc

es, g

row

th r

etar

datio

n an

d sk

elet

al

chan

ges,

alle

rgy,

resp

irato

ry d

istr

ess

synd

rom

e w

ith h

ighe

r-th

an-r

ecom

men

ded

dose

s12

Gas

troi

ntes

tinal

dis

turb

ance

s, r

ash,

incr

ease

in

seru

m c

reat

inin

e le

vel;

pote

ntia

lly fa

tal r

enal

an

d he

patic

impa

irm

ent o

r fa

ilure

, gas

tro-

inte

stin

al h

emor

rhag

e13

Agr

anul

ocyt

osis

and

neu

trop

enia

; gas

troi

ntes

tinal

dis

tur-

banc

es, a

rthr

opat

hy, i

ncre

ased

live

r-en

zym

e le

vels

, low

pl

asm

a zi

nc le

vel,

prog

ress

ion

of h

epat

ic fi

bros

is a

sso-

ciat

ed w

ith in

crea

se in

iron

ove

rloa

d or

hep

atiti

s C

11

57



anemia, and other congenital and acquired forms of refractory anemia.

There are alternatives to chelation in some patients. Some of the underlying disorders re-quiring transfusion may be cured by hematopoi-etic stem-cell transplantation. In some patients with sickle cell disease, exchange transfusion may reduce or obviate the need for iron chelation. In-frequently, phlebotomy may be an option for the removal of excess iron in the event of cure or re-mission of a refractory anemia. Iron-chelating therapy itself may sometimes decrease or elimi-nate the need for transfusion in patients with my-elodysplasia25 or myelofibrosis. Chelation therapy may not be needed in patients with myelodyspla-sia or other acquired refractory anemias who have an estimated survival of less than 1 year.26

With the exception of these groups, iron-chelating therapy is indicated in almost all pa-tients requiring long-term red-cell transfusion. Iron chelation is contraindicated in patients who are hypersensitive to the chelating agent or ex-cipients in the chelator formulation, and it re-quires specialized management in patients with several renal disease or anuria. Chelators should be avoided or used with great caution in patients who are pregnant or breast-feeding.

Ideally, iron-chelating therapy should be initi-ated prophylactically, before clinically significant iron accumulation has occurred. Treatment should begin when patients have received between 10 and 20 red-cell transfusions. Patients who have already undergone repeated transfusion without sufficient chelation can also be successfully treated, but they may require more intensive regimens (see below).

Evaluation of the patient before the initiation or adjustment of iron-chelating therapy includes a detailed characterization of the underlying dis-order, with thorough documentation of the his-tory of transfusion and chelation; determination of the body iron load by measurement of the hepatic iron and serum ferritin concentrations; estimation of the rate of transfusional iron load-ing; and assessment of cardiac iron deposition. The techniques for assessing cardiac iron over-load, transfusional iron loading, and body iron burden are described in the Supplementary Ap-pendix. The extent of any existing iron-induced hepatic, cardiac, or endocrine dysfunction should be established, and in children and adolescents, growth and maturation should be assessed. Nu-tritional evaluation with correction of deficien-cies is recommended.27

In the United States and Canada, the choice of an iron chelator for transfusional iron over-load is either parenteral deferoxamine or oral deferasirox. The decision is best made with the patient and, if the patient is a child, with his or her parents. Despite the lack of data on long-term effectiveness, most patients now opt for deferasirox because of the ease of oral adminis-tration. Deferasirox is preferred for prophylactic or maintenance therapy. Deferoxamine, which has been proved to reverse iron-induced heart disease and increase long-term survival,28 may be indicated if deferasirox is ineffective in a par-ticular patient, and it may be favored for severe iron overload, especially with cardiac involvement. Conversely, deferasirox may be the better choice in patients who are unable to tolerate subcutane-ous infusions of deferoxamine. Deferasirox also may be substituted for deferoxamine after suc-cessful clearance of cardiac iron. Deferiprone is available in the United States on a compassion-ate-use basis, usually in combination with defer-oxamine, in patients in whom iron-induced heart failure has developed or who are at high risk for the development of heart failure.29,30

Deferoxamine is administered subcutaneously or intravenously, usually with a portable pump, for 8 to 10 hours each day, 5 to 7 days per week. Subcutaneous administration is preferred except in patients with severe cardiac iron deposition, for whom continuous intravenous deferoxamine ther-apy is recommended.28,31 Deferasirox is adminis-tered orally once daily, and deferiprone is admin-istered orally three times daily.

The dose of an iron-chelating agent is deter-mined by three principal factors: the presence or absence of cardiac iron overload, the rate of transfusional iron loading, and the body iron burden (see the Supplementary Appendix and Table 2). In brief, if cardiac iron overload is pres-ent, ridding the heart of the excess iron becomes the critical therapeutic goal. In the absence of cardiac iron overload, the long-term objective is to maintain the body iron at a level that permits safe storage while avoiding chelator toxicity. The greater the rate of transfusional iron loading, the greater the dose of an iron chelator that will be needed to control the accumulation of iron.

During treatment, tests to monitor chelator-associated toxicity should be performed, depend-ing on the potential adverse effects of the specific agent to be used (see Table 1 and the Adverse Effects section below). In patients who receive

58



Tabl

e 2.

Usu

al D

oses

of D

efer

oxam

ine

or D

efer

asir

ox fo

r Tr

ansf

usio

nal I

ron

Ove

rloa

d.*

Hep

atic

Iro

n C

once

ntra

tion

No

Car

diac

Iro

n O

verl

oad

(T2*

, ≥20

mse

c)C

ardi

ac I

ron

Ove

rloa

d (T

2*, <

20 m

sec)

Dai

ly T

rans

fusi

onal

Iron

Inta

keM

ild to

Mod

erat

eSe

vere

<0.3

mg/

kg o

f bod

y w

eigh

t0.

3 to

0.5

mg/

kg o

f bod

y w

eigh

t>0

.5 m

g/kg

of b

ody

wei

ght

T 2*,

10

to <

20 m

sec

T 2*,

<10

mse

c

≥15

mg/

g, d

ry w

eigh

tD

efer

oxam

ine:

40–

50 m

g/kg

/da

y, 8

to 1

0 hr

/day

, 6 o

r 7

days

/wk,

by

subc

utan

eous

in

fusi

on; d

efer

asir

ox: o

ral

dose

of 3

0–40

mg/

kg d

aily

Def

erox

amin

e: 4

0–50

mg/

kg/

day,

8 to

10

hr/d

ay, 6

or

7 da

ys/w

k, b

y su

bcut

aneo

us

infu

sion

; def

eras

irox

: ora

l do

se o

f 30–

40 m

g/kg

dai

ly

Def

erox

amin

e: 4

0–50

mg/

kg/

day,

8 to

10

hr/d

ay, 6

or

7 da

ys/w

k, b

y su

bcut

aneo

us

infu

sion

; def

eras

irox

: ora

l do

se o

f 30–

40 m

g/kg

dai

ly

Def

erox

amin

e: 5

0 m

g/kg

/day

by

con

tinuo

us in

trav

enou

s in

fusi

on28; d

efer

asir

ox: o

ral

dose

of 4

0 m

g/kg

dai

ly, b

ut

unce

rtai

n ef

ficac

y in

red

uc-

ing

card

iac

iron

Def

erox

amin

e: 5

0 m

g/kg

/day

by

con

tinuo

us in

trav

enou

s in

fusi

on28; d

efer

asir

ox: o

ral

dose

of 4

0 m

g/kg

dai

ly, b

ut

unce

rtai

n ef

ficac

y in

red

uc-

ing

card

iac

iron

7 to

<15

mg/

g, d

ry

wei

ght

Def

erox

amin

e: 3

0–40

mg/

kg/

day,

8 to

10

hr/d

ay, 5

day

s/w

k, b

y su

bcut

aneo

us in

fu-

sion

; def

eras

irox

: ora

l dos

e of

20–

30 m

g/kg

dai

ly

Def

erox

amin

e: 4

0–50

mg/

kg/

day,

8 to

10

hr/d

ay, 6

or

7 da

ys/w

k, b

y su

bcut

aneo

us

infu

sion

; def

eras

irox

: ora

l do

se o

f 30–

40 m

g/kg

dai

ly

Def

erox

amin

e: 4

0–50

mg/

kg/

day,

8 to

10

hr/d

ay, 6

or

7 da

ys/w

k, b

y su

bcut

aneo

us

infu

sion

; def

eras

irox

: ora

l do

se o

f 30–

40 m

g/kg

dai

ly

Def

erox

amin

e: 4

0–50

mg/

kg/

day,

8 to

10

hr/d

ay, 6

or

7 da

ys/w

k, b

y su

bcut

aneo

us

infu

sion

; def

eras

irox

: ora

l do

se o

f 30–

40 m

g/kg

dai

ly

Def

erox

amin

e: 4

0–50

mg/

kg/

day

by c

ontin

uous

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59



deferoxamine, these tests include annual assess-ments of auditory function and vision. In patients who receive deferasirox, serum creatinine, serum aminotransferases, and bilirubin levels and com-plete blood counts should be assessed monthly. In patients who receive deferiprone, weekly as-sessment of complete blood counts and monthly assessments of serum aminotransferases should be performed.

The effectiveness of iron-chelating therapy is best monitored by periodic measurements of car-diac iron concentrations by magnetic resonance imaging (MRI), of cardiac function, and of he-patic iron concentrations and by review of the actual rate of transfusional iron loading once or twice a year, depending on the severity of the iron overload (see the Supplementary Appendix). Dose adjustments can be made according to the guidelines in Table 2. Serum ferritin concentra-tions are usually measured at least quarterly. As at baseline, hepatic, cardiac, and endocrine function should be assessed periodically along with nutritional status, and, in children and adolescents, growth and maturation should be monitored.

In the United States, on the basis of 2006 wholesale acquisition prices, the annual costs of deferoxamine for iron-chelating therapy have been estimated to range from $6,824 to $29,209, plus $9,286 for infusion, and the estimated annual costs of deferasirox range from $24,404 to $53,095, with the actual cost depending on dose and body weight.7 Administration of a chelator will be needed as long as transfusion is continued and will be lifelong in most patients.

A DV ER SE EFFEC T S

Discomfort or pain at the site of subcutaneous infusion develops in almost all patients treated with subcutaneous deferoxamine, and induration or erythema develops in some patients. These symptoms can often be mitigated with topical anesthetic or glucocorticoid creams. Visual and auditory toxicity associated with deferoxamine has been reported, and in one series involving 89 patients treated with this agent, 13 presented with vision loss, deafness, or both.33 Subsequent stud-ies suggest a much lower incidence of toxicity,34 and these risks can be minimized by not exceed-ing doses of 50 mg per kilogram of body weight in patients with iron overload and by decreasing

the dose as the hepatic iron concentration ap-proaches normal levels. Although treatment with deferoxamine may reduce endocrine complica-tions of iron overload, such as a delay of puberty, the chelator itself can interfere with growth,35 apparently as a result of skeletal dysplasia.36 To minimize this effect, the dose of deferoxamine in young children should not exceed 25 to 30 mg per kilogram.37

In the registration trial of deferasirox de-scribed above,19 gastrointestinal disturbances occurred in approximately 15% of patients, rash in 11%, and increases in serum creatinine levels in 38%. Similar rates have been observed in subsequent trials.20-22 In January 2010, on the basis of postmarketing studies, the Food and Drug Administration required a change in the prescribing information for deferasirox. The new information states that the drug could cause potentially fatal renal and hepatic impairment or failure as well as gastrointestinal hemorrhage.13 These adverse effects were reported to occur more frequently in older patients and in patients with high-risk myelodysplastic syndromes, throm-bocytopenia, or underlying renal or hepatic im-pairment.

The most common adverse effects of deferi-prone are diarrhea and gastrointestinal effects, arthropathy (including severe arthritis with clin-ically significant disability), increased levels of serum liver enzymes, and progression of hepatic fibrosis associated with an increase in iron over-load or hepatitis C.11 The most serious adverse effects are agranulocytosis (incidence, 1.1%) and neutropenia (incidence, 4.9%); weekly monitor-ing of the neutrophil count is recommended. Neurologic abnormalities have been reported with higher-than-recommended doses of deferi-prone.38


Several areas of uncertainty exist with regard to the optimal approach to iron-chelating therapy. First, a variety of binary combinations of chelat-ing agents are being examined in off-label uses, with either synchronous or sequential adminis-tration. The clinical usefulness of such combina-tion therapies is unclear at present, in the ab-sence of unequivocal evidence of the superiority of any specific combination over treatment with a single agent.24

60



Second, MRI performed to evaluate the iron content of the liver, heart, and other organs has become the method of choice for guiding iron-chelating therapy, but calibrated methods are not available for all patients. A 1-year study of de-ferasirox involving patients with various types of anemias used an alternative approach; the inves-tigators based the initial dose on the rate of transfusional iron loading and subsequently ad-justed the dose according to measurements of serum ferritin levels and safety markers.23 The long-term efficacy and safety of this strategy are uncertain.

Third, in patients with myelodysplastic syn-dromes who have undergone long-term transfu-sion and for whom prolonged survival is antici-pated, iron-chelating therapy may be appropriate. In individual patients, the benefit of such treat-ment may vary, given the morbidity associated with chelation, the variable prognosis for the underlying disorder, and the latency period be-tween the onset of the transfusion and the de-velopment of clinical manifestations of iron overload. Data are lacking from prospective, randomized trials examining the clinical cir-cumstances in which morbidity and mortality improve with iron-chelating therapy in these patients39; one such trial is currently recruiting patients.40

Fourth, there is evidence to suggest that iron overload is associated with lower rates of cardio-myopathy, endocrinopathy, and other conditions among patients with sickle cell disease than among patients with thalassemia.41 The effects of the systemic inflammatory state on iron han-dling in patients with sickle cell disease,42 as well as differences in the rate and duration of transfusion and in the age of the patient at the initiation of long-term transfusion, the extent of ineffective erythropoiesis, and gastrointestinal iron absorption, may be involved. It is unclear whether these data provide sufficient grounds to recommend a higher body iron threshold for chelation therapy in patients with sickle cell disease, especially given the potential risks of iron-induced liver disease.

Finally, there is a lack of certainty with respect to the optimal hepatic iron concentrations (Table 2) for minimizing the risk that hepatic fibrosis will progress to cirrhosis and its ultimate compli-cation, hepatocellular carcinoma.43,44

Guidelines

Guidelines and consensus statements on the man-agement of sickle cell disease,45,46 thalasse-mia,32,47 Diamond–Blackfan anemia,48 aplastic anemia,49 and myelodysplastic syndromes26,50 all include recommendations for iron-chelating therapy for transfusional iron overload. All these guidelines are generally consistent with the ap-proach outlined in this review, although there are variations in the individual recommenda-tions, depending in part on the year of publica-tion and the specific underlying disorder. For example, the guidelines for iron chelation in thalassemia32,47 generally endorse measurement of serum ferritin levels as a useful way to moni-tor iron overload, whereas the guidelines for the management of sickle cell disease45,46 emphasize that ferritin levels can be altered by liver disease and inflammation. The guidelines on the man-agement of thalassemia by the Italian Society of Hematology47 endorse deferoxamine as first-line therapy over the oral chelators, whereas most of the other guidelines do not state an explicit pref-erence in this regard.

R ecommendations

After discussing the need for iron-chelating ther-apy with the patient and his family, I would de-scribe the advantages and disadvantages of sub-cutaneous deferoxamine and oral deferasirox so that a genuinely informed decision can be made. At present, the most frequent choice is oral de-ferasirox. Before the initiation of treatment, I would obtain information about the number of previous transfusions and the rate of ongoing transfusion and would arrange for cardiac T2* and hepatic transverse relaxation rate (R2) mea-surements, an MRI evaluation of cardiac function, and echocardiographic and electrocardiographic studies. Auditory and ophthalmic testing, includ-ing slit-lamp examination and dilated-fundus ex-amination, should be performed. Laboratory tests should include a complete blood count with a differential count and measurement of serum creatinine, serum aminotransferases, bilirubin levels, and iron indexes. After transfusion of a total of 10 to 20 units of blood, or with the he-patic iron concentration between 3 and 7 mg per gram, I would administer once-daily oral therapy

61



with deferasirox at a dose of 20 mg per kilogram. With good support and careful monitoring, this regimen, adjusted as needed, should provide long-term protection against the complications of transfusional iron overload in this patient.

Supported by grants from the St. Giles Foundation, the Food

and Drug Administration (R01 FD003702), and the National In-stitutes of Health (R37 DK049108; R01 DK066251).

Dr. Brittenham reports that his institution filed a patent application in April 2010 for a rapid MRI method. No other potential conflict of interest relevant to this article was re-ported.


References

1. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfu-sions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5-11.2. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF. Changes in the epide-miology of thalassemia in North Ameri-ca: a new minority disease. Pediatrics 2005;116(6):e818-e825.3. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010;115:4331-6.4. Weatherall DJ, Clegg JB. The thalas-semia syndromes. 4th ed. Oxford, Eng-land: Blackwell Science, 2001.5. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Circum-stances of death in adult sickle cell disease patients. Am J Hematol 2006;81:858-63.6. Finch CA, Lee MY, Leonard JM. Con-tinuous RBC transfusions in a patient with sickle cell disease. Arch Intern Med 1982;142:279-82.7. Delea TE, Sofrygin O, Thomas SK, Baladi JF, Phatak PD, Coates TD. Cost ef-fectiveness of once-daily oral chelation therapy with deferasirox versus infusional deferoxamine in transfusion-dependent thalassaemia patients: US healthcare sys-tem perspective. Pharmacoeconomics 2007;25:329-42.8. Delea TE, Edelsberg J, Sofrygin O, et al. Consequences and costs of noncompli-ance with iron chelation therapy in pa-tients with transfusion-dependent thalas-semia: a literature review. Transfusion 2007;47:1919-29.9. Fillet G, Beguin Y, Baldelli L. Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation. Blood 1989;74:844-51.10. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci 2000;23:185-92.11. European Medicines Agency. Ferriprox (deferiprone): summary of product charac-teristics. European public assessment report 2009, rev. ed. 14. (http://www.ema.europa.eu/humandocs/Humans/EPAR/ferriprox/ferriprox.htm.)12. Novartis Pharmaceuticals. Desferal (deferoxamine mesylate) prescribing infor-mation. 2010. (http://www.desferal.com.)13. Novartis Pharmaceuticals. Exjade (de-

ferasirox) prescribing information. 2010. (http://www.exjade.com.)14. De Domenico I, Ward DM, Kaplan J. Specific iron chelators determine the route of ferritin degradation. Blood 2009;114:4546-51.15. Waldmeier F, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalas-semic patients with transfusion-depen-dent iron overload who are at pharmaco-kinetic steady state. Drug Metab Dispos 2010;38:808-16.16. Barry M, Flynn DM, Letsky EA, Ris-don RA. Long-term chelation therapy in thalassaemia major: effect on liver iron concentration, liver histology, and clini-cal progress. BMJ 1974;2:16-20.17. Modell B, Letsky EA, Flynn DM, Peto R, Weatherall DJ. Survival and desferriox-amine in thalassaemia major. Br Med J (Clin Res Ed) 1982;284:1081-4.18. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complica-tions in patients with thalassemia major treated with transfusion and deferox-amine. Haematologica 2004;89:1187-93.19. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006;107:3455-62.20. Piga A, Galanello R, Forni GL, et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haema-tologica 2006;91:873-80.21. Porter J, Galanello R, Saglio G, et al. Relative response of patients with myelo-dysplastic syndromes and other transfu-sion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008;80:168-76.22. Vichinsky E, Onyekwere O, Porter J, et al. A randomised comparison of defera-sirox versus deferoxamine for the treat-ment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501-8.23. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Hae-matologica 2010;95:557-66.24. Roberts DJ, Brunskill SJ, Doree C,

Williams S, Howard J, Hyde CJ. Oral de-feriprone for iron chelation in people with thalassaemia. Cochrane Database Syst Rev 2007;3:CD004839.25. Jensen PD, Heickendorff L, Pedersen B, et al. The effect of iron chelation on haemopoiesis in MDS patients with trans-fusional iron overload. Br J Haematol 1996;94:288-99.26. Gattermann N. Overview of guide-lines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hema-tol 2008;88:24-9.27. Claster S, Wood JC, Noetzli L, et al. Nutritional deficiencies in iron overload-ed patients with hemoglobinopathies. Am J Hematol 2009;84:344-8.28. Davis BA, Porter JB. Long-term out-come of continuous 24-hour deferoxamine infusion via indwelling intravenous cathe-ters in high-risk beta-thalassemia. Blood 2000;95:1229-36.29. Cohen AR. Compassionate use of de-feriprone for patients with thalassemia and iron-induced heart disease. (ClinicalTrials.gov identifier no. NCT00293098.) (http://www.clinicaltrials.gov/ct2/show/NCT00293098?term=deferiprone+thalassemia&rank=2.)30. Borgna-Pignatti C, Cappellini MD, De Stefano P, et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 2006;107:3733-7.31. Anderson LJ, Westwood MA, Holden S, et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospec-tive study using T2* cardiovascular mag-netic resonance. Br J Haematol 2004;127:348-55.32. Iron overload. In: Cappellini MD, Co-hen A, Eleftheriou A, Piga A, Porter J, Taher A. Guidelines for the clinical man-agement of thalassemia. 2nd ed. rev. Nicosia, Cyprus: Thalassaemia Interna-tional Federation, November 2008:33-63.33. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in pa-tients receiving subcutaneous deferox-amine infusions. N Engl J Med 1986;314:869-73.34. Cohen A, Martin M, Mizanin J, Kon-kle DF, Schwartz E. Vision and hearing during deferoxamine therapy. J Pediatr 1990;117:326-30.35. De Sanctis V, Roos M, Gasser T, et al.

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Impact of long-term iron chelation thera-py on growth and endocrine functions in thalassemia. J Pediatr Endocrinol Metab 2006;19:471-80.36. Chan YL, Pang LM, Chik KW, et al. Patterns of bone diseases in transfusion-dependent homozygous thalassemia ma-jor: predominance of osteoporosis and desferrioxamine-induced bone dysplasia. Pediatr Radiol 2002;32:492-7.37. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997;89:739-61. [Er-ratum, Blood 1997;89:2621.]38. Beau-Salinas F, Guitteny MA, Dona-dieu J, Jonville-Bera AP, Autret-Leca E. High doses of deferiprone may be associ-ated with cerebellar syndrome. BMJ 2009;338:a2319.39. Leitch HA. Controversies surround-ing iron chelation therapy for MDS. Blood Rev 2010 October 26 (Epub ahead of print).40. Novartis Pharmaceuticals. Myelodys-plastic syndromes (MDS) event free sur-vival with iron chelation therapy study

(TELESTO). (ClinicalTrials.gov identifier no. NCT00940602.) (http://www.clinicaltrials.gov/ct2/show/NCT00940602?term=telesto&rank=1.)41. Vichinsky E, Butensky E, Fung E, et al. Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol 2005;80:70-4.42. Walter PB, Fung EB, Killilea DW, et al. Oxidative stress and inflammation in iron-overloaded patients with beta-thal-assaemia or sickle cell disease. Br J Hae-matol 2006;135:254-63.43. Borgna-Pignatti C, Vergine G, Lom-bardo T, et al. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Hae-matol 2004;124:114-7.44. Ko C, Siddaiah N, Berger J, et al. Prev-alence of hepatic iron overload and asso-ciation with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007;27:1394-401.45. Division of Blood Diseases and Re-sources NHLBI. The management of sick-le cell disease. Bethesda, MD: National

Heart, Lung, and Blood Institute, 2002. (http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf.)46. Standards for the clinical care of adults with sickle cell disease in the UK. London: Sickle Cell Society, 2008. (http://www.sicklecellsociety.org/pdf/CareBook.pdf.)47. Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008;93:741-52.48. Vlachos A, Ball S, Dahl N, et al. Diag-nosing and treating Diamond Blackfan anaemia: results of an international clini-cal consensus conference. Br J Haematol 2008;142:859-76.49. Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and manage-ment of aplastic anaemia. Br J Haematol 2009;147:43-70.50. Bennett JM. Consensus statement on iron overload in myelodysplastic syn-dromes. Am J Hematol 2008;83:858-61.Copyright © 2011 Massachusetts Medical Society.

SPECIALTIES AND TOPICS AT NEJM.ORG

Specialty pages at the Journal’s Web site (NEJM.org) feature articles in cardiology, endocrinology, genetics, infectious disease, nephrology, pediatrics, and many other medical specialties. These pages, along with collections of articles on clinical and nonclinical topics, offer links to interactive and multimedia content and feature recently published articles as well as material from the NEJM archive (1812–1989).

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the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.

Bisphosphonates for OsteoporosisMurray J. Favus, M.D.

From the Department of Medicine, Uni-versity of Chicago, Chicago. Address re-print requests to Dr. Favus at the Depart-ment of Medicine, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, or at [email protected].


A 67-year-old woman was referred by her primary care physician for treatment of os-teoporosis and progressive bone loss. One year before the visit, the patient had dis-continued hormone-replacement therapy. She had subsequently begun to experience midback pain and lost 3.8 cm (1.5 in.) in height. A dual-energy x-ray absorptiometry (DXA) scan showed bone mineral density T scores of −3.1 at the lumbar spine and −2.8 at the femoral neck, which are consistent with a diagnosis of osteoporosis. One year later, a second scan showed a further decrease of 5.4% in bone mineral density at the lumbar spine (Fig. 1), as well as a compression fracture of the 11th thoracic vertebra (Fig. 2). Results of blood and urine tests ruled out the common secondary causes of osteoporosis. To prevent additional vertebral fractures, oral bisphosphonate therapy was recommended.


Osteoporosis is a systemic skeletal disorder that is characterized by the loss of bone tissue, disruption of bone architecture, and bone fragility, leading to an increased risk of fractures.1 Bone loss and low bone mass are asymptomatic until fractures occur. Estrogen deficiency after menopause is the most common cause of osteopo-rosis, but secondary causes2 must be ruled out before treatment is undertaken (Table 1).

Osteoporosis is the most common metabolic bone disease and the most common cause of fractures in older adults in the United States. Ten million people in the United States have osteoporosis, and an additional 33 million people have low bone mass (osteopenia) and are at increased risk for fractures.4,5 More than 2 million fractures occur each year as a result of osteoporosis or osteopenia, including 300,000 hip fractures, 547,000 vertebral fractures, and 135,000 pelvic fractures. Post-menopausal white women have a 40% lifetime risk of at least one osteoporotic fracture.4

Osteoporotic hip fractures are associated with the highest morbidity and mor-tality. Up to 50% of patients with such fractures have permanently impaired mobil-ity, and 25% lose the skills necessary to live independently.6,7 A recent meta-analysis showed that among older men and women, the rate of death from any cause is increased by a factor of 5 to 8 during the first 3 months after a hip fracture.8

Pathoph ysiol ogy a nd Effec t of Ther a py

Estrogen deficiency due to either spontaneous or surgical menopause9 increases the production by bone marrow stromal cells and osteoblasts of the receptor activator of nuclear factor κB ligand (RANKL), which, in turn, increases the binding of RANKL10 to the osteoclast cell-surface receptor nuclear factor κB (RANK). Increased

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n engl j med 363;21 nejm.org november 18, 20102028

binding of RANKL to RANK initiates the prolif-eration of osteoclast precursors and their differ-entiation into mature osteoclasts.10-12 The expand-ed osteoclast population increases bone turnover and the depth and number of resorption pits (Fig. 3). Later in the course of menopause, age-related bone loss and accompanying changes in the properties of bone material exacerbate the bone loss and fragility associated with estrogen deficiency.10 At the microscopical level, the in-creased number and activity of osteoclasts disrupt trabecular connectivity and increase cortical po-rosity.9,11 Resorption pits are incompletely filled, since osteoblastic new bone formation does not keep pace with rates of bone resorption.10 Re-duced bone density and bone quality compromise the mechanical weight-bearing properties of the skeleton and confer a predisposition to fractures occurring either spontaneously or when falls cause mechanical overload.11

Bisphosphonates reduce fractures by suppress-ing bone resorption.12,13 The m olecular structure of the bisphosphonates (P-C-P) is analogous to that of the naturally occurring pyrophosphates (P-O-P), with two short side chains (R1 and R2) attached to the C core.

The R1 side chain determines bone-binding af-finity, and the R2 side chain determines antire-sorption potency. Bisphosphonates that are ap-proved for use in the United States (alendronate, ibandronate, risedronate, and zoledronate) have nitrogen-containing R2 side chains14 that en-hance antiresorptive and antifracture potency. Variations in the structure of the side chains deter-mine the strength with which the biphospho-nate binds to bone, the distribution through bone, and the amount of time it remains in the bone after treatment is discontinued.15

In bone, bisphosphonates accumulate in the hydroxyapatite mineral phase, and the concentra-tion of the bisphosphonates is increased by a factor of 8 at sites of active bone resorption.14,16,17 The bound nitrogen-containing bisphosphonates en-ter osteoclasts and reduce resorption through inhi-

bition of farnesyl pyrophosphate synthase (FPPS), an enzyme in the mevalonate-to-cholesterol path-way.18,19 Inhibition of FPPS interferes with iso-prenylation of small guanosine triphosphatases (GTPases) at the ruffled border of the osteoclasts and disrupts the attachment of osteoclasts to the bone surface, which stops resorption and pro-motes early cell death.16,20

Clinic a l E v idence

Three of the most important phase 3 trials of the use of bisphosphonates for the treatment of os-teoporosis are described below. In these trials, a reduction in the rate of fractures was the primary end point, and increases in bone mineral density at the lumbar spine and a reduction in markers of bone turnover were secondary end points.

In the Fracture Intervention Trial (FIT),21 2027 postmenopausal women at high risk for fracture, with low bone density at the femoral neck and at least one vertebral fracture, were randomly as-signed to either placebo or alendronate, at a dose of 5 mg daily for 24 months, followed by 10 mg daily for the final 12 months of the trial. At 36 months, 15.0% of the women who received the placebo and 8.0% of the women who were treated with alendronate had sustained one or more new vertebral fractures, as assessed by radiography (P = 0.001). New hip fractures occurred in 2.1% of the women in the placebo group and 1.1% of the women in the alendronate group (P = 0.05).

In the Vertebral Efficacy with Risedronate Therapy (VERT) trial,22 2458 postmenopausal women with at least one vertebral fracture and a T score at the lumbar spine of –2.0 or less were randomly assigned to either placebo or risedro-nate at a dose of 2.5 mg or 5 mg daily. During the course of the trial, data from other studies sug-gested that a dose of 2.5 mg was less effective than a dose of 5 mg; therefore the 2.5-mg group was discontinued. In the two remaining groups, the rate of new vertebral fractures after 3 years was 11.3% among subjects treated with 5 mg of risedronate daily, as compared with 16.3% in the placebo group (P = 0.003). In a subsequent trial, risedronate was shown to be effective in reducing the rate of hip fractures as well.23

The efficacy of zoledronic acid in the treatment of osteoporosis was evaluated in the Health Out-comes and Reduced Incidence with Zoledronic Acid Once Yearly trial (HORIZON; ClinicalTrials.gov number, NCT00049829).24 In this trial,

Bisphosphonates Pyrophosphates

O O

COH

OH OH

OHP P

R1

R2

O O

OOH

OH OH

OHP P

65



7765 postmenopausal women with osteoporosis (T score of –2.5 or less or –1.5 or less with evi-dence of vertebral fracture) were randomly as-signed to either zoledronic acid, at a dose of 5 mg administered at baseline, 12 months, and 24 months, or placebo. At 36 months, the absolute rate of new vertebral fractures as assessed by stan-dard radiography was 3.3% in the zoledronic acid group, as compared with 10.9% in the placebo group (P<0.001). There were 52 new hip fractures (1.4%) in the zoledronic acid group, as compared with 88 (2.5%) in the placebo group (P<0.001).

Randomized, placebo-controlled trials of other oral bisphosphonates, including ibandronate,25 clodronate,26 and etidronate,27 have shown that these drugs also have efficacy in reducing the risk of new vertebral fractures. However, because these

trials were not powered to show efficacy for the treatment of hip fractures, the clinical usefulness of these agents for preventing hip fractures is currently unknown. Pamidronate has been used to treat a variety of bone diseases in children and adults. However, no randomized, placebo-con-trolled trial has been performed with sufficient power to assess the efficacy of the drug for the treatment of hip fracture in women with post-menopausal osteoporosis.

Clinic a l Use

All postmenopausal women with measurements of bone mineral density at either the spine or the hip that meet World Health Organization (WHO) criteria for osteoporosis (T score of less than −2.5)

BM

D (g

/cm

2 )

Youn

g-A

dult

T Sc

ore

1.44

1.19

1.32

1.07

0.95

0.70

0.58

0.82

0.00

2

0

1

−1

−2

−4

−3

−5

0 20 30 40 50 60 70 80 90 100

Age (yr)

Reference: L1–L4Anteroposterior Spine Bone Density

Cha

nge

from

Bas

elin

e (%

)

2

0

1

−1

−2

−4

−5

−3

−60 65 66 67

Age (yr)

L1L2L3L4L1–L4

Region

0.8050.7430.7060.7860.758

BMDg/cm2

Young-Adult

7161596664

%

−2.7−3.9−4.1−3.4−3.5

T scoreAge-Matched

8170677573

%

−1.5−2.7−2.9−2.2−2.3

z score

04/13/200505/14/2004

Date Measured

66.765.8

Ageyr

0.7580.798

BMDg/cm2

Change fromBaseline

−4.9Baseline

%

−5.4Baseline

%/yr

Normal

Osteopenia

Osteoporosis

A B

Trend: L1–L4C

Figure 1. Dual-Energy X-Ray Absorptiometry (DXA) Scan of the Lumbar Spine.

Bone mineral density (BMD) was measured with the use of DXA in the 67-year-old woman described in the vignette (Panel A). The wom-an’s BMD is analyzed from lumbar spine L1 through L4 (Panel B). The BMD (rectangle) meets World Health Organization criteria for os-teoporosis (T score of less than −2.5), as shown in the reference graph. The T score is the standard-deviation change in BMD from the theoretical peak bone mass this woman had in her mid-20s to the current BMD. The z score is the standard-deviation difference be-tween the mean BMD of a population matched for age, race, and sex and the patient’s current BMD. The current study (Panel C) shows that her BMD (solid rectangle) is 5.4% lower than that indicated by the previous scan (open rectangle). A clinically significant change is a change of more than 2.8%.

66



should receive long-term therapy with an agent that has been proven to prevent fractures. In con-trast, it may be difficult to decide whom to treat among the large number of patients who have os-teopenia (T score of −1.0 to −2.5). Many postmeno-pausal women in whom fractures develop have osteopenia rather than osteoporosis; in these wom-en, the fractures may occur because of the contri-butions of risk factors that are independent of bone mineral density.28 I often use the WHO Fracture Risk Assessment Tool (FRAX; www.sheffield.ac.uk/FRAX/) to assist in making treatment deci-sions. FRAX is a calculator algorithm that incor-porates risk factors with measurements of bone mineral density, generating a quantitative esti-mate of the 10-year probability of a major osteo-porotic fracture (hip, vertebral, humerus, or fore-

arm) or of a hip fracture alone in patients who have not yet begun therapy. In general, I initiate pharmacologic treatment in patients who have a 10-year probability of a hip fracture that exceeds 3% or a 10-year probability of a major osteopo-rotic fracture that exceeds 20%.29

In addition to weighing the objective evidence, I consider the patient’s lifestyle. I am more likely to initiate treatment for low bone mass in a pa-tient who wishes to continue participating in sports or recreational activities such as cycling, tennis, skiing, and running. Such patients are likely to have a greater risk of falls and fractures than are sedentary patients.

A major consideration in selecting therapy is the risk of hip fracture. All treatments that have been approved by the Food and Drug Administra-tion (FDA) have shown efficacy in reducing the rates of vertebral fracture, but not all have been clearly shown to reduce the rate of hip fractures. If bone mineral density at the hip is low, I usu-ally select an agent for which there are trials showing efficacy in preventing hip fractures. I recommend either alendronate or risedronate if the patient is capable of taking an oral agent. If the patient cannot tolerate oral bisphosphonates, then I may select intravenous zoledronic acid. If bone density at the hip is normal or only mildly reduced, I may select oral or intravenous ibandro-nate, which has not been shown to be effective in reducing the risk of hip fracture.

Alternatives to bisphosphonates include the anabolic agent teriparatide (parathyroid hormone 1-34), which reduces the risk of vertebral and non-vertebral fractures but, among subjects in a large, pivotal trial, did not reduce the risk of hip frac-ture alone.30 Teriparatide is also more expensive than the bisphosphonates and requires daily sub-cutaneous injection. Estrogen is effective in de-creasing the risk of vertebral and hip fractures in postmenopausal women31 but may confer in-creased risks of breast cancer and cardiovascular disease. Raloxifene is an oral selective estrogen-receptor modulator (SERM) that decreases the risk of vertebral fractures by 40 to 49%, but it may not reduce the risk of nonvertebral fractures.32 Cal-citonin administered by means of a nasal spray is an antiresorptive agent that has limited effi-cacy in reducing the risk of vertebral fractures and lacks efficacy in preventing hip fracture.33

Oral bisphosphonates must be taken after an overnight fast either once weekly (alendronate at a dose of 70 mg or risedronate at a dose of 35 mg),

A

T6

L4

T4

T11

T12

B

Figure 2. Dual-Energy X-Ray Absorptiometry (DXA) Scan of the Thoracic and Lumbar Spine.

Vertebral deformation at the thoracic and lumbar spine was assessed in the patient described in the vignette, with the use of the vertebral-fracture as-sessment on the same DXA scanner as that used for the measurement of bone mineral density in Figure 1. Panel A shows thoracic kyphosis due to a 75% loss of height of T11. For comparison, Panel B shows a normal verte-bral-fracture assessment in a 58-year-old woman without osteoporosis.

67



once monthly (ibandronate at a dose of 150 mg or risedronate at a dose of 150 mg), or on 2 con-secutive days once monthly (risedronate at a dose of 75 mg). The tablets are taken with 6 to 8 oz of tap water. The patient should remain upright for at least 30 minutes after taking the drug to mini-mize gastroesophageal reflux. To optimize ab-sorption, food, medications, and liquids other than tap or filtered water should be avoided for at least 30 to 45 minutes to allow for dissolution of the tablet and gastric emptying.

Intravenous bisphosphonates include ibandro-nate (at a dose of 3 mg every 3 months) and zole-dronic acid (at a dose of 5 mg every 12 months). They are usually administered in an outpatient facility that has the resources for administering and monitoring intravenous infusions.

Oral and intravenous bisphosphonates are con-traindicated in patients who have had a prior al-lergic reaction to a bisphosphonate or who have an estimated creatinine clearance of 35 ml per minute or less, vitamin D depletion (serum 25-hydroxyvitamin D levels should be more than 30 ng per milliliter before initiating bisphosphonates), osteomalacia (vitamin D depletion or deficiency causing defective mineralization), or hypocalce-mia. Oral bisphosphonates are contraindicated in patients who have impaired swallowing or esoph-ageal disorders such as achalasia, esophageal vari-ces, or severe gastroesophageal reflux or who are unable to sit up for at least 30 minutes after tak-ing the medication. There are no known interac-tions between bisphosphonates and other medi-cations.

After initiating bisphosphonate therapy, I typi-cally reevaluate the patient in 1 month to assess tolerance and thereafter at 3 months, 6 months, and 1 year. At 3 months and 6 months, I obtain measurements of bone-turnover markers, such as osteocalcin or serum C-terminal telopeptide of type 1 collagen (CTX). At 1 year, and every 2 years thereafter, I repeat the assessment of bone min-eral density with the use of DXA. An increase in bone mineral density is not required for a therapy to be considered effective, but a substantial de-cline in bone mineral density requires further evaluation.

Poor adherence to therapy should be suspected if the patient has an otherwise unexplained de-cline in bone mineral density, a new fracture, continued bone loss, or high rates of bone turn-over that persist after 12 months of therapy. When I suspect poor adherence, I ask the patient wheth-

er he or she has had any side effects and attempt to document the patient’s use of the drug by measuring markers of bone turnover. Evidence of treatment failure in a patient with good adher-ence to an oral bisphosphonate regimen requires a change to either intravenous zoledronic acid or another class of medications such as anabolic agents (e.g., teriparatide).

The optimal duration of bisphosphonate ther-apy remains unresolved. However, on the basis of available data, it seems likely that discontinu-ing therapy after 5 years, at least for a temporary drug holiday, is not harmful and may be advan-tageous.34 Patients with mildly reduced bone min-eral density may be the most suitable candidates for a 1-year to 2-year drug holiday, because the risk of fracture will be low if bone loss occurs while the person is not receiving therapy.

Generic alendronate was introduced in 2008 and is less expensive than other agents, with cost ranging from $4 to $40 per month. The cost of risedronate ranges from $60 to $120 per month; generic risedronate will become available in the near future. The cost of oral ibandronate ranges from $90 to $130 per month. One infusion of zole-dronic acid is estimated to cost $1,300; intrave-nous ibandronate costs about $1,300 per year.

A dv er se Effec t s

An acute-phase reaction characterized by fever, myalgia, bone pain, and weakness35 occurs in 20% of patients after an initial intravenous infusion of

Table 1. Common Secondary Causes of Osteoporosis and Laboratory Evalua-tions.*

Possible Cause of Osteoporosis Laboratory Test

Vitamin D deficiency Measurement of serum 25-hydroxyvitamin D level

Primary hyperparathyroidism Measurement of fasting serum calcium and parathyroid hormone levels

Celiac disease Measurement of serum tissue transgluta-minase, total IgA, and gliadin levels

Idiopathic hypercalciuria Measurement of 24-hour urine calcium excretion after discontinuation of calcium supplements

Hyperthyroidism Measurement of serum thyrotropin and total thyroxine levels

Myeloma Serum and urine immunoelectrophoresis

* Additional information regarding secondary causes of osteoporosis can be found in Tannenbaum et al.2 and Jamal et al.3

68



bisphosphonates and in a very small number of patients during oral therapy. Erosive esophagitis, ulceration, and bleeding have been associated with daily oral alendronate or risedronate therapy but occur rarely with current (nondaily) regimens. Heartburn, chest pain, hoarseness, and vocal-cord irritation36 may occur with weekly (alendronate or risedronate) or monthly (ibandronate or rised-ronate) therapy. A relationship between esopha-geal cancer and oral bisphosphonates, suggested on the basis of a small number of case reports, has not been substantiated.37

Transient renal toxic effects can occur after rapid intravenous administration.38,39 Slow infu-sion rates (no less than 15 minutes) and lower doses minimize peak drug serum levels and the risk of renal damage. Bisphosphonates are not recommended when creatinine clearance is less than 35 ml per minute.38 Dose reductions may be required for patients with stage III chronic kid-ney disease (as defined by an estimated glomeru-lar filtration rate between 59 and 30 ml per minute per 1.73 m2 of body-surface area). Mild transient hypocalcemia is a rare complication of intrave-

nous bisphosphonate therapy that may require an interruption in treatment,40 but once the serum calcium level has returned to the normal range, therapy can be resumed. Severe hypocalcemia is a contraindication for continued administration.

Osteonecrosis of the jaw is a rare but serious complication of long-term bisphosphonate ther-apy that may appear either spontaneously or after an oral surgical procedure. Exposed mandibu-lar or maxillary dead bone, nonhealing mucosa, and chronic infection may persist for weeks to years.41-43 More than 95% of cases of osteone-crosis of the jaw occur in patients who are re-ceiving zoledronic acid or pamidronate for the treatment of myeloma, breast cancer, or other bone cancers at doses 10 to 12 times as high as those used for the treatment of osteoporosis.42,44

Case reports suggest that atypical femoral frac-tures (in the subtrochanteric and mid-diaphyseal portions of the femur) may be more common during bisphosphonate therapy.37,45 Recent data from a cross-sectional study of femur fractures recorded in the Danish national health registry46 and a pooled post hoc analysis of the trials that

Figure 3. Cellular Elements Involved in Postmenopausal Trabecular Bone Turnover before and during Bisphosphonate Therapy.

Panel A shows the untreated postmenopausal state, in which osteoclast-mediated bone resorption occurs at a high rate, exceeding os-teoblast-driven bone formation and leading to net bone loss. Panel B shows the initial events associated with bisphosphonate therapy, including the localization and concentration of bisphosphonates in bone through binding to sites of active bone resorption. Panel C shows the effects of bisphosphonates after 6 months of therapy. The number of osteoclasts has decreased owing to early apoptosis. As a result, bone resorption is decreased, and osteoblasts and bone formation are also decreased. The bisphosphonate concentration is re-duced around previous resorption pits. A lower steady-state rate of bone turnover, similar to premenopausal rates, is established.

69



studied the effects of alendronate and zoledron-ic acid on the incidence of fractures47 showed no relationship between the use of bisphosphonates and atypical femur fractures. However, these re-ports are not definitive, and the possibility of a relationship continues to be investigated.


The optimal duration of bisphosphonate therapy remains uncertain. Recent retrospective studies and case reports suggest that long-term bisphos-phonate therapy may result in the suppression of bone turnover and confer a predisposition to in-creased bone fragility, with an increased risk for atypical femur fractures.37 Markers of bone turn-over underestimate the extent of suppressed bone formation,12,48 and their usefulness in monitoring long-term safety may therefore be limited. An ac-cumulation of microcracks in bone-biopsy speci-mens was found in one study of patients receiv-ing alendronate therapy when the analysis was adjusted for potential confounders such as age and bone mineral density at the femoral neck49 but not in another study of long-term alendro-nate therapy (mean, 6.5 years).50 Prospective stud-ies are needed to estimate the long-term risk of side effects associated with bisphosphonate ther-apy, including osteonecrosis of the jaw and atyp-ical femur fractures. Until a better estimate of the risk of these complications emerges, one must balance the long-term risk of these uncommon complications against the known efficacy of the agents in reducing rates of common osteoporotic fractures. It is also not known whether these com-plications can be minimized by periodic rotation of treatment from one class of agents to another.

Guidelines

Guidelines for the management of osteoporosis published by the National Osteoporosis Founda-tion,51 the American Association of Clinical En-docrinologists,52 the American College of Physi-cians,53 the American College of Obstetricians and

Gynecologists,54 and the North American Meno-pause Society 6 agree that persons with osteopo-rosis (bone mineral density T score of less than −2.5) or low bone mass and hip or vertebral frac-tures should receive treatment. These guidelines also suggest that persons with T scores higher than −1.5 should not receive therapy unless there is clinical evidence of osteoporosis. Thus, contro-versy remains regarding the indications for treat-ment among people with mild reductions in bone density. The guidelines include oral bisphospho-nates among the first-line therapies for osteopo-rosis but do not name specific FDA-approved drugs.

R ecommendations

The patient described in the vignette is at high risk for additional fractures on the basis of her history of vertebral compression fracture and a bone mineral density T score in the osteoporosis range. A drug with efficacy in preventing hip and spinal fractures is required, and I would treat the patient with either alendronate or risedronate for 5 years. After 5 years of treatment, I would decide whether a drug holiday might be appropriate for this patient, taking into consideration the fact that she is at high risk for recurrent fracture. I would suggest a calcium intake of 1200 mg per day from dietary sources, with calcium supple-ments as a second choice. I would also measure the serum 25-hydroxyvitamin D level and select an appropriate level of vitamin D intake, encour-age regular weight-bearing exercise, and empha-size the importance of adherence to procedures for taking the medication. I would use measure-ments of bone mineral density to monitor her re-sponse to therapy 12 months after treatment is initiated and then at 24-month intervals as needed. A decline in bone mass or another low-trauma fracture would require careful review of the treat-ment plan and possible selection of another agent.

Dr. Favus reports receiving honoraria and consulting fees from CVS Caremark and Amgen. No other potential conflict of interest relevant to this article was reported.


References

1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diag-nosis, and therapy. JAMA 2001;285:785-95.2. Tannenbaum C, Clark J, Schwartzman

K, et al. Yield of laboratory testing to iden-tify secondary contributors to osteoporo-sis in otherwise healthy women. J Clin Endocrinol Metab 2002;87:4431-7.3. Jamal SA, Leiter RE, Bayoumi AM,

Bauer DC, Cummings SR. Clinical utility of laboratory testing in women with os-teoporosis. Osteoporos Int 2005;16:534-40.4. Bone health and osteoporosis: a re-port of the Surgeon General. Rockville,

70



MD: Department of Health and Human Services, 2004.5. Advisory Group on Osteoporosis. Re-port. London: Department of Health, 1994.6. Management of osteoporosis in post-menopausal women: 2010 position state-ment of the North American Menopause Society. Menopause 2010;17:25-54.7. Cooper C, Atkinson EJ, Jacobsen SJ, O’Fallon WM, Melton LJ III. Population-based study of survival after osteoporotic fractures. Am J Epidemiol 1993;137:1001-5.8. Haentjens P, Magaziner JS, Colón-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 2010;152:380-90.9. Raisz LG. Pathogenesis of osteoporo-sis: concepts, conflicts, and prospects. J Clin Invest 2005;115:3318-25.10. Khosla S. Pathogenesis of osteoporo-sis. In: Robertson RP, ed. Translational endocrinology & metabolism: osteoporo-sis update. Chevy Chase, MD: The Endo-crine Society, 2010:55-86. (http://www.endojournals.org/translational/issues/osteoporosis.pdf.)11. Seeman E, Delmas PD. Bone quality — the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61.12. Hofbauer LC, Schoppet M. Bone biol-ogy underlying therapeutic approaches. In: Robertson RP, ed. Translational endocri-nology & metabolism: osteoporosis update. Chevy Chase, MD: The Endocrine Society, 2010:117-48. (http://www.endojournals.org/translational/issues/osteoporosis.pdf.)13. Rodan G, Reszka A, Golub E, Rizzoli R. Bone safety of long-term bisphospho-nate treatment. Curr Med Res Opin 2004;20:1291-300.14. McClung MR. Bisphosphonates. En-docrinol Metab Clin North Am 2003;32:253-71.15. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differ-ences and their potential influence on clini-cal efficacy. Osteoporos Int 2008;19:733-59.16. Sato M, Grasser W, Endo N, et al. Bisphosphonate action: alendronate local-ization in rat bone and effects on osteo-clast ultrastructure. J Clin Invest 1991;88:2095-105.17. Masarachia P, Weinreb M, Balena R, Rodan GA. Comparison of the distribu-tion of 3H-alendronate and 3H-etidronate in rat and mouse bones. Bone 1996;19:281-90.18. Bergstrom JD, Bostedor RG, Masara-chia PJ, Reszka AA, Rodan GA. Alendro-nate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Bio-chem Biophys 2000;373:231-41.19. Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: gera-nylgeraniol, an intermediate in the meval-

onate pathway, prevents inhibition of os-teoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133-8.20. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell RG, Rogers MJ. Nitro-gen-containing bisphosphonates inhibit mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998;13:581-9.21. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alen-dronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-41.22. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporo-sis: a randomized controlled trial. JAMA 1999;282:1344-52.23. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333-40.24. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-22.25. Chestnut CH III, Skag A, Christiansen C, et al. Effects of oral ibandronate ad-ministered daily or intermittently on frac-ture risk in postmenopausal osteoporo-sis. J Bone Miner Res 2004;19:1241-9.26. McCloskey E, Selby P, Davies M, et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or sec-ondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 2004;19:728-36.27. Wells GA, Cranney A, Peterson J, et al. Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Data-base Syst Rev 2008;1:CD003376.28. Cranney A, Tugwell P, Adachi J, et al. Meta-analyses of therapies for postmeno-pausal osteoporosis. III. Meta-analysis of risedronate for the treatment of post-menopausal osteoporosis. Endocr Rev 2002;23:517-23.29. Dawson-Hughes B, Looker AC, Toste-son AN, Johansson H, Kanis JA, Melton LJ III. The potential impact of new National Osteoporosis Foundation guidance on treatment patterns. Osteoporos Int 2010;21:41-52.30. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporo-sis. N Engl J Med 2001;344:1434-41.31. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290:1729-38.32. Cranney A, Tugwell P, Zytaruk N, et al.

Meta-analyses of therapies for postmeno-pausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treat-ment of postmenopausal osteoporosis. Endocr Rev 2002;23:524-8.33. Cranney A, Tugwell P, Zytaruk N, et al. Meta-analyses of therapies for post-menopausal osteoporosis. VI. Meta-analy-sis of calcitonin for the treatment of post-menopausal osteoporosis. Endocr Rev 2002;23:540-51.34. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alen-dronate after 5 years of treatment: the Fracture Intervention Trial Long-term Ex-tension (FLEX): a randomized trial. JAMA 2006;296:2927-38.35. Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after bisphos-phonate administration. Calcif Tissue Int 1987;41:326-31.36. Ribeiro A, DeVault KR, Wolfe JT III, Stark ME. Alendronate-associated esoph-agitis: endoscopic and pathologic fea-tures. Gastrointest Endosc 1998;47:525-8.37. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 2010;95:1555-65.38. Lewiecki EM, Miller PD. Renal safety of intravenous bisphosphonates in the treatment of osteoporosis. Expert Opin Drug Saf 2007;6:663-72.39. Boonen S, Sellmeyer DE, Lippuner K, et al. Renal safety of annual zoledronic acid infusions in osteoporotic postmeno-pausal women. Kidney Int 2008;74:641-8.40. Maalouf NM, Heller HJ, Odvina CV, Kim PJ, Sakhaee K. Bisphosphonate-induced hypocalcemia: report of 3 cases and review of the literature. Endocr Pract 2006;12:48-53.41. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphospho-nates: a review of 63 cases. J Oral Maxil-lofac Surg 2004;62:527-34.42. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-91.43. Bilezikian JP. osteonecrosis of the jaw — do bisphosphonates pose a risk? N Engl J Med 2006;355:2278-81.44. Woo SB, Hellstein JW, Kalmar JR. Sys-temic review: bisphosphonates and osteo-necrosis of the jaws. Ann Intern Med 2006;144:753-61. [Erratum, Ann Intern Med 2006;145:235.]45. Shane E. Evolving data about subtro-chanteric fractures and bisphosphonates. N Engl J Med 2010;362:1825-7.46. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendro-nate: a register-based national cohort study. J Bone Miner Res 2009;24:1095-102.

71



47. Black DM, Kelly MP, Genant HK, et al. Bisphosphonates and fractures of the sub-trochanteric or diaphyseal femur. N Engl J Med 2010;362:1761-71.48. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CYC. Se-verely suppressed bone turnover: a poten-tial complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-301.49. Stepan JJ, Burr DB, Pavo I, et al. Low bone mineral density is associated with bone microdamage accumulation in post-menopausal women with osteoporosis. Bone 2007;41:378-85.50. Chapurlat RD, Arlot M, Burt-Pichat B,

et al. Microcrack frequency and bone re-modeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res 2007;22:1502-9. [Erratum, J Bone Miner Res 2008;23:1153.]51. Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation, 2008.52. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporo-

sis: 2001 edition, with selected updates for 2003. Endocr Pract 2003;9:544-64. [Erra-tum, Endocr Pract 2004;10:90.]53. Qaseem A, Snow V, Shekelle P, Hop-kins R Jr, Forciea MA, Owens DK. Phar-macologic treatment of low bone density or osteoporosis to prevent fractures: a clini-cal practice guideline from the American College of Physicians. Ann Intern Med 2008;149:404-15.54. American College of Obstetricians and Gynecologists Women’s Health Care Physicians. Osteoporosis. Obstet Gynecol 2004;104:Suppl:66S-76S.Copyright © 2010 Massachusetts Medical Society.

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n engl j med 363;17 nejm.org october 21, 20101648


the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations.

Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration

James C. Folk, M.D., and Edwin M. Stone, M.D., Ph.D.

From the Department of Ophthalmology and Visual Sciences (J.C.F., E.M.S.) and the Howard Hughes Medical Institute (E.M.S.), University of Iowa Carver Col-lege of Medicine, Iowa City. Address re-print requests to Dr. Stone at the Depart-ment of Ophthalmology and Visual Sciences, University of Iowa, 375 Newton Rd., 4111 MERF, Iowa City, IA 52242, or at [email protected].


A n ophthalmologist refers a 66-year-old man for consultation with a retinal specialist. The patient has had blurred and distorted vision in his right eye for the past 2 weeks. Examination reveals drusen beneath the

retina in both eyes. His right eye also has a subretinal hemorrhage just temporal to the center of the macula, as well as subretinal fluid (Fig. 1A). A fluorescein angio-gram shows subfoveal neovascularization (Fig. 1B). Optical coherence tomography reveals fluid beneath and within the layers of the retina (Fig. 1C). The retinal spe-cialist diagnoses neovascular age-related macular degeneration (AMD) and recom-mends intraocular injections of ranibizumab.


AMD is the leading cause of blindness in the United States. All patients initially have a form of the disorder called dry AMD, characterized by the development and accumulation of drusen, which are localized deposits of extracellular material that appear as yellow spots in the retina on ophthalmoscopy. As dry AMD progresses, focal areas of atrophy of the retinal pigment epithelium appear. Wet, or neovascu-lar, AMD then develops in some patients with established dry AMD. Wet AMD is characterized by the growth of abnormal vessels beneath the retinal pigment epi-thelium and between the retinal pigment epithelium and the overlying retina.

The Eye Diseases Prevalence Research Group estimates that in the year 2000, a total of 1.2 million residents of the United States had neovascular AMD, 973,000 had dry AMD with atrophy of the retinal pigment epithelium, and 7.3 million had large drusen (≥125 μm in diameter) and were therefore at increased risk for atrophy or neovascularization. The same group estimates that these numbers will increase by more than 50% by the year 2020 as a result of aging of the population.1

Many patients with AMD have moderate vision loss, between 20/50 and 20/100 in the better eye. These patients have quality-of-life measurements that are 32% below normal, similar to those among patients with severe angina or hip fractures.2 A person with very severe neovascular disease may have 20/800 vision in the better eye and will have a reduction in quality of life of 60%, similar to that of a patient who is bedridden with a catastrophic stroke.2 AMD is estimated to cost the United States $30 billion a year.2

Pathoph ysiol ogy a nd Effec t of Ther a py

Despite decades of intensive investigation, the molecular mechanisms underlying the pathogenesis of AMD are still obscure. It is likely that in most patients, a num-

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n engl j med 363;17 nejm.org october 21, 2010 1649

ber of genetic factors3-12 and environmental fac-tors (e.g., smoking)13 contribute incrementally to the development of the disease. Genomewide as-sociation studies of patients with AMD and con-trol subjects have shown that the largest single genetic factor contributing to AMD is a variant of codon 402 in the gene encoding complement fac-tor H. This observation strongly supports the long-held belief that the immune system is an impor-tant contributor to AMD.3-5,14,15

The photoreceptor cells of the retina depend on the underlying retinal pigment epithelium for phagocytosis of their continuously renewed out-er segments, as well as for reisomerization of their light-sensitive, vitamin-A–based chromophore16

(Fig. 2A). Both the photoreceptors and the reti-nal pigment epithelium depend on the chorio-capillaris for oxygen, nutrients, and removal of metabolic waste products.17 In patients with AMD, drusen form between the retinal pigment epithe-lium and Bruch’s membrane. In some patients with AMD, there is apoptotic atrophy of the reti-nal pigment epithelium and choriocapillaris in the macula (the central region of the fundus).14,18

Neovascularization occurs in about 10% of patients with AMD for reasons that are still un-known but that may be due in part to injury or degeneration of Bruch’s membrane. This compli-cation is responsible for most (perhaps as much as 90%) of the severe vision loss caused by this disease.19 In neovascular AMD, abnormal capil-laries grow from the choroid through Bruch’s membrane and into spaces beneath the retinal pigment epithelium and retina (Fig. 2B). As these vessels proliferate, they leak serum or blood, which causes swelling beneath and within the retina and loss of visual acuity. If left unchecked, the vessels eventually cause a subretinal fibrotic scar and permanent loss of vision.20,21

Vascular endothelial growth factor A (VEGF-A) is closely associated with the growth and perme-ability of neovascular vessels.22-26 Ranibizumab is the Fab fragment of a recombinant, human-ized, monoclonal antibody that binds to all forms of VEGF-A. The inhibition of VEGF-A re-duces the permeability of the neovascular ves-sels, as well as their further growth.27 In tu-mors, long-term VEGF blockade results in vessel maturation and remodeling, decreased numbers of endothelial cells, increased coverage of the vessel wall by pericytes, and a more stable, non-leaking vessel28 (Fig. 2C). When vessel growth

and leakage are stopped, the retinal swelling usually diminishes and vision can stabilize or improve. Studies in primate models have shown that when ranibizumab is injected into the eye, effective retinal concentrations are maintained for about 1 month.27

A

B

C

Figure 1. Clinical Characteristics of Neovascular Age-Related Macular Degeneration.

A color photograph of the right eye at presentation shows scattered yellow drusen, multilayered hemor-rhage, and serous fluid in the macula (Panel A). A late-phase fluorescein angiogram of the right eye shows hy-perfluorescence of occult choroidal neovascularization involving the center of the macula (Panel B). The dark area to the left is caused by hemorrhage, which blocks the underlying fluorescence. A time-domain optical co-herence tomogram taken through the center of the right macula reveals fluid (arrow) within and beneath the retina (Panel C).

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Two main patterns of choroidal neovasculari-zation are seen on fluorescein angiography in patients with AMD. Classic neovascularization fluoresces brightly in the early phases of the angiogram and leaks profusely in the late phas-es, whereas occult neovascularization fills more slowly and leaks much less.29 Large, random-ized, controlled trials have evaluated the benefit of ranibizumab for the treatment of both forms of neovascularization.

In the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treat-ment of Neovascular Age-Related Macular De-generation (MARINA) trial (ClinicalTrials.gov number, NCT00056836), investigators compared monthly intraocular injections of ranibizumab with placebo in patients who had AMD with the predominantly occult type of choroidal neovas-cularization.30 At 1 year, only 5% of patients who were treated with either 0.3 mg or 0.5 mg of ranibizumab had lost 15 letters of vision (about three lines on a standard eye chart), as compared with 38% of control subjects. Of the patients who were treated with ranibizumab, 34% of those receiving the 0.5-mg dose and 25% of those receiving the 0.3-mg dose gained 15 letters of vision, as compared with only 5% of control subjects.30 Ranibizumab had a positive treatment effect in all subgroups of patients with neovascular AMD.31

Figure 2. Therapeutic Action of Ranibizumab.

In the normal retina, the retinal pigment epithelium is attached to Bruch’s membrane and the choroid sup-plies oxygen and nutrients to the outer layers of the retina (Panel A). In patients with neovascular age-related macular degeneration (AMD), new blood vessels grow from choroidal capillaries through Bruch’s membrane and proliferate beneath the retinal pigment epithelium (Panel B). Vascular endothelial growth factor A (VEGF-A) binds with its receptor and promotes vascular growth and leakage. Fluid or blood accumulates beneath the retina, detaching it from the retinal pigment epithelium. Fluid can also accumulate within the retinal layers. Rani-bizumab binds to VEGF-A and prevents it from binding to its receptor (Panel C). Long-term blockade of VEGF-A causes shrinkage and maturing of the vessels so that they no longer leak. The accumulation of fluid within and beneath the retina resolves, and the photoreceptors reattach to the underlying retinal pigment epithelium.

Retina

Choroid

Photoreceptors

Bruch’s membrane

New blood- vessel growth

Fluid leakage fromimmature vessels

Fluid accumulationwithin retinal layers

Fluid accumulationbeneath the retina

Reattachment of photoreceptorsto retinal pigment epithelium

VEGF-A

VEGF-Areceptor

Shrinkage andmaturation of vessels

Ranibizumab

Retinal pigment epithelium

Choriocapillaris

A Normal Retina

B Neovascular AMD

C Ranibizumab Therapy

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In the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascu-larization in Age-Related Macular Degeneration (ANCHOR) study (NCT00061594), investigators compared monthly intraocular injections of ra-nibizumab with photodynamic therapy in patients who had AMD with the predominantly classic type of neovascularization.32 Photodynamic therapy involves the intravenous injection of verteporfin, a photosensitizing dye, followed by application of a nonthermal red laser light (at a wavelength of 689 nm) to the area of neovascularization.33 The red laser light stimulates the dye, which causes the formation of singlet oxygen and secondary dam-age to the vessels. Only 4% of patients who were treated with 0.5 mg of ranibizumab and 5% of those treated with 0.3 mg lost 15 letters of vision at 1 year, as compared with 36% of patients who were treated with laser-activated verteporfin. Among patients who were treated with ranibi-zumab, 40% of those receiving the 0.5-mg dose and 36% of those receiving the 0.3-mg dose gained 15 letters of vision, as compared with only 6% in the verteporfin group.

Clinic a l Use

In the absence of anti-VEGF therapy, neovascular AMD usually results in a substantial loss of vision. An alternative treatment is thermal laser photo-coagulation, but this therapy damages the over-lying and surrounding retina and is associated with a high rate of recurrent neovascularization. At 24 months after laser treatment of neovascu-larization that extended beneath the center of the macula, only 1% of treated eyes had better than 20/100 vision.34 Another alternative is photody-namic therapy, but the ANCHOR study showed that treatment with ranibizumab is superior.32

Bevacizumab is an agent that is commonly used as an alternative to ranibizumab. Bevaci-zumab is also a monoclonal antibody that binds to VEGF-A, but the Food and Drug Administra-tion (FDA) has approved it only for the treatment of colon cancer. The similarity between the two molecules has led many clinicians to hypothesize that the two drugs might be equally effective for the treatment of neovascular AMD, although this hypothesis has not been formally confirmed. When bevacizumab is used for the treatment of AMD, a pharmacy can split a vial into small

doses that can be administered intraocularly. Generally, the dose that is used is 1.25 mg, which costs about $75, as compared with approximately $2,000 for a dose of ranibizumab. It should be emphasized that this use of bevacizumab for neo-vascular AMD is considered off-label therapy.

Ranibizumab is injected into the eye in an out-patient clinic (see video, available with the full text of this article at NEJM.org). Hospitalization is not needed. We perform injections in a room specially designed for minor surgery. Informed consent should be obtained before the procedure. We be-gin the injection procedure by giving anesthetic drops of proparacaine hydrochloride 0.5% and tetracaine hydrochloride 0.5%, followed by an an-tibiotic drop. Many retinal specialists do not use subconjunctival anesthesia, but for most of our patients, we inject about 0.2 ml of 1% lidocaine without epinephrine beneath the conjunctiva in the superotemporal quadrant, 3 mm posterior to the corneal limbus. After waiting about 4 min-utes, we place a lid speculum into the eye to hold the lids open and drop 5% povidone–iodine onto the conjunctiva.

We use calipers to mark the injection site 3.5 mm posterior to the limbus (the outer border of the cornea). We use a 30-gauge needle on a 1-mm tuberculin syringe to inject 0.05 ml (0.5 mg of ranibizumab) into the middle of the vitreous cavity, then place a sterile cotton swab firmly over the injection site as the needle is withdrawn to prevent backflush of fluid through the injec-tion site. We then remove the lid speculum and gently irrigate the eye to remove any residual povidone–iodine.

We give an additional drop of antibiotic and instruct the patient to use the drops twice more that day and then four times per day for the next 3 days. Some retinal specialists no longer use pro-phylactic antibiotic drops because they believe that the drops do not reduce the risk of infectious endophthalmitis. We tell the patient to call if vi-sion decreases or the eye becomes painful. We give the patient a sheet that contains the instruc-tions for using the antibiotic drops, warnings, and numbers to call if there are problems. The patient makes an appointment to return in 1 month.

Intraocular hemorrhage is rare after injections of ranibizumab. As noted, the needle is small (30 gauge), and the injection site is chosen to avoid major ocular blood vessels. The injection of the

A video showing injection of ranibizumab is available at NEJM.org

Click here to access video.




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drug temporarily raises the intraocular pressure to or even above the vascular perfusion pressure of the eye, which effectively tamponades any bleeding until clotting occurs. Therefore, there is no need for a patient to stop taking warfarin or antiplatelet drugs. There are no known interac-tions with other drugs, and no adjustments need to be made for other medical conditions.

At the 1-month follow-up appointment, the patient’s vision is checked, and the eye is exam-ined for signs of inflammation, new hemor-rhage, or fluid within or under the retina. We then give a second injection and repeat the pro-cess again 1 month later, for a total of three monthly treatments. At subsequent visits, we give additional ranibizumab injections, but we carefully extend the follow-up period between the visits by 1 week if the eye remains stable, with no fluid or hemorrhage.35 Once the follow-up interval reaches 3 months and the eye is stable, consideration can be given to stopping the injections, but the patient should still be seen every 3 to 4 months to detect any late recur-rences. Patients should be reminded frequently to call if vision loss or distortion occurs.

If a patient has only a partial response or no response to serial injections, it may be appropri-ate to stop the treatment. This decision should be made jointly with the patient. It often de-pends somewhat on whether the better eye is being treated. Patients often wish to forgo injec-tions of modest benefit if the poorer eye is being treated, whereas they may be reluctant to stop if the injections are being given in the better eye.

Brown and colleagues36 calculated that the cost of treating a patient with monthly injections of ranibizumab over a 2-year period, as described in the MARINA trial, would be $52,652. Of this total (which includes incidental procedural costs), $44,812 would be the cost of the drug, and $5,981 the physician’s fees.36


The injection of either anesthetic or ranibizumab can cause mild subconjunctival hemorrhage. The blood is cosmetically unappealing but resolves without sequelae. Many clinicians use topical an-esthetics only, but in our experience, most pa-tients who are treated in this manner feel some pain when the needle pierces the wall of the eye.

Any intraocular injection can cause bacterial endophthalmitis, a serious complication that threatens vision. In the MARINA study, the pre-sumed rate of endophthalmitis (presumed be-cause not all eyes showed positive cultures) was 1.0% (infection in 5 of 477 patients); the rate per injection was 0.05% (infection associated with 5 of 10,443 injections).30 Patients in whom endo-phthalmitis develops have vision loss or an in-crease in floaters, almost always within the first week after the injection. The eye is red and may be painful. Patients with such symptoms after ranibizumab injection should be seen promptly by their retinal specialist.

In the MARINA and ANCHOR trials, the re-spective risks of nonocular hemorrhage were 9% and 6% in the treated groups versus 6% and 2% in the comparator groups, which may indicate a systemic anti-VEGF effect.30,32 In the MARINA trial, rates of stroke were 2.5% in the 0.5-mg group and 1.3% in the 0.3-mg group versus 0.8% in the sham group. Rates of myocardial infarc-tion were 1.3% in the 0.5-mg group and 2.5% in the 0.3-mg group versus 1.7% in the sham group.30 Similar effects were seen in the 2-year results from the ANCHOR trial.37 None of these differences were statistically significant.

As noted above, bevacizumab is also an anti–VEGF-A monoclonal antibody. In a meta-analysis of trials of bevacizumab in patients with meta-static cancer, arterial thromboembolic events, including cardiac ischemia and stroke, occurred in 3.3% of patients who had received the drug, as compared with 2.0% who had not.38 The total-body dose of bevacizumab that was used in these trials was more than 1000 times the dose used in the treatment of AMD.


A major area of uncertainty is whether bevaci-zumab is as effective as ranibizumab in the treat-ment of neovascular AMD. This issue has been evaluated in several small studies, with encour-aging results.39-42 However, these findings are provisional. To answer the question definitively, a large, randomized clinical trial, called the Comparison of AMD Treatments Trial (CATT; NCT00593450), is currently being conducted. Re-sults from this trial are expected in the spring of 2011.43 Since the cost of the dose of bevacizumab

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that is commonly used in AMD is so much less than the cost of the standard dose of ranibizum-ab ($75 vs. $2,000), the majority of our patients choose to be treated with bevacizumab on the basis of currently available data.

Another area of uncertainty is the optimal treatment schedule. Some specialists administer ranibizumab on a fixed monthly schedule, whereas others administer the agent only when fluid is present on optical coherence tomogra-phy or when leakage is seen on fluorescein an-giography.44 In CATT, investigators are compar-ing these two approaches to treatment, as well as comparing ranibizumab with bevacizumab. If the study shows that the difference in outcome between the fixed and as-needed approaches is minimal, patients and physicians may opt for less-frequent injections. All the groups in CATT are being followed monthly, but most patients dislike having to return for a visit every month. An additional trial may be warranted in the fu-ture, comparing monthly visits with gradual ex-tension of the follow-up interval for patients whose condition is stable. Some pharmacoki-netic data, though not conclusive, support the hypothesis that bevacizumab may have a longer intraocular half-life than ranibizumab.45

Guidelines

The American Academy of Ophthalmology includ-ed ranibizumab in its September 2008 Preferred Practice Pattern Guidelines for Age-Related Macu-lar Degeneration, grading such therapy as level A (most important to the care process) and level I (greatest strength of evidence).46 The same guide-lines also listed bevacizumab as a recommended treatment, grading it level A for importance but only level III (the lowest level) with respect to strength of evidence. The guidelines state that when using bevacizumab, “the ophthalmologist should provide appropriate informed consent with respect to the off-label status.” The guidelines committee of the European Society of Retina Spe-cialists make similar recommendations in a state-ment published in August 2007.47

R ecommendations

The patient described in the vignette is an appro-priate candidate for either ranibizumab or beva-cizumab therapy. We would explain to the pa-tient that only ranibizumab has been approved by the FDA for use in AMD. We would also explain that the efficacy of bevacizumab is thought to be similar to that of ranibizumab, although such efficacy has not been evaluated in definitive tri-als, and that bevacizumab is substantially less expensive.

Regardless of the patient’s choice of agent, we would carry out the initial injection in our outpatient minor surgery unit, as described in the Clinical Use section. After the first injec-tion of either bevacizumab or ranibizumab, we would ask the patient to return for another in-jection in 4 weeks. After the second injection, we would ask him to return in 4 weeks if he received ranibizumab and in 6 weeks if he re-ceived bevacizumab. We would continue injec-tions at these intervals until the retina was dry. We would then gradually extend the interval between follow-up visits, depending on the ex-amination findings.

In our experience, most treatment failures are due to missed follow-up visits. Patients should be reminded repeatedly to call if their vision wors-ens. Physicians should have a system in place for calling patients who have been lost to follow-up because such patients have a high risk of recur-rent neovascularization with permanent scarring and vision loss. Finally, ophthalmologists should be aware of the patient’s overall medical condi-tion and should communicate clearly with the patient’s other physicians when warranted.

Supported by the Robert C. Watzke Research Fund, Research to Prevent Blindness, the Foundation Fighting Blindness, a grant (EY016822) from the National Eye Institute, and the Howard Hughes Medical Institute.

No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are avail-able with the full text of this article at NEJM.org.

We thank Robert F. Mullins, Ph.D., for his critical review and advice; Alton Szeto Illustration for the drawings that served as the design for Figure 2; and Patricia Duffel for her reference help.

References

1. Friedman DS, O’Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564-72.2. Brown GC, Brown MM, Sharma S, et al.

The burden of age-related macular degen-eration: a value-based medicine analysis. Trans Am Ophthalmol Soc 2005;103:173-86.3. Edwards AO, Ritter R III, Abel KJ,

Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005;308:421-4.4. Hageman GS, Anderson DH, Johnson

78



LV, et al. A common haplotype in the com-plement regulatory gene factor H (HF1/CFH) predisposes individuals to age- related macular degeneration. Proc Natl Acad Sci U S A 2005;102:7227-32.5. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degenera-tion. Science 2005;308:419-21.6. Hammond CJ, Webster AR, Snieder H, Bird AC, Gilbert CE, Spector TD. Genetic influence on early age-related maculopa-thy: a twin study. Ophthalmology 2002;109:730-6.7. Heiba IM, Elston RC, Klein BE, Klein R. Sibling correlations and segregation analy-sis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol 1994;11:51-67. [Erratum, Genet Epidemiol 1994;11:571.]8. Klaver CC, Wolfs RC, Assink JJ, van Duijn CM, Hofman A, de Jong PT. Genetic risk of age-related maculopathy: popula-tion-based familial aggregation study. Arch Ophthalmol 1998;116:1646-51.9. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-9.10. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 2005;14:3227-36.11. Seddon JM, Cote J, Page WF, Aggen SH, Neale MC. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influ-ences. Arch Ophthalmol 2005;123:321-7.12. Zareparsi S, Buraczynska M, Bran-ham KE, et al. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet 2005;14:1449-55.13. Thornton J, Edwards R, Mitchell P, Har-rison RA, Buchan I, Kelly SP. Smoking and age-related macular degeneration: a review of association. Eye (Lond) 2005;19:935-44.14. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of im-mune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-32.15. Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiologi-cal aspects of macular degeneration. Prog Retin Eye Res 2001;20:385-414.16. Bok D. The retinal pigment epitheli-um: a versatile partner in vision. J Cell Sci Suppl 1993;17:189-95.17. Hayreh SS, Baines JA. Occlusion of the posterior ciliary artery. II. Chorio-ret-inal lesions. Br J Ophthalmol 1972;56:736-53.

18. Zarbin MA. Current concepts in the pathogenesis of age-related macular de-generation. Arch Ophthalmol 2004;122:598-614.19. Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36:182-91.20. Green WR. Histopathology of age-relat-ed macular degeneration. Mol Vis 1999;5:27.21. Green WR, Enger C. Age-related mac-ular degeneration histopathologic studies: the 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100:1519-35.22. Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and cho-roidal neovascular membranes. Am J Ophthalmol 1996;122:393-403.23. Kvanta A, Algvere PV, Berglin L, Sere-gard S. Subfoveal fibrovascular mem-branes in age-related macular degenera-tion express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996;37:1929-34.24. Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR. Transdifferentiat-ed retinal pigment epithelial cells are im-munoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related cho-roidal neovascular membranes. Invest Ophthalmol Vis Sci 1996;37:855-68.25. Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular an-giogenesis in a primate model. Am J Pathol 1994;145:574-84.26. Otani A, Takagi H, Oh H, et al. Vascu-lar endothelial growth factor family and receptor expression in human choroidal neovascular membranes. Microvasc Res 2002;64:162-9.27. Ferrara N, Damico L, Shams N, Low-man H, Kim R. Development of ranibizum-ab, an anti-vascular endothelial growth fac-tor antigen binding fragment, as therapy for neovascular age-related macular degenera-tion. Retina 2006;26:859-70.28. Jain RK. Normalization of tumor vas-culature: an emerging concept in anti-angiogenic therapy. Science 2005;307:58-62.29. Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the mac-ular photocoagulation study. Arch Oph-thalmol 1991;109:1242-57.30. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31.31. Boyer DS, Antoszyk AN, Awh CC, Bhisitkul RB, Shapiro H, Acharya NR.

Subgroup analysis of the MARINA study of ranibizumab in neovascular age-relat-ed macular degeneration. Ophthalmology 2007;114:246-52.32. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degen-eration. N Engl J Med 2006;355:1432-44.33. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials — TAP report. Arch Ophthalmol 1999;117:1329-45. [Erratum, Arch Oph-thalmol 2000;118:488.]34. Laser photocoagulation of subfoveal neovascular lesions in age-related macu-lar degeneration: results of a randomized clinical trial. Arch Ophthalmol 1991;109:1220-31.35. Spaide R. Ranibizumab according to need: a treatment for age-related macular degeneration. Am J Ophthalmol 2007;143:679-80.36. Brown MM, Brown GC, Brown HC, Peet J. A value-based medicine analysis of ranibizumab for the treatment of sub-foveal neovascular macular degeneration. Ophthalmology 2008;115:1039-45.37. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neo-vascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116:57-65.38. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogen-esis inhibitor bevacizumab in cancer pa-tients: a meta-analysis of randomized con-trolled trials. Acta Oncol 2010;49:287-97.39. Bashshur ZF, Haddad ZA, Schakal AR, Jaafar RF, Saad A, Noureddin BN. Intravit-real bevacizumab for treatment of neovas-cular age-related macular degeneration: the second year of a prospective study. Am J Ophthalmol 2009;148(1):59-65.40. Fong DS, Custis P, Howes J, Hsu JW. Intravitreal bevacizumab and ranibizum-ab for age-related macular degeneration: a multicenter, retrospective study. Oph-thalmology 2010;117:298-302.41. Ehlers JP, Spirn MJ, Shah CP, et al. Ra-nibizumab for exudative age-related mac-ular degeneration in eyes previously treat-ed with alternative vascular endothelial growth factor inhibitors. Ophthalmic Surg Lasers Imaging 2010;41:182-9.42. Tufail A, Patel PJ, Egan C, et al. Beva-cizumab for neovascular age related mac-ular degeneration (ABC Trial): multicen-tre randomised double masked study. BMJ 2010;340:c2459.43. Martin DF, Maguire MG, Fine SL. Identifying and eliminating the road-blocks to comparative-effectiveness re-search. N Engl J Med 2010;363:105-7.44. Lalwani GA, Rosenfeld PJ, Fung AE, et

79



al. A variable-dosing regimen with intra-vitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43-58.45. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of be-vacizumab after a single intravitreal injec-

tion in humans. Am J Ophthalmol 2008;146:508-12.46. American Academy of Ophthalmology Retina Panel. Preferred practice pattern guidelines. age-related macular degenera-tion. San Francisco: American Academy of Ophthalmology, 2008. (http://one.aao.org/CE/PracticeGuidelines/PPP_Content

.aspx?cid=f413917a-8623-4746-b441-f817265eafb4.)47. Schmidt-Erfurth UM, Richard G, Au-gustin A, et al. Guidance for the treat-ment of neovascular age-related macular degeneration. Acta Ophthalmol Scand 2007;85:486-94.Copyright © 2010 Massachusetts Medical Society.

Palmyra, Syria Christian Müller, M.D.

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Dietary Therapy in HypertensionFrank M. Sacks, M.D., and Hannia Campos, Ph.D.

From the Department of Nutrition, Har-vard School of Public Health (F.M.S., H.C.); and Channing Laboratory and Cardiology Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (F.M.S.) ― all in Boston. Address reprint requests to Dr. Sacks at the Department of Nutrition, Harvard School of Public Health, Bldg. 1, 2nd Fl., Boston, MA 02115, or at [email protected].

N Engl J Med 2010:362:2102-12.Copyright © 2010 Massachusetts Medical Society.

A 57-year-old woman presents to an outpatient clinic for evaluation of hypertension. She has no history or symptoms of cardiovascular disease and reports having gained 15 kg over the past 30 years. Her blood pressure is 155/95 mm Hg, her weight 86 kg, her height 165 cm, her body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) 31, and her waist circumference 98 cm. Her serum triglyceride level is 175 mg per deciliter (2.0 mmol per liter), high-density lipoprotein cholesterol 42 mg per deciliter (1.1 mmol per liter), low-density lipoprotein cholesterol 110 mg per deciliter (2.8 mmol per liter), and glucose 85 mg per deciliter (4.7 mmol per liter). Her clinical profile is thus consistent with the metabolic syndrome.1 She is a nonsmoker, is sedentary, and eats a diet that is high in white bread, processed meats, and snacks and drinks containing sugars and sodium and is low in fruits and vege-tables. She is interested in adopting a healthier lifestyle.


Hypertension is defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.2 However, morbidity increases among persons whose blood pressure is above 115/75 mm Hg. High blood pressure is associated with an increased risk of stroke, myocardial infarction, heart failure, renal failure, and cognitive impairment.2-4 Systolic blood pressure above 115 mm Hg is the most important determinant of the risk of death worldwide,2 being respon-sible for 7.6 million cardiovascular deaths annually.3

From 1960 through 1991, blood pressure decreased in the United States, and after the first 10 years of this interval, the rate of cardiovascular deaths decreased.2 Effective hypertension screening and treatment were probably the reason for these beneficial trends. However, from 1990 through 2002, blood pressure increased.5,6 Intake of fruits and vegetables and adherence to healthful dietary patterns de-clined during this period7,8 and the prevalence of abdominal obesity increased9; both trends have contributed to hypertension.

Among most populations in industrialized countries, the prevalence of hyper-tension increases dramatically with age; in the United States it rises from about 10% in persons 30 years of age to 50% in those 60 years of age.6 However, some persons, including strict vegetarians,10-12 populations whose diet consists mostly of vegetable products,11,13 and those whose sodium intake is low,13-15 have virtu-ally no increase in hypertension with age.


Pathophysiology and Effect of Therapy

Essential hypertension is the name for hypertension that cannot be attributed to a specific renal or adrenal disease, such as chronic renal failure or an adrenal tumor;

81



the vast majority of patients with hypertension have essential hypertension. The pathophysiology of essential hypertension is complex, with much remaining to be discovered (Fig. 1, and Section 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The three cornerstones of dietary treatment of hyper-tension — a healthful dietary pattern, reduced sodium intake, and reduced body fat — influence the pathophysiology of hypertension at many of its points of control.

High sodium intake is strongly correlated with the development of hypertension.16-18 Sodium intake initiates an autoregulatory sequence that leads to increased intravascular fluid volume and cardiac output, peripheral resistance, and blood pressure. The elevation in blood pressure results in a phenomenon called pressure natriuresis, in which increased renal perfusion pressure leads to increased excretion of f luid and sodium. In essential hypertension, however, sodium excre-tion is impaired. It is hypothesized that in most cases essential hypertension is a genetic disorder involving many individual genes, each of which influences the body’s handling of sodium to varying degrees18 and becomes expressed in the context of an unhealthful dietary environment, particularly one characterized by excessive intake of salt.

Numerous other factors contribute to the pathophysiology of hypertension. Especially in the elderly, large conduit arteries such as the aorta and carotid arteries become stiff and less compliant, increasing systolic blood pressure.19 Proliferation of smooth-muscle cells and endo-thelial dysfunction occur in resistance vessels, including small arteries and arterioles, causing vasoconstriction and increasing peripheral vascu-lar resistance.20-22 Although the systemic renin–angiotensin–aldosterone axis is often suppressed in the presence of elevated blood pressure, angio-tensin II activity is increased locally in various tissues, including the kidneys, vascular endothe-lium, and adrenal glands.23,24 Increased activity in the sympathetic nervous system may also be a factor.25-30 Both aging19,31-33 and obesity25-30

contribute to the pathogenesis of hypertension through several mechanisms (Fig. 1, and Section 1 in the Supplementary Appendix).

Two effective interventions for lowering blood pressure in patients with hypertension are reduc-ing sodium intake and reducing weight. Reduc-tions in dietary salt lessen the amount of sodium

the kidney has to excrete to restore normal blood volume. Compliance in the aorta and carotid artery in older patients with hypertension is im-proved when sodium intake is reduced.34 Reduc-tion in sodium intake also improves arterial vaso-dilatation.21,22 Weight loss moderates activation of the renin–angiotensin–aldosterone axis35,36 and the sympathetic nervous system37,38 and di-minishes sodium retention.39 Decreases in ab-dominal visceral fat also improve the function-ing of both conduit and resistance vessels.40

In addition to sodium restriction and weight loss, several other dietary modifications that are collectively termed “a healthful dietary pattern” have been shown to reduce blood pressure. Al-though the mechanisms of these diets have not been fully clarified, adherence to these diets has been found to reset the pressure–natriuresis curve so that a lower pressure suffices to excrete so-dium and reduce blood volume,41 reduce aortic stiffness,42 and improve vasodilatation in small resistance vessels.43,44 As compared with the typical U.S. diet, the kinds of dietary patterns that have been proved to lower blood pressure emphasize fruits, vegetables, and low-fat dairy products; include whole grains, poultry, fish, and nuts; make use of unsaturated vegetable oils; and contain smaller amounts of red meat, sweets, and sugar-containing beverages.45,46 Clinical trials of such diets have not usually emphasized the identification of specific nutrients or single foods that lower blood pressure but rather have used epidemiologic data to define dietary patterns, such as Mediterranean-style diets47,48 and vegetar-ian diets.11,12 (see Section 2 in the Supplemen-tary Appendix for a discussion of the effects of specific foods and nutrients on blood pressure).

Clinical Evidence

The most carefully studied and established health-ful dietary patterns are the Dietary Approaches to Stop Hypertension (DASH) diet,45,49 variants of that diet,46,50 and variations of the Mediterra-nean diet.51,52 In the original DASH trial,49 459 adults whose systolic blood pressure was less than 160 mm Hg and whose diastolic blood pressure was 80 to 95 mm Hg, 133 of whom had hyperten-sion, were randomly assigned to a control diet typical of the average U.S. diet, a diet rich in fruits and vegetables, or a combination diet rich in fruits, vegetables, and low-fat dairy products and relatively low in saturated and total fat. So-dium intake and body weight were maintained at

82



High-sodium, high-calorie diet

Low-sodium, low-calorie diet

Increased blood pressure

Decreased blood pressure

Increased sympatheticnervous systemactivity

Weight loss reducessympathetic nervoussystem activity

Weight loss, low sodium intake,and healthy diet reduce stiffnessof large conduit arteries

Large conduit arteriesbecome less compliant

High sodium level activates localangiotensin II in heart and arteries

Increased cardiac output

Abnormal pressure natriuresisand sodium retention

Increased tissue angiotensin IIin kidneys and adrenal glands

Smooth-muscle cell proliferation and rearrangementEndothelial-cell dysfunction in small resistance vesselsIncreased peripheral resistance

Abdominal fat further increases conduit artery stiffness, sympatheticnervous system activity, and angiotensin II levels

Decreased abdominal fat

Weight loss, low sodium intake, andhealthy diet improve function of smallresistance vessels and decrease peripheral resistance

Healthy diet improves renalsodium excretion

Intrinsic renal factors(genetic and prenatal)regulate sodium excretion

A

B

Figure 1. Mechanisms Linked to Increases in Blood Pressure and the Therapeutic Effects of Healthful Dietary Patterns, Sodium Reduction, and Weight Loss.

83



constant levels. After 8 weeks, among the par-ticipants with hypertension, the diet rich in fruits and vegetables reduced systolic and diastolic blood pressure by 7.2 and 2.8 mm Hg more, re-spectively, than the control diet (P<0.001 and P = 0.01, respectively). The combination diet re-sulted in greater reductions (11.4 and 5.5 mm Hg, respectively, as compared with the control diet; P<0.001 for each). The effects were less pro-nounced among participants who did not have hypertension at baseline.

In a subsequent trial, the effect of various levels of sodium intake was studied in the con-text of the DASH diet in 412 participants with blood pressure levels at enrollment similar to those of participants in the original DASH trial.53 Patients were randomly assigned to either the DASH “combination” diet (now commonly termed the DASH diet) or a control diet. Participants in each group were then given a diet with high, intermediate, and low levels of sodium (3.5, 2.3, and 1.2 g per day, respectively) for 30 days each in random order. Body weight was held constant by adjusting total caloric intake. Reducing sodi-um intake resulted in a significant incremental reduction in both systolic and diastolic blood pressure in both groups (Fig. 2).

In a secondary analysis from the sodium trial, the blood-pressure–lowering effects of the DASH diet and low sodium were each accentuated as age increased54 (Fig. 3). Systolic blood pressure was 12 mm Hg higher among participants be-tween 55 and 76 years of age than among those between 21 and 41 years of age when they were given a typical U.S. diet that was high in sodium. This difference in systolic blood pressure is simi-lar to that in the U.S. population when the same age groups are compared.55 In marked contrast, systolic blood pressure was the same among older and younger participants when they were given the DASH diet with low sodium content. This finding suggests that the typical rise in blood pressure that occurs with age during adult life may be prevented or reversed if the low-sodium DASH diet is followed.

Women, blacks, and those with the metabolic syndrome have a mildly enhanced reduction in blood pressure in response to a low-sodium diet.53,54,56,57 It is not possible to identify indi-vidual patients for whom sodium reduction is especially effective58 (see Section 3 in the Sup-plementary Appendix).

Two reduced-carbohydrate versions of the

DASH diet were studied in 164 adults enrolled in the Optimal Macronutrient Intake Trial to Pre-vent Heart Disease (OmniHeart).46,50 One diet higher in unsaturated fat and another higher in protein were compared with a diet similar to the standard DASH diet but slightly higher in carbo-hydrates. As compared with the high-carbohy-drate diet, the high-protein diet reduced mean systolic blood pressure in participants with hy-pertension by 3.5 mm Hg and mean diastolic blood pressure by 2.4 mm Hg (P = 0.006 and P = 0.008, respectively).50 The comparable effects of the diet high in unsaturated fat were 2.9 and 1.9 mm Hg, respectively (P = 0.02 for both). As with the DASH diet itself, these effects were less pronounced in participants who did not have hypertension at baseline.

The traditional Mediterranean diet47,48 has many similarities to DASH-type diets, especially

Mea

n Sy

stol

ic B

lood

Pre

ssur

e (m

m H

g)

145

135

140

130

125

0

Dietary Sodium

High (3.5 g) Intermediate (2.3 g) Low (1.2 g)

Control diet

DASH diet

−2.1 (−0.1 to −4.0)

−1.6 (0.6 to −3.8)

−5.1 (−3.0 to −7.3)

−6.0 (−4.0 to −7.9) −8.0 (−4.9 to−11.1) −7.5 (−4.2 to

−10.8)

−6.7 (−3.5 to−9.8)

Higher to lower sodiumControl: −8DASH: −7

Lower-sodium DASH vs. higher-sodium control: −15

Figure 2. Sodium Reduction, the DASH Diet, and Changes in Systolic Blood Pressure.

The figure shows the additive beneficial effects of the DASH diet and reduced intake of sodium on systolic blood pressure in patients with mild hyperten-sion who were older than 45 years of age. The participants were a subgroup of those in the study of the effects of the DASH diet and reductions in dietary sodium,53 who were randomly assigned to follow a DASH diet (33 partici-pants) or a typical U.S. diet (37 participants) for 90 days. During that period, each group consumed three versions of the diet adjusted for daily sodium content. The participants in each group consumed each of the sodium- adjusted diets for 30 days in a crossover design; body weight was held con-stant. The two downward-sloping arrows on the left depict the effect of in-termediate sodium intake as compared with higher sodium intake, and the two downward-sloping arrows on the right depict the effect of lower sodium intake as compared with intermediate sodium intake. The dotted lines show the effect of the DASH diet as compared with the typical U.S. diet at each level of dietary sodium. Numbers shown represent the mean changes with 95% confidence intervals. Adapted from Bray et al.54

84



to the diet from the OmniHeart study that was higher in unsaturated fat. In controlled trials involving patients with the metabolic syndrome51 or type 2 diabetes,52 a reduced-carbohydrate Med-iterranean diet lowered blood pressure and im-proved serum lipid levels more than a low-fat diet. In these trials, unlike the DASH trials, weight was not held constant through caloric adjustment; in both cases, patients assigned to the Mediterranean diet lost more weight than those assigned to the low-fat diet.

Epidemiologic studies generally support evi-dence from clinical trials on the effects of di-etary management, as do community-based and clinic-based intervention programs (see Sections 4 and 5 in the Supplementary Appendix).

The effect of adding weight loss to the DASH diet was evaluated in 144 adults in the Exercise

and Nutrition Interventions for Cardiovascular Health (ENCORE) study.59 Participants were ran-domly assigned to a control diet, to the DASH diet alone, or to a reduced-calorie modification of the DASH diet. At 4 months, blood pressure was reduced by 3.4/3.8 mm Hg in the control group, by 11.2/7.5 mm Hg in the group given the DASH diet alone (P<0.001 for both systolic and diastolic pressures as compared with the control diet), and 16.1/9.9 mm Hg with the DASH diet plus weight management (P = 0.02 for systolic blood pressure and P = 0.05 for diastolic blood pressure as compared with the DASH diet alone).

Clinical Use

Dietary management is appropriate for all pa-tients with hypertension. In addition, patients with prehypertension (systolic blood pressure between 120 and 139 mm Hg or diastolic blood pressure between 80 and 89 mm Hg) should adopt the same dietary changes, given the benefit of di-etary therapy at these blood-pressure levels.

Drug therapy plays an essential role in treat-ing hypertension. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pres-sure emphasizes that in patients for whom life-style modification (including dietary therapy, physical activity, and moderation of alcohol con-sumption) does not reduce blood pressure below 140/90 mm Hg (or 130/80 mm Hg for patients with diabetes or chronic renal disease), drug therapy should be implemented and modified over time given a patient’s response.2 However, medication should not supplant dietary manage-ment; rather, the two forms of treatment should be considered complementary. The DASH diet is effective in combination with angiotensin-recep-tor blockers.60 Sodium reduction is highly effec-tive in older patients with hypertension who are taking antihypertensive medicines61 and in those with resistant hypertension taking several anti-hypertensive agents.62

We guide patients in adopting a healthful diet with the use of a chart or table such as that shown in Table 1. In simple terms, we encourage patients to eat poultry, fish, nuts, and legumes instead of red meat; low-fat and nonfat dairy products instead of full-fat dairy products; veg-etables and fruit instead of snacks and desserts high in sugars; breads and pastas made from whole grain instead of white flour; fruit itself

Mea

n Sy

stol

ic B

lood

Pre

ssur

e (m

m H

g) 145

135

140

130

125

115

120

023–41 48–5442–47 55–76

Age (yr)

Typical diet,high sodium

DASH diet,low sodium

Figure 3. Effects of a Low-Sodium DASH Diet on Systolic Blood Pressure with Increasing Age.

A total of 412 participants were randomly assigned to follow a DASH diet (208 participants) or a typical U.S. diet (control group, 204 participants) for 90 days. Dur-ing that period, each group consumed three versions of the diet adjusted for daily sodium content: high (3.5 g), intermediate (2.3 g), and low (1.2 g). The participants in each group consumed each of the sodium-adjusted diets for 30 days in a crossover design; body weight was held constant. Mean (±SD) systolic blood pressure is depicted for the DASH group during the period of low sodium intake and for the control group during the period of high sodium intake, according to age, at the end of the 30-day period; there were 45 to 58 partici-pants per group in each of the four age ranges shown. The slope for the control group during the period of high sodium intake was 0.3 mm Hg per year, spanning 30 years. The slope for the DASH-diet group during the period of low sodium intake was 0 mm Hg per year. I bars denote 95% confidence intervals. Data are from Sacks et al.53

85



rather than fruit juice; and polyunsaturated and monounsaturated cooking oils such as olive, cano-la, soybean, peanut, corn, sunflower, or safflower rather than butter, coconut oil, or palm-kernel oil. Table 1 provides information about the num-ber of servings and portion sizes for each type of food that should be consumed in 1 week.

Adopting a healthful dietary approach means making the correct choices at the market so that the most healthful foods will be available at home. The recommendations in Table 1 include a food-shopping guide. In the United States, it is common to place healthful foods at the periphery of the market; most weekly shopping should be concentrated there. Use of canned and processed foods should be limited, unless their salt content has been reduced or virtually eliminated. For con-venience, low-sodium, frozen, or canned vegeta-bles can be substituted for fresh ones. Sections of the market that contain sweetened beverages, candies, and cookies should be avoided entirely.

Sodium restriction is central to the dietary management of hypertension. Patients should be-come familiar with reading the food labels that specify the sodium content of packaged and processed foods.63 Processed foods are often high in sodium. A low sodium diet is sometimes less palatable for patients who are accustomed to a high-sodium diet; however, tastes adapt quickly, and studies have shown that low-sodium diets can be as acceptable to patients as higher-sodium diets.64 Herbs, spices, and citrus fruit (juice or peel) and other acidic ingredients such as vinegar can be added to dishes to compensate for low sodium content and may even be preferred over foods with higher amounts of sodium.

Patients should not skip meals, should con-sume one third of their daily food intake at break-fast, and should limit eating in restaurants to no more than once weekly. Eating in many restau-rants subverts the goal of a low-sodium diet, since one serving of some soups, sandwiches, fried chicken, or pizza can far exceed the total recommended daily amount of sodium.65 The health care reform law includes a requirement that all chain restaurants with more than 20 locations provide information for consumers regarding the amount of sodium and other di-etary components in menu items.66

Compliance with dietary therapy is better, and success rates in achieving blood-pressure control are higher, when accompanied by active guidance

or counseling of the patient by clinicians or an-cillary medical personnel with expertise in dietary management.67-72 We always recommend that pa-tients record their dietary intake for 1 or 2 weeks and discuss this record with a dietitian, who will provide specific meal plans. This is especially important when weight loss is needed. Follow-up with a dietitian is essential, whether arranged in individual or group appointments. In addition, numerous Web sites73-76 and books77-80 can pro-vide patients with further information and guid-ance on healthful diets.

The costs associated with dietary treatment of hypertension are relatively modest. In one study in the Boston area conducted in 2006, the cost of the DASH meal plan was $31 per week in areas with low socioeconomic status and $40 per week in areas with high socioeconomic status; perceived affordability was similar for patients interviewed in clinics in both areas.81 An initial consultation with a dietitian costs approximately $150, and follow-up consultations about $100. Coverage of this service by health insurance or employer programs varies.

Adverse Effects

Adverse events generally occurred less frequently in persons following the DASH diet and its vari-ants or Mediterranean diets49,52,53 (see Section 6 in the Supplementary Appendix).


One crucial frontier of dietary research is that of devising and evaluating effective behavioral and community-based interventions. In the DASH trials, dietary modifications were studied over a short time span, and participants were carefully monitored for compliance. Compliance is an es-sential element in the long-term dietary treatment therapy of hypertension, and we need to learn what components of behavioral interventions lead to adherence.82 In addition, no large, long-term, clinical-outcomes trial of these diets has been performed, although one long-term obser-vational study of an earlier randomized trial and one relatively short-term randomized trial report-ed a decrease in the incidence of cardiovascular events with sodium reduction (see Section 7 in the Supplementary Appendix).83,84 However, we be-lieve that it is not necessary to conduct a large-scale, randomized trial to address this question in

86



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view of the known benefits of healthful diets with regard to blood pressure and other risk factors.

Guidelines

We recommend the American Heart Association guidelines for cardiovascular health and the di-etary management of hypertension.85,86 These guidelines endorse foods and approaches to diet similar to those included in the DASH diet and cite intake of 65 mmol, or 1.5 g, of sodium per day as optimal. In addition, a target BMI of less than 25 is recommended. Finally, the guidelines recommend no more than two alcoholic drinks per day for men and one for women and people of lighter weight. (One drink is equivalent to 12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof liquor, each of which represents approximately 14 g of ethyl alcohol.)


The diet of the patient described in our vignette is very different from the healthful diets recom-

mended for the management of hypertension, and it is therefore reasonable to assume that di-etary change could normalize her blood pres-sure. The patient should be given written instruc-tions on how to adopt a healthful diet such as the DASH diet, a reduced-carbohydrate version of the DASH diet, or a Mediterranean-style diet. The in-structions should include ways to substantially reduce sodium intake. We also recommend a small consistent daily reduction in caloric intake of 200 to 300 kcal per day, coupled with an in-crease in physical activity. Her physician should schedule a consultation with a dietitian, including a regular schedule of follow-up visits. The pa-tient should monitor her blood pressure at home, with an automated machine, at least once a month, preferably more frequently. A trial of inten-sive dietary treatment is warranted for 6 months to try to achieve the targeted goal for blood pres-sure (systolic blood pressure <140 mm Hg, dia-stolic blood pressure <90 mm Hg) before medi-cation is introduced.

No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References

1. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the Interna-tional Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; Ameri-can Heart Association; World Heart Feder-ation; International Atherosclerosis Soci-ety; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Eval-uation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52.3. Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet 2008;371:1513-8.4. Rao MV, Qiu Y, Wang C, Bakris G. Hypertension and CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES), 1999-2004. Am J Kidney Dis 2008;51:Suppl 2:S30-S37.5. Hajjar I, Kotchen JM, Kotchen TA. Hy-pertension: trends in prevalence, incidence and control. Annu Rev Public Health 2006;27:465-90.6. Ezzati M, Oza S, Danaei G, Murray CJ. Trends and cardiovascular mortality ef-fects of state-level blood pressure and uncontrolled hypertension in the United States. Circulation 2008;117:905-14.

7. Mellen PB, Gao SK, Vitolins MZ, Goff DC Jr. Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 1999-2004. Arch Intern Med 2008;168:308-14.8. Blanck HM, Gillespie C, Kimmons JE, Seymour JD, Serdula MK. Trends in fruit and vegetable consumption among U.S. men and women, 1994-2005. Prev Chron-ic Dis 2008;5:A35.9. Okosun IS, Prewitt TE, Cooper RS. Abdominal obesity in the United States: prevalence and attributable risk of hyper-tension. J Hum Hypertens 1999;13:425-30.10. Saile F. Uber den einf lus der vege-tarischen ernahrung auf den blutdruck. Med Klin 1930;25:929-31.11. Sacks FM, Rosner B, Kass EH. Blood pressure in vegetarians. Am J Epidemiol 1974;100:390-8.12. Sacks FM, Kass EH. Low blood pres-sure in vegetarians: the effects of specific foods and nutrients. Am J Clin Nutr 1988;48:Suppl:795-800.13. Epstein FH, Eckoff RD. The epidemi-ology of high blood pressure — geo-graphic distributions and etiological fac-tors. In: Stamler J, Stamler R, Pullman TN, eds. The epidemiology of hypertension. New York: Grune & Stratton, 1967:155-66.14. Rodriguez BL, Labarthe DR, Huang B, Lopez-Gomez J. Rise in blood pressure with age: new evidence of population dif-ferences. Hypertension 1994;24:779-85.

15. Elliott P, Stamler J, Nichols R, et al. Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations. BMJ 1996;312:1249-53. [Erratum, BMJ 1997;315:458.]16. Adrogué HJ, Madias NE. Sodium and potassium in the pathogenesis of hyper-tension. N Engl J Med 2007;356:1966-78.17. Primary hypertension: pathogenesis. In: Kaplan NM. Kaplan’s clinical hyper-tension. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2006:50-121.18. O’Shaughnessy KM, Karet FE. Salt handling and hypertension. Annu Rev Nutr 2006;26:343-65.19. Blacher J, Safar ME. Large-artery stiff-ness, hypertension and cardiovascular risk in older patients. Nat Clin Pract Cardio-vasc Med 2005;2:450-5.20. Berk BC. Biology of the vascular wall in hypertension. In: Brenner BM, ed. Brenner & Rector’s the kidney. 7th ed. Vol. 2. Phil-adelphia: Saunders Elsevier, 2004:1999-2022.21. Gates PE, Strain WD, Shore AC. Hu-man endothelial function and microvas-cular ageing. Exp Physiol 2009;94:311-6.22. de Jongh RT, Serné EH, Ijzerman RG, Stehouwer CD. Microvascular function: a potential link between salt sensitivity, insulin resistance and hypertension. J Hy-pertens 2007;25:1887-93.23. Lee MA, Böhm M, Paul M, Ganten D. Tissue renin-angiotensin systems: their

89



role in cardiovascular disease. Circulation 1993;87:Suppl:IV-7–IV-13.24. Re RN. Mechanisms of disease: local renin-angiotensin-aldosterone systems and the pathogenesis and treatment of cardio-vascular disease. Nat Clin Pract Cardio-vasc Med 2004;1:42-7.25. Landsberg L, Young JB. Diet and the sympathetic nervous system: relationship to hypertension. Int J Obes 1981;5:Suppl 1:79-91.26. Esler M, Straznicky N, Eikelis N, Masuo K, Lambert G, Lambert E. Mecha-nisms of sympathetic activation in obesity-related hypertension. Hypertension 2006;48:787-96.27. Victor RG, Shafiq MM. Sympathetic neural mechanisms in human hyperten-sion. Curr Hypertens Rep 2008;10:241-7.28. Feldstein C, Julius S. The complex in-teraction between overweight, hyperten-sion, and sympathetic overactivity. J Am Soc Hypertens 2009;3:353-65.29. Hall JE, Hildebrandt DA, Kuo J. Obe-sity hypertension: role of leptin and sym-pathetic nervous system. Am J Hypertens 2001;14:103S-115S.30. Hall JE. The kidney, hypertension, and obesity. Hypertension 2003;41:625-33.31. Seals DR, Moreau KL, Gates PE, Es-kurza I. Modulatory influences on ageing of the vasculature of healthy humans. Exp Gerontol 2006;41:501-7.32. Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney dis-ease: the role of fetal programming. Hyper-tension 2006;47:502-8.33. Sealey JE, Blumenfeld JD, Bell GM, Pecker MS, Sommers SC, Laragh JH. On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasocontriction-volume relationship. J Hypertens 1988;6:763-77.34. Safar ME, Temmar M, Kakou A, Lacol-ley P, Thornton SN. Sodium intake and vascular stiffness in hypertension. Hyper-tension 2009;54:203-9.35. Engeli S, Böhnke J, Gorzelniak K, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005;45:356-62.36. Ho JT, Keogh JB, Bornstein SR, et al. Moderate weight loss reduces renin and aldosterone but does not influence basal or stimulated pituitary-adrenal axis func-tion. Horm Metab Res 2007;39:694-9.37. Straznicky NE, Lambert EA, Lambert GW, Masuo K, Esler MD, Nestel PJ. Effects of dietary weight loss on sympathetic ac-tivity and cardiac risk factors associated with the metabolic syndrome. J Clin Endo-crinol Metab 2005;90:5998-6005.38. Straznicky NE, Lambert EA, Nestel PJ, et al. Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome sub-jects. Diabetes 2010;59:71-9.

39. Rocchini AP, Key J, Bondie D, et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese ado-lescents. N Engl J Med 1989;321:580-5.40. Pierce GL, Beske SD, Lawson BR, et al. Weight loss alone improves conduit and resistance artery endothelial function in young and older overweight/obese adults. Hypertension 2008;52:72-9.41. Akita S, Sacks FM, Svetkey LP, Conlin PR, Kimura G. Effects of the Dietary Ap-proaches to Stop Hypertension (DASH) diet on pressure-natriuresis relationship. Hypertension 2003;42:8-13.42. Al-Solaiman Y, Jesri A, Zhao Y, Morrow JD, Egan BM. Low-sodium DASH reduces oxidative stress and improves vascular function in salt-sensitive humans. J Hum Hypertens 2009;23:826-35.43. Rallidis LS, Lekakis J, Kolomvotsou A, et al. Close adherence to a Mediterranean diet improves endothelial function in sub-jects with abdominal obesity. Am J Clin Nutr 2009;90:263-8.44. McCall DO, McGartland CP, McKinley MC, et al. Dietary intake of fruits and veg-etables improves microvascular function in hypertensive subjects in a dose-dependent manner. Circulation 2009;119:2153-60.45. Sacks FM, Obarzanek E, Windhauser MM, et al. Rationale and design of the Dietary Approaches to Stop Hypertension trial (DASH): a multicenter controlled-feeding study of dietary patterns to lower blood pressure. Ann Epidemiol 1995;5:108-18.46. Swain JF, McCarron PB, Hamilton EF, Sacks FM, Appel LJ. Characteristics of the dietary patterns tested in the Optimal Mac-ronutrient Intake Trial to Prevent Heart Disease (OmniHeart): options for a heart-healthy diet. J Am Diet Assoc 2008;108:257-65.47. Trichopoulou A. Mediterranean diet: the past and the present. Nutr Metab Car-diovasc Dis 2001;11:Suppl:1-4.48. Kokkinos P, Panagiotakos DB, Poly-chronopoulos E. Dietary inf luences on blood pressure: the effect of the Mediter-ranean diet on the prevalence of hyperten-sion. J Clin Hypertens (Greenwich) 2005;7:165-70.49. Appel LJ, Moore TJ, Obarzanek E, et al. The effect of dietary patterns on blood pressure: results from the Dietary Ap-proaches to Stop Hypertension trial. N Engl J Med 1997;336:1117-24.50. Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the Omni-Heart randomized trial. JAMA 2005;294:2455-64.51. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292:1440-6.

52. Esposito K, Maiorino MI, Ciotola M, et al. Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes: a randomized trial. Ann Intern Med 2009;151:306-14. [Erratum, Ann Intern Med 2009;151:591.]53. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approach-es to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3-10.54. Bray GA, Vollmer WM, Sacks FM, Obarzanek E, Svetkey LP, Appel LJ. A fur-ther subgroup analysis of the effects of the DASH diet and three dietary sodium levels on blood pressure: results of the DASH-Sodium Trial. Am J Cardiol 2004;94:222-7. [Erratum, Am J Cardiol 2010;105:579.]55. Goff DC, Howard G, Russell GB, La-barthe DR. Birth cohort evidence of popu-lation influences on blood pressure in the United States, 1887-1994. Ann Epidemiol 2001;11:271-9.56. Uzu T, Kimura G, Yamauchi A, et al. Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in es-sential hypertension. J Hypertens 2006;24:1627-32.57. Chen J, Gu D, Huang J, et al. Meta-bolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study. Lan-cet 2009;373:829-35.58. Obarzanek E, Proschan MA, Vollmer WM, et al. Individual blood pressure re-sponses to changes in salt intake: results from the DASH-Sodium trial. Hyperten-sion 2003;42:459-67.59. Blumenthal JA, Babyak MA, Hinder-liter A, et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and car-diovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 2010;170:126-35.60. Conlin PR, Erlinger TP, Bohannon A, et al. The DASH diet enhances the blood pressure response to losartan in hyper-tensive patients. Am J Hypertens 2003;16:337-42.61. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA 1998;279:839-46.62. Pimenta E, Gaddam KK, Oparil S, et al. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension. Hypertension 2009;54:475-81.63. Grimes CA, Riddell LJ, Nowson CA. Consumer knowledge and attitudes to salt intake and labelled salt information. Appetite 2009;53:189-94.64. Karanja N, Lancaster KJ, Vollmer WM, et al. Acceptability of sodium-reduced re-

90



search diets, including the Dietary Ap-proaches to Stop Hypertension diet, among adults with prehypertension and stage 1 hypertension. J Am Diet Assoc 2007;107:1530-8.65. Salt-assault: brand-name comparisons of processed foods. 2nd ed. Washington, DC: Center for Science and the Public Interest, 2008:1-31. (Accessed May 7, 2010, at http://www.cspinet.org/new/pdf/saltupdatedec08.pdf.)66. Pear R. New health initiatives put spot-light on prevention. New York Times. April 5, 2010:A10. (Accessed May 7, 2010, at http://www.nytimes.com/2010/04/05/health/policy/05health.html.)67. Rankins J, Sampson W, Brown B, Jenkins-Salley T. Dietary Approaches to Stop Hypertension (DASH) intervention reduces blood pressure among hyperten-sive African American patients in a neigh-borhood health care center. J Nutr Educ Behav 2005;37:259-64.68. Svetkey LP, Stevens VJ, Brantley PJ, et al. Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial. JAMA 2008;299:1139-48.69. Hsieh YC, Hung CT, Lien LM, et al. A significant decrease in blood pressure through a family-based nutrition health education programme among community residents in Taiwan. Public Health Nutr 2008;12:570-7.70. Wood DA, Kotseva K, Connolly S, et al. Nurse-coordinated multidisciplinary, family-based cardiovascular disease pre-vention programme (EUROACTION) for

patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster-randomised controlled trial. Lancet 2008;371:1999-2012.71. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with dif-ferent compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360:859-73.72. Eriksson MK, Franks PW, Eliasson M. A 3-year randomized trial of lifestyle inter-vention for cardiovascular risk reduction in the primary care setting: the Swedish Björknäs study. PLoS One 2009;4(4):e5195.73. Oldways Web site. (Accessed May 7, 2010, at http://www.oldwayspt.org.)74. Mediterranean Foods Alliance Web site. (Accessed May 7, 2010, at http://mediterraneanmark.org/index.html.)75. MayoClinic.com. DASH diet recipes. (Accessed May 7, 2010, at http://www.mayoclinic.com/health/dash-diet-recipes/RE00089.)76. DASH for Health Web site. (Accessed May 7, 2010, at http://www.dashforhealth.com.)77. Katzen M, Willett W. Eat, drink, and weigh less: a flexible and delicious way to shrink your waist without going hungry. New York: Hyperion, 2006.78. Your guide to lowering your blood pressure with DASH. Bethesda, MD: Na-tional Heart, Lung, and Blood Institute, 2006.79. Moore T, Svetkey L, Lin PH, Karanja N. The DASH diet for hypertension. New York: Free Press, 2001:1-264.

80. American Heart Association. No-fad diet: a personal plan for healthy weight loss. New York: Clarkson Potter, 2005.81. Young CM, Batch BC, Svetkey LP. Ef-fect of socioeconomic status on food availability and cost of the Dietary Ap-proaches to Stop Hypertension (DASH) dietary pattern. J Clin Hypertens (Green-wich) 2008;10:603-11.82. Williamson DA, Anton SD, Han H, et al. Adherence is a multi-dimensional con-struct in the POUNDS LOST trial. J Behav Med 2010;33:35-46.83. Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduc-tion on cardiovascular disease outcomes: observational follow-up of the Trials of Hypertension Prevention (TOHP). BMJ 2007;334:885-8.84. Chang HY, Hu YW, Yue CS, et al. Ef-fect of potassium-enriched salt on cardio-vascular mortality and medical expenses of elderly men. Am J Clin Nutr 2006;83:1289-96.85. Appel LJ, Brands DW, Daniels SR, Karanja N, Elmer PJ, Sacks FM. Dietary approaches to prevent and treat hyperten-sion: a scientific statement from the Amer-ican Heart Association. Hypertension 2006;47:296-308.86. Lichtenstein AH, Appel LJ, Brands M, et al. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006;114:82-96. [Errata, Circulation 2006;114(1):e27, 114(23):e629.]Copyright © 2010 Massachusetts Medical Society.

COLLECTIONS OF ARTICLES ON THE JOURNAL’S WEB SITE

The Journal’s Web site (NEJM.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient

entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.

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n engl j med 361;23 nejm.org december 3, 2009 2261



Mitral-Valve Repair for Mitral-Valve ProlapseSubodh Verma, M.D., Ph.D., and Thierry G. Mesana, M.D., Ph.D.

From the Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto (S.V.); and the Division of Cardiac Surgery, Ottawa Heart Institute, Univer-sity of Ottawa, Ottawa (T.G.M.). Address reprint requests to Dr. Verma at St. Mi-chael’s Hospital, University of Toronto, 30 Bond St., Toronto, ON M5B 1W8, Can-ada, or at [email protected].


A 55-year-old man with a holosystolic murmur of increasing intensity has been seen regularly by his family physician for the past 3 years. He is referred to a cardiologist. The patient reports no shortness of breath, chest pain, or palpitations. An electrocar-diogram shows normal sinus rhythm. A transthoracic echocardiogram reveals se-vere, anteriorly directed mitral regurgitation with isolated prolapse of the middle scallop of the posterior leaflet. Flow reversal is detected in the pulmonary veins. The calculated regurgitant volume is 75 ml, the regurgitant fraction 63%, and the effec-tive regurgitant orifice 53 mm2, features consistent with severe mitral regurgitation. The transthoracic echocardiogram also shows mildly depressed left ventricular func-tion (ejection fraction, 58%), slightly elevated left ventricular dimensions (end-systolic dimension, 42 mm), and normal right ventricular systolic pressure. The patient is referred to a cardiac surgeon for consideration of mitral-valve repair.


Mitral-valve prolapse is defined as the displacement of some portion of one or both leaflets of the mitral valve into the left atrium during systole. In developed coun-tries, it is the most common cause of chronic mitral regurgitation; in a study of the Framingham Offspring Study cohort, the prevalence of mitral-valve prolapse was 2.5%.1 More than 150 million people worldwide may be affected.2-4 The disorder has both genetic and acquired forms, and several chromosomal loci for autosomal dominant mitral-valve prolapse have been identified.5-9 Although mitral-valve pro-lapse is more common in women, more men are referred for surgery4; whether this reflects a difference between the sexes in the morphologic features or natural his-tory of the disorder or referral bias is unclear.

The natural history of mitral-valve prolapse is heterogeneous and is largely determined by the severity of mitral regurgitation. Although a majority of patients remain asymptomatic and may have a near-normal life expectancy, approximately 5 to 10% have progression to severe mitral regurgitation.10,11 Left untreated, mitral-valve prolapse with severe mitral regurgitation results in limiting symptoms, left ventricular dysfunction, heart failure, pulmonary hypertension, and atrial fibrilla-tion. Spontaneous rupture of mitral chordae may occur, and endocarditis and stroke are serious complications. The mortality rate of persons who have mitral-valve prolapse with severe mitral regurgitation is approximately 6 to 7% per year.12,13

Pathoph ysiol ogy a nd the Effec t of Ther a py

The mitral valve and subvalvular apparatus include the annulus, valve leaflets, chor-dae tendineae, papillary muscles, and left ventricular wall. The valve has anterior and posterior leaflets, and each leaflet typically consists of three discrete segments or scallops. These are designated P1, P2, and P3 in the posterior mitral-valve leaflet,

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n engl j med 361;23 nejm.org december 3, 20092262

and A1, A2, and A3 in the anterior leaflet (Fig. 1). The valve leaflets receive chordae tendineae from the antero lateral and posteromedial papillary

muscles. Competence of the mitral valve relies on coordinated interaction of the valve and subvalvu-lar apparatus. During systole, the papillary mus-

Left coronaryartery

Circumflexartery

AC PC

AC

B C

A

A1

P1

P2

P3A2

A3 PC

Left fibroustrigone

Right fibroustrigone

Bundle ofHis

Anterior leaflet

Posterior leaflet

Annulus

Annulus

Leaflet

Primarycord

Papillarymuscle

Secondarycord

Coronarysinus

Aortic valve

Figure 1. The Mitral Valve.

The mitral valve has anterior and posterior leaflets, which are separated by the anterior commissure (AC) and the posterior commissure (PC) (Panel A). The leaflets are inserted on the circumference of the mitral annulus, which is in continuity with the aortic annulus and the left and right fibrous trigones. The circumflex coronary artery, coronary sinus, aortic valve, and bundle of His are all close to the mitral valve. Panel B shows the mitral-valve leaflets, each of which usually consists of three discrete segments or scallops. These are designated A1, A2, and A3 for the anterior leaflet and P1, P2, and P3 for the posterior leaflet. The valve leaflets each receive chordae tendineae from the anter-olateral and posteromedial papillary muscles (Panel C). Primary chordae are attached to the free edge of the valve leaflet, and secondary chordae are attached to the ventricular surface of the leaflet.

93



cles contract, increasing tension on the chordae tendineae and preventing the valve leaflets from everting into the left atrium.

Mitral-valve prolapse is characterized predom-inantly by myxomatous degeneration. In younger patients, the disease is often manifested by excess leaflet tissue and is known as Barlow’s syndrome, the most extreme form of myxomatous degen-eration. On the other hand, in older patients, the prolapsing mitral valve tends not to have excess leaflet tissue, an entity known as fibroelastic deficiency. Both conditions can lead to leaflet prolapse and chordal elongation or rupture, repre-senting the spectrum of degenerative mitral-valve disease.14 These anatomic abnormalities result in the mitral orifice not closing completely dur-ing systole, causing regurgitation. Annular dila-tation may also develop over time, leading to further progression of mitral regurgitation.

Patients with mild-to-moderate mitral regur-gitation from mitral-valve prolapse may remain asymptomatic and without clinical deterioration for many years. However, increasing severity of mitral regurgitation, even among asymptomatic patients, imposes a volume load on the left ven-tricle, which, if sustained over time, results in ventricular dilatation, hypertrophy, neurohumoral activation, and heart failure. In addition, elevation in the mean left atrial pressure leads to left atrial enlargement, atrial fibrillation, pulmonary congestion, and pulmonary hypertension.

The goal of surgical correction for mitral-valve prolapse is to restore a competent mitral valve. There are two options for surgical correction of severe mitral regurgitation due to mitral-valve prolapse: valve replacement or valve repair.

Mitral-valve replacement can be performed with the use of either a mechanical or a biologic prosthesis. However, there are several drawbacks to mitral-valve replacement. These include the need for lifelong anticoagulation therapy and the risk of thromboembolism with the use of me-chanical valves; the risk of prosthetic-valve dete-rioration and failure with the use of bioprosthetic valves; and the risk of prosthetic-valve endo-carditis. In addition, if the chordae tendineae are severed during surgery, the ventricular wall is no longer anchored to the valve apparatus, and the tethering effect of the chordae is lost. As a re-sult, left ventricular wall stress increases and left ventricular function deteriorates.15-19 The goals of mitral-valve repair are to obtain a proper line of coaptation on both leaflets, to correct annular

dilatation, and to preserve (or repair, if neces-sary) the subvalvular apparatus.


We are unaware of any randomized trials that have compared medical management to surgery for severe mitral regurgitation due to mitral-valve prolapse. However, evidence from observational series strongly suggests that surgical interven-tion is beneficial.12,20-22 One study evaluated the effect of early surgery on long-term outcomes in 221 patients who had mitral regurgitation with flail leaflets.20 The 63 patients undergoing sur-gery within 1 month after diagnosis had a sig-nificantly better 10-year survival rate than those whose mitral regurgitation was managed con-servatively (79% vs. 65%; adjusted risk ratio, 0.30; 95% confidence interval [CI], 0.12 to 0.71; P = 0.008). In another report, 394 patients with mitral regurgitation and flail leaflets were stud-ied.21 During a median follow-up period of 3.9 years, the linearized mortality rate associated with nonsurgical management was 2.6% per year. Mitral-valve surgery was performed in 315 pa-tients (repair in 250, replacement in 65). Surgical intervention was independently associated with a reduced risk of death (adjusted hazard ratio for death, 0.42; 95% CI, 0.21 to 0.84; P = 0.01).

To our knowledge, there are also no random-ized trials comparing mitral-valve repair with replacement. Again, however, data from obser-vational studies suggest a benefit of mitral re-pair.23-26 A meta-analysis of 29 studies compared mitral-valve repair with replacement for various conditions, including myxomatous degenera-tion.23 Mitral-valve replacement was associated with lower survival than was repair (hazard ratio for death, 1.58; 95% CI, 1.41 to 1.78).

In a study from Finland, mitral-valve repair was compared with replacement in 184 consecu-tive patients who were followed for a mean of 7.3 years.24 There was a significant survival benefit for the patients who underwent mitral-valve repair as compared with those who underwent replacement (5-year survival, 81.2% vs. 73.5%), which persisted after adjustment for baseline propensity score (P = 0.02). In contrast, in a report from the Cleveland Clinic, 3286 patients who underwent an isolated primary operation for degenerative mitral-valve disease (mitral repair, 93%; mitral replacement, 7%) between 1985 and 2005 were studied.25 Propensity scoring was

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used to select 195 matched pairs for analysis. Among the propensity-matched patients, there was no significant difference in survival at 5, 10, or 15 years.

Clinic a l Use

Patients with mitral-valve prolapse should have a careful assessment of symptoms and should un-dergo electrocardiography (primarily to evaluate cardiac rhythm) and transthoracic echocardiog-raphy to assess the mechanism and severity of mitral regurgitation, as well as left ventricular size and function. A semiquantitative scale is often used to grade mitral regurgitation: 1+ (trace), 2+ (mild), 3+ (moderate), and 4+ (severe). How-ever, quantitative Doppler assessments are recom-mended to define severe mitral regurgitation more precisely; these variables include a regurgi-tant volume of at least 60 ml, a regurgitant frac-tion of at least 50%, and an effective regurgitant orifice of at least 40 mm2.27

Patients who have severe mitral regurgitation with symptoms or with left ventricular dysfunc-tion (ejection fraction, <60%), dilatation (left ventricular end-systolic dimension, >40 mm), or both should be offered surgery.28,29 Likewise, asymptomatic patients without left ventricular dysfunction or dilatation but with atrial fibrilla-tion or pulmonary hypertension should be con-sidered for surgery. Asymptomatic persons with mild-to-moderate mitral regurgitation and no evidence of left ventricular dysfunction or dilata-tion should be observed until the development of either symptoms or severe mitral regurgitation.

Before the advent of mitral-valve repair, valve replacement was the preferred procedure for se-vere mitral regurgitation. Valve replacement may still be preferred in certain situations, such as in patients with advanced age, infective endocardi-tis, a requirement for a combined or complex surgical procedure, or extensive calcifications of the leaflets or annulus. In such cases, chordal-sparing valve replacement for mitral regurgitation may be a suitable alternative to repair.

Individual and institutional experience is cru-cial in determining the likelihood of success of a repair procedure. High-volume centers have the lowest mortality rates and the highest propor-tion of patients undergoing mitral-valve repair rather than replacement.30 In counseling the pa-tient, the surgeon should precisely evaluate the likelihood of successful repair in light of his or

her own experience and may recommend a sec-ond opinion. If there is a possibility that intra-operative conversion to mitral replacement may be necessary, the decision between a mechanical valve and a bioprosthesis should be discussed with the patient before the operation.

Mitral-valve surgery is not recommended in patients with clinically significant coexisting conditions, such as advanced respiratory, hepatic, or renal dysfunction, or those with marked extra-cardiac arteriopathy or recent cerebrovascular events. Depressed left ventricular function is an independent predictor of poor outcomes but is not a contraindication to mitral-valve repair.31 In patients with coexisting coronary artery disease, mitral-valve repair combined with coronaryartery bypass surgery should be the procedure of choice.32 Two validated scoring systems for de-termining risk during cardiac surgery are com-monly used to determine perioperative risk.33,34

We routinely perform intraoperative trans-esophageal echocardiography during all mitral-valve repair procedures.28,29 Transesophageal echocardiography provides precise anatomic and functional information that is helpful in plan-ning the operation, including the extent of leaf-let deformity, the mechanism and severity of mitral regurgitation, the condition of the subval-vular apparatus, the diameter of the mitral an-nulus, left atrial dimensions, and ventricular function.35

Successful mitral-valve repair encompasses four general principles.36 First, repair must re-store an adequate surface of coaptation of both leaflets in systole.14,37 Second, full leaflet motion should be restored or preserved. Third, to pre-vent progressive dilatation, an annuloplasty ring or band should be used to reinforce the repair by stabilizing the annulus. Mitral-valve repair with-out annuloplasty reinforcement is not recom-mended. Last, the surgeon should ensure that no more than trace-to-mild mitral regurgitation is present at the completion of the repair.

In patients with isolated prolapse of the pos-terior middle scallop (P2), which is encountered in the majority of patients with degenerative mi-tral regurgitation, repair usually involves limited resection of this scallop, including the removal of the minimum number possible of adjacent chordae and supporting apparatus. The remain-ing segments of the posterior leaflet, namely P1 and P3, are then brought together (Fig. 2). If excessive posterior-leaflet tissue is present, the

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A

A1

A2

A3

A4

B1

B2

B3

B4

BIsolated prolapse ofthe posterior middle scallop

P1P2

P3

Incision line

Resectedarea

Plicationsutures

Reapproximationof remaining tissue

Completedsliding plasty

Excessivetissue

Incision lines

Annuloplastyring

Annuloplastyring

Resectedarea

Figure 2. Mitral-Valve Prolapse.

The most common leaflet abnormality seen in mitral-valve prolapse is isolated prolapse of the posterior middle scallop (P2) (Panel A1). In patients with isolated prolapse of P2, repair usually involves limited resection of this scallop by means of a quadrangular or triangular incision (Panel A2). The remaining parts of the posterior leaflet, namely P1 and P3, are then brought together (Panel A3). After the leaflet repair is complete, an annuloplasty ring or band is used to reinforce and stabilize the annulus, thus preventing progressive dilatation (Panel A4). If excessive posterior leaflet tissue is present (Panel B1), the height of the posterior leaflet is reduced by incising P1 and P3 from the annulus (Panel B2), followed by reapproximation of the free edges (“sliding plasty”) (Panel B3). After the leaflet repair is complete, an annuloplasty ring or band is inserted (Panel B4).

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height of the posterior leaflet is reduced by inci-sions in P1 and P3, followed by reapproximation of the free edges (“sliding plasty”) (Fig. 2). Finally, the annulus, which is distorted or dilated or both, is stabilized with an annuloplasty ring or band (Fig. 2). Limited resection, artificial chordal replacement (with Gore-Tex expanded polytetra-fluoroethylene sutures), or both may be appro-priate, followed by annuloplasty reinforcement, in cases of mitral-valve prolapse without redun-dant leaflet tissue.

Repairs of the anterior leaflet, either in isola-tion or with concomitant posterior leaflet repair, are more complex procedures that are best han-dled by surgeons who are experienced in mitral repair. Various techniques may be used, including limited triangular resection of the anterior leaf-let, chordal transposition, chordal shortening, artificial (Gore-Tex) chordal replacement, and edge-to-edge repair10,21,28,38-41 (Fig. 3).

The repair is assessed initially by visual inspec-tion and by injecting saline through the mitral valve to look for regurgitation (the “saline test”), and then by intraoperative transesophageal echo-cardiography after the patient is weaned from cardiopulmonary bypass. Patients should not leave the operating theater with more than 1+ mitral regurgitation on transesophageal echo-cardiography.36,42 Since anesthesia may result in substantial changes in preload and afterload, it is important to perform the intraoperative trans-esophageal echocardiography under conditions that approximate postoperative conditions in a patient who is awake. This can be achieved by adjusting inotropes and vasopressors to raise the afterload and blood pressure.

After mitral-valve repair, the left ventricle must be able to eject the entire stroke volume into the aorta. This constitutes a substantial in-crease in afterload as compared with ejection into the left atrium. Therefore, afterload reduc-tion is important to maintain optimal cardiac output. In addition, because myocardial dysfunc-tion may be present (even in patients with an apparently normal preoperative ejection frac-tion),43 inotropic support may be necessary to improve contractility. Patients with a low preop-erative ejection fraction and heart failure may require more intensive treatment to allow the left ventricle to recover, including temporary pacing, intraaortic balloon counterpulsation, or in rare cases, support with a ventricular assist device.

In the absence of preoperative atrial fibrilla-tion, and if normal sinus rhythm is maintained throughout hospital admission, aspirin alone may be sufficient for patients who had mitral-valve repair with ring annuloplasty. Otherwise, patients typically undergo anticoagulation with warfarin for 3 months, with a target international normal-ized ratio of 2.0 to 2.5. Antibiotic prophylaxis for dental procedures is recommended in all patients receiving an annuloplasty ring or other prosthetic material.44

There are currently no standard recommenda-tions regarding postoperative echocardiographic follow-up after mitral-valve repair. It is customary at our center to perform transthoracic echocar-diography once before discharge and again at 6 to 8 weeks after discharge. Usually patients are then transferred to the care of their cardiologist and family physician, and we recommend that echo-cardiography be performed annually thereafter.

We estimate that the overall costs for mitral-valve repair, including hospital admission, profes-sional fees, operating time, and prosthetic mate-rial (annuloplasty ring or band), are currently approximately $40,000 at our institution. Data from the Nationwide Inpatient Sample indicate that the mean estimated institutional cost for mitral repair in the United States increased from $28,405 in 2001 to $38,642 in 2005.45


Mitral-valve repair is associated with an operative mortality of 3% or less.22,38,46-50 This figure is nearer 1% in high-volume centers.30 The most common cause of death is heart failure. Predic-tors of death include advanced age, poorer New York Heart Association class, atrial fibrillation, lower preoperative ejection fraction, greater pre-operative left ventricular end-systolic dimension, and coexisting conditions including diabetes, renal disease, chronic lung disease, and obesity.22,38,51,52

In an analysis from the Society of Thoracic Surgeons National Adult Cardiac Surgery Data-base,52 major postoperative complications before discharge included prolonged (>24 hours) venti-latory support (7.3% of patients), renal failure (2.6%), and stroke (1.4%). Reoperation during initial hospitalization was required in 6.3% of patients. Thromboembolism after mitral-valve repair occurs in approximately 5% of patients within the first 5 years after surgery.38,39

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Intraoperative conversion to mitral-valve re-placement occurs in 2 to 10% of cases. Systolic anterior motion of the mitral valve may occur postoperatively if leaflet coaptation is not opti-mal, and mitral stenosis can occur if the annu-loplasty ring is too small. Other rare adverse effects of mitral-valve repair include damage to important structures around the mitral appara-tus, such as the circumflex coronary artery, the aortic valve, and the bundle of His.

The most important late complication of mi-tral-valve repair is recurrent mitral regurgitation, which may occur in as many as 30% of pa-tients.36 Reoperation to treat recurrent mitral re-gurgitation after primary repair is required in ap-proximately 0.5 to 1.5% of patients per year.49,51


We are unaware of any randomized trials that have compared mitral-valve repair with mitral-valve replacement for mitral-valve prolapse, and it is unlikely that such a trial will be conducted. Therefore, the current recommendation for mitral-valve repair in the treatment of severe degenera-tive mitral regurgitation is based on observation-al data.

It is unclear whether asymptomatic patients who have severe mitral regurgitation without left ventricular dysfunction or dilatation, atrial fibril-lation, or pulmonary hypertension should under-go early surgery. Some investigators have found evidence of reduced morbidity and mortality with surgery and recommend early intervention,22,50 whereas others have found that watchful waiting does not seem to result in worse outcomes.46 The guidelines of the American Heart Associa-tion (AHA) and the American College of Cardiol-ogy (ACC) recommend mitral-valve repair for such patients if the operative success rate is expected to exceed 90%.28,29 Conversely, the European So-

A

Gore-Tex sutures

Rupturedchorda tendinea

B

C

Chordal replacement

Chordal transfer

Edge-to-edge repair

Missing primarychorda tendinea

Transfer

Secondarychorda tendinea

Anterior leaflet

Posterior leaflet

Annuloplastyring

Figure 3. Special Repair Techniques.

Ruptured chordae tendineae can be replaced with an artificial substitute (Gore-Tex expanded polytetrafluoro-ethylene sutures) (Panel A). Ruptured or surgically severed primary chordae can be replaced with secondary chordae, a process called chordal transfer (Panel B). Edge-to-edge repair (Panel C) is performed by sewing the anterior and posterior leaflets together at the central points of their middle scallops, which corrects the prolapse while leaving two functional valve orifices on each side.

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ciety of Cardiology (ESC) recommends watchful waiting.53

There is growing experience with minimally invasive mitral-valve repair performed through a right minithoracotomy. In a single-center series involving 1339 patients, the 30-day mortality rate was 2.4%, the 5-year survival rate was estimated to be 82.6%, and the reoperation rate was 3.7%.54 These results are similar to those obtained with traditional mitral-valve repair. This approach re-quires further evaluation with respect to wide-spread generalizability and cost-effectiveness; it is currently performed at only a few specialized centers.

Guidelines

The ACC and the AHA established guidelines for the management of valvular disease in 2006, with an update in 2008.28,29 These guidelines gave a class I recommendation to mitral-valve surgery for chronic severe mitral regurgitation in the presence of symptoms, a left ventricular ejection fraction of less than 60%, or an end-systolic di-mension of more than 40 mm. Mitral-valve repair was recommended over replacement for most pa-tients (class I recommendation). The guidelines advise that such persons be referred to surgical centers at which the surgeons are experienced in mitral-valve repair. The ESC guidelines of 2007 made similar recommendations.53 As noted above,

the societies differ somewhat in terms of their recommendations for patients who have asymp-tomatic mitral-valve prolapse with severe mitral regurgitation but normal left ventricular volumes and function; the ACC–AHA guidelines give a class IIA recommendation in this regard.

R ecommendations

The patient in the vignette is asymptomatic but has signs of ventricular dysfunction and elevated left ventricular dimensions. He should therefore be offered mitral-valve surgery and should be re-ferred to a center with demonstrated expertise in mitral-valve repair. His operative risk should be formally assessed with the use of one of the vali-dated risk-scoring algorithms. Intraoperative trans-esophageal echocardiography should be per-formed to provide a detailed anatomical and functional assessment at the time of surgery that would permit a final decision to be made about the specifics of the operative procedure. Unless severe deformity of the valve leaflets or subvalvu-lar apparatus is present, we would recommend mitral-valve repair rather than replacement. Since mitral-valve prolapse is often genetically trans-mitted, it may be worth considering echocardio-graphic screening of first-degree relatives.

Dr. Mesana reports receiving honoraria from Medtronic. No oth-er potential conflict of interest relevant to this article was reported.

We thank Dr. Gilbert Tang for assistance in preparation of the manuscript.

References

1. Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med 1999;341:1-7.2. The changing spectrum of valvular heart disease pathology. In: Braunwald E, ed. Harrison’s advances in cardiology. New York: McGraw-Hill, 2002:317-23.3. Hayek E, Gring CN, Griffin BP. Mitral valve prolapse. Lancet 2005;365:507-18.4. Avierinos JF, Inamo J, Grigioni F, Gersh B, Shub C, Enriquez-Sarano M. Sex differences in morphology and outcomes of mitral valve prolapse. Ann Intern Med 2008;149:787-95.5. Shell WE, Walton JA, Clifford ME, Willis PW III. The familial occurrence of the syndrome of mid-late systolic click and late systolic murmur. Circulation 1969;39:327-37.6. Devereux RB, Brown WT, Kramer-Fox R, Sachs I. Inheritance of mitral valve pro-lapse: effect of age and sex on gene ex-pression. Ann Intern Med 1982;97:826-32.7. Disse S, Abergel E, Berrebi A, et al. Mapping of a first locus for autosomal dominant myxomatous mitral-valve pro-

lapse to chromosome 16p11.2-p12.1. Am J Hum Genet 1999;65:1242-51.8. Freed LA, Acierno JS Jr, Dai D, et al. A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4. Am J Hum Genet 2003;72:1551-9.9. Nesta F, Leyne M, Yosefy C, et al. New locus for autosomal dominant mitral valve prolapse on chromosome 13: clini-cal insights from genetic studies. Circula-tion 2005;112:2022-30.10. Barlow JB, Pocock WA. Mitral valve prolapse, the specific billowing mitral leaflet syndrome, or an insignificant non-ejection systolic click. Am Heart J 1979;97:277-85.11. Abrams J. Mitral valve prolapse: a plea for unanimity. Am Heart J 1976;92:413-5.12. Ling LH, Enriquez-Sarano M, Seward JB, et al. Clinical outcome of mitral regur-gitation due to flail leaflet. N Engl J Med 1996;335:1417-23.13. Rosen SE, Borer JS, Hochreiter C, et al. Natural history of the asymptomatic/minimally symptomatic patient with se-vere mitral regurgitation secondary to

mitral valve prolapse and normal right and left ventricular performance. Am J Cardiol 1994;74:374-80.14. Filsoufi F, Salzberg SP, Aklog L, Ad-ams DH. Acquired disease of the mitral valve. In: Selke F, Swanson S, del Nido P, eds. Sabiston and Spencer surgery of the chest. 7th ed. Philadelphia: Elsevier Saun-ders, 2005:1299-333.15. Pitarys CJ II, Forman MB, Panayiotou H, Hansen DE. Long-term effects of exci-sion of the mitral apparatus on global and regional ventricular function in humans. J Am Coll Cardiol 1990;15:557-63.16. Goldman ME, Mora F, Guarino T, Fuster V, Mindich BP. Mitral valvuloplasty is superior to valve replacement for pres-ervation of left ventricular function: an intraoperative two-dimensional echocar-diographic study. J Am Coll Cardiol 1987;10:568-75.17. Yacoub M, Halim M, Radley-Smith R, McKay R, Nijveld A, Towers M. Surgical treatment of mitral regurgitation caused by floppy valves: repair versus replacement. Circulation 1981;64:II-210–II-216.

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18. David TE, Uden DE, Strauss HD. The importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation. Circulation 1983;68:II-76–II-82.19. Okita Y, Miki S, Ueda Y, Tahata T, Sakai T, Matsuyama K. Comparative evalu-ation of left ventricular performance after mitral valve repair or valve replacement with or without chordal preservation. J Heart Valve Dis 1993;2:159-66.20. Ling LH, Enriquez-Sarano M, Seward JB, et al. Early surgery in patients with mitral regurgitation due to flail leaflets: a long-term outcome study. Circulation 1997;96:1819-25.21. Grigioni F, Tribouilloy C, Avierinos JF, et al. Outcomes in mitral regurgitation due to f lail leaf lets: a multicenter Euro-pean study. JACC Cardiovasc Imaging 2008;1:133-41.22. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, et al. Quantitative de-terminants of the outcome of asymptom-atic mitral regurgitation. N Engl J Med 2005;352:875-83.23. Shuhaiber J, Anderson RJ. Meta-analy-sis of clinical outcomes following surgi-cal mitral valve repair or replacement. Eur J Cardiothorac Surg 2007;31:267-75.24. Jokinen JJ, Hippeläinen MJ, Pitkänen OA, Hartikainen JE. Mitral valve replace-ment versus repair: propensity-adjusted survival and quality-of-life analysis. Ann Thorac Surg 2007;84:451-8.25. Gillinov AM, Blackstone EH, Nowicki ER, et al. Valve repair versus valve replace-ment for degenerative mitral valve dis-ease. J Thorac Cardiovasc Surg 2008;135:885-93.26. Zhao L, Kolm P, Borger MA, et al. Comparison of recovery after mitral valve repair and replacement. J Thorac Cardio-vasc Surg 2007;133:1257-63.27. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgi-tation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777-802.28. American College of Cardiology, Amer-ican Heart Association Task Force on Prac-tice Guidelines. ACC/AHA 2006 guide-lines for the management of patients with valvular heart disease: a report of the American College of Cardiology/Ameri-can Heart Association Task Force on Prac-tice Guidelines (Writing Committee to revise the 1998 guidelines for the man-agement of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiol-ogists endorsed by the Society for Cardio-vascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48(3):e1-e148.29. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporat-ed into the ACC/AHA 2006 guidelines for the management of patients with valvular

heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guide-lines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease): en-dorsed by the Society of Cardiovascular Anesthesiologists, Soceity for Cardiovas-cular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52(13):e1-e142.30. Gammie JS, O’Brien SM, Griffith BP, Ferguson TB, Peterson ED. Influence of hospital procedural volume on care pro-cess and mortality for patients undergo-ing elective surgery for mitral regurgita-tion. Circulation 2007;115:881-7.31. Talwalkar NG, Earle NR, Earle EA, Lawrie GM. Mitral valve repair in patients with low left ventricular ejection fractions: early and late results. Chest 2004;126:709-15.32. Gillinov AM, Faber C, Houghtaling PL, et al. Repair versus replacement for degenerative mitral valve disease with co-existing ischemic heart disease. J Thorac Cardiovasc Surg 2003;125:1350-62.33. Society of Thoracic Surgeons (STS) on-line risk calculator. (Accessed November 6, 2009, at http://209.220.160.181/STSWebRiskCalc261/.)34. European System for Cardiac Opera-tive Risk Evaluation (EUROSCORE). (Ac-cessed November 6, 2009, at http://www.euroscore.org/calc.html.)35. Shernan SK. Perioperative transesoph-ageal echocardiographic evaluation of the native mitral valve. Crit Care Med 2007;35:Suppl:S372-S383.36. Filsoufi F, Carpentier A. Principles of reconstructive surgery in degenerative mi-tral valve disease. Semin Thorac Cardio-vasc Surg 2007;19:103-10.37. Adams DH, Filsoufi F. Another chap-ter in an enlarging book: repair degen-erative mitral valves. J Thorac Cardiovasc Surg 2003;125:1197-9.38. Gillinov AM, Cosgrove DM III, Black-stone EH, et al. Durability of mitral valve repair for degenerative disease. J Thorac Cardiovasc Surg 1998;116:734-43.39. Duran CG, Pomar JL, Revuelta JM, et al. Conservative operation for mitral in-sufficiency: critical analysis supported by postoperative hemodynamic studies of 72 patients. J Thorac Cardiovasc Surg 1980;79:326-37.40. Mesana TG, Ibrahim M, Kulik A, et al. The “hybrid flip-over” technique for ante-rior leaflet prolapse repair. Ann Thorac Surg 2007;83:322-3.41. Mesana T, Ibrahim M, Hynes M. A technique for annular placation to facili-tate sliding plasty after extensive mitral valve posterior leaflet resection. Ann Tho-rac Surg 2005;79:720-2.42. David TE. Outcomes of mitral valve repair for mitral regurgitation due to de-generative disease. Semin Thorac Cardio-vasc Surg 2007;19:116-20.

43. Starling MR, Kirsh MM, Montgomery DG, Gross MD. Impaired left ventricular contractile function in patients with long-term mitral regurgitation and normal ejec-tion fraction. J Am Coll Cardiol 1993;22:239-50.44. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart As-sociation: a guideline from the American Heart Association Rheumatic Fever, Endo-carditis, and Kawasaki Disease Commit-tee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdis-ciplinary Working Group. Circulation 2007;116:1736-54.45. Barnett SD, Ad N. Surgery for aortic and mitral valve disease in the United States: a trend of change in surgical prac-tice between 1998 and 2005. J Thorac Car-diovasc Surg 2009;137:1422-9.46. Rosenhek R, Rader F, Klaar U, et al. Outcome of watchful waiting in asymp-tomatic severe mitral regurgitation. Cir-culation 2006;113:2238-44.47. Mohty D, Orszulak TA, Schaff HV, Avierinos JF, Tajik JA, Enriquez-Sarano M. Very long-term survival and durability of mitral valve repair for mitral valve pro-lapse. Circulation 2001;104:Suppl 1:I-1–I-7.48. Akins CW, Hilgenberg AD, Buckley MJ, et al. Mitral valve reconstruction ver-sus replacement for degenerative or is-chemic mitral regurgitation. Ann Thorac Surg 1994;58:668-75.49. Lee EM, Shapiro LM, Wells FC. Supe-riority of mitral valve repair in surgery for degenerative mitral regurgitation. Eur Heart J 1997;18:655-63.50. Kang D-H, Kim JH, Rim JH, et al. Comparison of early surgery versus con-ventional treatment in asymptomatic se-vere mitral regurgitation. Circulation 2009;119:797-804.51. Suri RM, Schaff HV, Dearani JA, et al. Survival advantage and improved durabil-ity of mitral repair for leaflet prolapse subsets in the current era. Ann Thorac Surg 2006;82:819-26.52. O’Brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2 — isolated valve surgery. Ann Thorac Surg 2009;88:Suppl:S23-S42.53. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of val-vular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230-68.54. Seeburger J, Borger MA, Falk V, et al. Minimal invasive mitral valve repair for mitral regurgitation: results of 1339 con-secutive patients. Eur J Cardiothorac Surg 2008;34:760-5.Copyright © 2009 Massachusetts Medical Society.

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Current Concepts articles present current approaches to a wide variety of clinical problems. These concise reviews are intended for the practicing physician.

Current Concepts

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review article

Current Concepts

Point-of-Care UltrasonographyChristopher L. Moore, M.D., and Joshua A. Copel, M.D.

From the Departments of Emergency Medicine (C.L.M.) and Obstetrics, Gynecol-ogy, and Reproductive Sciences (J.A.C.), Yale University School of Medicine, New Haven, CT. Address reprint requests to Dr. Moore at the Department of Emer-gency Medicine, Yale University School of Medicine, 464 Congress Ave., Suite 260, New Haven, CT 06519, or at [email protected].


Ultrasonography is a safe and effective form of imaging that has been used by physicians for more than half a century to aid in diagnosis and guide procedures. Over the past two decades, ultrasound equipment

has become more compact, higher quality, and less expensive, which has facilitated the growth of point-of-care ultrasonography — that is, ultrasonography performed and interpreted by the clinician at the bedside. In 2004, a conference on compact ultrasonography hosted by the American Institute of Ultrasound in Medicine (AIUM) concluded that “the concept of an ‘ultrasound stethoscope’ is rapidly moving from the theoretical to reality.” This conference included representatives from 19 medical organizations; in November 2010, the AIUM hosted a similar forum attended by 45 organizations.1-3 Some medical schools are now beginning to provide their students with hand-carried ultrasound equipment for use during clinical rotations.4

Although ionizing radiation from computed tomographic (CT) scanning is in-creasingly recognized as a potentially major cause of cancer, ultrasonography has been used in obstetrics for decades, with no epidemiologic evidence of harmful ef-fects at normal diagnostic levels.5,6 However, ultrasonography is a user-dependent technology, and as usage spreads, there is a need to ensure competence, define the benefits of appropriate use, and limit unnecessary imaging and its consequenc-es.7-10 This article provides an overview of the history and current status of compact, point-of-care ultrasonography, with examples and discussion of its use.

His t or y of Ultr asonogr a ph y a nd the Basic Technol ogy

Medical ultrasonography was developed from principles of sonar pioneered in World War I,11 and the first sonographic images of a human skull were published in 1947.12 The first ultrasound images of abdominal disease were published in 1958,13 and ultrasonography was widely adopted in radiology, cardiology, and ob-stetrics over the next several decades. Although clinicians from other specialties occasionally reported using ultrasonography, point-of-care ultrasonography did not really begin to progress until the 1990s, when more compact and affordable ma-chines were developed. The early portable machines were hampered by poor image quality, but in 2010, many point-of-care units can nearly match the imaging quality of the larger machines.

Ultrasound is defined as a frequency above that which humans can hear, or more than 20,000 Hz (20 kHz). Therapeutic ultrasound, designed to create heat using mechanical sound waves, is typically lower in frequency than diagnostic ultrasound and is not discussed in this article. The frequency of diagnostic ultra-sound is in the millions of Hertz (MHz). Lower-frequency ultrasound has better penetration, but at lower resolution. Higher-frequency ultrasound provides better images, but it does not visualize deep structures well. A typical transabdominal or

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cardiac probe has a frequency in the range of 2 to 5 MHz, whereas some dermatologic ultrasound probes have frequencies as high as 100 MHz.

Ultrasonography uses a “crystal” — a quartz or composite piezoelectric material — that gen-erates a sound wave when an electric current is applied. When the sound wave returns, the ma-terial in turn generates a current. The crystal thus both transmits and receives the sound. Early ultra-sonography used a single crystal to create a one-dimensional image known as A-mode. The stan-dard screen image that machines now generate is known as B-mode (also called two-dimensional or gray-scale ultrasonography), and is created by an array of crystals (often 128 or more) across the face of the transducer. Each crystal produces a scan line that is used to create an image or frame, which is refreshed many times per second to produce a moving image on the screen (Fig. 1). Additional modes, including three-dimensional, four-dimensional, Doppler, and tissue Doppler modes, are now commonly available but are not addressed in this article.

Ultrasound penetrates well through fluid and solid organs (e.g., liver, spleen, and uterus); it does not penetrate well through bone or air, limiting its usefulness in the skull, chest, and areas of the abdomen where bowel gas obscures the image. Fluid (e.g, blood, urine, bile, and as-cites), which is completely anechoic, appears black on ultrasound images, making ultrasonog-raphy particularly useful for detecting fluid and differentiating cystic or vascular areas from solid structures.

Two-dimensional ultrasound is used to visual-ize a plane that is then shown on the screen. This plane may be directed by the user in any anatomical plane on the patient: sagittal (or longi-tudinal), transverse (or axial), coronal (or frontal), or some combination (oblique). An indicator on the probe is used to orient the user to the orien-tation of the plane on the screen. By convention, in general and obstetrical imaging, the indicator corresponds to the left side of the screen as it is viewed. Cardiology uses the opposite convention for echocardiography, with the indicator corre-sponding to the right of the screen. Users should be aware of these conventions when conducting integrated examinations that include both gen-eral and cardiac imaging.14

Poin t- of- C a r e A pplic ations

Point-of-care ultrasonography is defined as ultra-sonography brought to the patient and performed by the provider in real time. Point-of-care ultra-sound images can be obtained nearly immedi-ately, and the clinician can use real-time dynam-ic images (rather than images recorded by a sonographer and interpreted later), allowing find-ings to be directly correlated with the patient’s presenting signs and symptoms.15 Point-of-care ultrasonography is easily repeatable if the patient’s condition changes. It is used by various special-ties in diverse situations (Table 1) and may be broadly divided into procedural, diagnostic, and screening applications.

Procedural Guidance

Ultrasound guidance may improve success and decrease complications in procedures performed by multiple specialties, including central and peripheral vascular access, thoracentesis, paracen-tesis, arthrocentesis, regional anesthesia, incision and drainage of abscesses, localization and re-moval of foreign bodies, lumbar puncture, biop-sies, and other procedures.16

Procedural guidance may be static or dynamic. With static guidance, the structure of interest is identified, and the angle required by the needle is noted, with the point of entry marked on the skin. In dynamic procedures, ultrasonography visualizes the needle in real time. Static guid-ance may initially be easier to perform, but prop-erly performed dynamic guidance provides more accurate guidance and is generally preferred by experienced users.

In response to the 1999 Institute of Medicine report To Err Is Human, the Agency for Healthcare Research and Quality listed “use of real-time ultrasound guidance during central line insertion to prevent complications” as 1 of the 12 most highly rated patient safety practices designed to decrease medical errors.17 The use of ultrasound to guide central venous access has been shown to reduce the failure rate, the risk of complica-tions, and the number of attempts, as compared with the landmark technique, particularly in the case of less experienced users or patients with more complex conditions.18,19 The evidence for these benefits of ultrasound guidance is greatest

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Current Concepts


Indicator topatient’s right

BA

Inferiorvena cava

Splenicvein

Spine Aorta

Indicator

Indicator

Sagittal plane

Coronalplane

Transverse plane

Figure 1. Basic (B-Mode) Two-Dimensional Ultrasound Image.

A typical ultrasound transducer, shown in Panel A, has 128 or more crystals arranged across the face of the probe. Each crystal trans-mits and receives bursts of sound (typically in the megahertz range), creating a scan line. The scan lines together make up a frame, which is refreshed many times per second and displayed on a two-dimensional screen to create a moving image. As shown in Panel B, the plane of the ultrasound can be directed in any anatomical plane or between planes. By convention, in abdominal imaging, the probe indicator (a bump or groove on the probe) is to the left of the screen and is generally directed toward the patient’s right side in a trans-verse plane. The ultrasound image shown is a transverse image of the abdominal aorta. The indicator is directed to the patient’s right side, corresponding to the left side of the screen. The aorta is black (fluid-filled) and located just anterior to the vertebral bodies. (See also Video 4, available with the full text of this article at NEJM.org.)

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for the internal jugular site, with less evidence for the femoral and subclavian sites and in pediatric patients.20

A needle may be imaged dynamically with the use of either an “in-plane” or “out-of-plane” ultra-sound approach (Fig. 2, and Video 1, available at NEJM.org). For vascular access, an in-plane ap-proach corresponds to the long axis of the vessel. An in-plane, or long-axis, approach is generally preferred for dynamic vascular access, particu-larly for central venous access, because the en-tire length of the needle, including the tip, can be visualized throughout the procedure. How-ever, it may be more difficult to keep the needle in view with the use of an in-plane approach, and for smaller vessels, it may be challenging to image the entire vessel in the long axis.

An out-of-plane approach is perpendicular to

the needle and corresponds to the short axis of the vessel. The advantage of this approach is that the needle can be centered over the middle of the vessel. It is also easier to keep the vessel and the needle in view in the short axis. However, an out-of-plane approach may underestimate the depth of the needle tip if the ultrasound plane cuts across the shaft of the needle, proximal to the tip. A detailed description of ultrasound-guided central venous access of the internal jugular vein is provided by Ortega et al. as part of the Journal’s Videos in Clinical Medicine series.21

Diagnostic Assessment

The concept of a focused (“limited,” or “goal-directed”) examination is important in point-of-care ultrasonography. Clinicians from diverse specialties can become very adept at using ultra-

Table 1. Selected Applications of Point-of-Care Ultrasonography, According to Medical Specialty.*

Specialty Ultrasound Applications

Anesthesia Guidance for vascular access, regional anesthesia, intraoperative monitoring of fluid status and cardiac function

Cardiology Echocardiography, intracardiac assessment

Critical care medicine Procedural guidance, pulmonary assessment, focused echocardiography

Dermatology Assessment of skin lesions and tumors

Emergency medicine FAST, focused emergency assessment, procedural guidance

Endocrinology and endocrine surgery Assessment of thyroid and parathyroid, procedural guidance

General surgery Ultrasonography of the breast, procedural guidance, intraoperative assessment

Gynecology Assessment of cervix, uterus, and adnexa; procedural guidance

Obstetrics and maternal–fetal medicine Assessment of pregnancy, detection of fetal abnormalities, procedural guidance

Neonatology Cranial and pulmonary assessments

Nephrology Vascular access for dialysis

Neurology Transcranial Doppler, peripheral-nerve evaluation

Ophthalmology Corneal and retinal assessment

Orthopedic surgery Musculoskeletal applications

Otolaryngology Assessment of thyroid, parathyroid, and neck masses; procedural guidance

Pediatrics Assessment of bladder, procedural guidance

Pulmonary medicine Transthoracic pulmonary assessment, endobronchial assessment, proce-dural guidance

Radiology and interventional radiology Ultrasonography taken to the patient with interpretation at the bedside, procedural guidance

Rheumatology Monitoring of synovitis, procedural guidance

Trauma surgery FAST, procedural guidance

Urology Renal, bladder, and prostate assessment; procedural guidance

Vascular surgery Carotid, arterial, and venous assessment; procedural assessment

* FAST denotes focused assessment with sonography for trauma.

Videos showing point-of-care

ultrasonography are available at

NEJM.org

Click here to access

videos.




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Current Concepts


sonography to examine a particular organ, dis-ease, or procedure that is directly relevant to their area of expertise, whereas imaging specialists typically perform more comprehensive examina-tions (Table 1).

Point-of-care ultrasonography may involve the use of a series of focused ultrasonographic ex-aminations to efficiently diagnose or rule out certain conditions in patients presenting with particular symptoms or signs, such as hypoten-

Needleshaft Needle tip

Needle incross-section

Reverberationartifact

A

B

In-plane view of the needle(long axis of the vessel)

Out-of-plane view of the needle(short axis of the vessel)

Figure 2. Ultrasound Guidance for Vascular Access and Other Procedures Involving Needles.

Panel A shows a long-axis, “in-plane” view of the needle. Although it may be more difficult to keep the needle and structure of interest in view, the long-axis view is advantageous because it shows the entire needle, including the tip (ultrasound image at right). Panel B shows a short-axis approach, with the characteristic “target sign” of the needle in the vessel lumen. The ultrasound image also shows a rever-beration artifact, which occurred in this case when the ultrasound beam struck a metallic object. The artifact appears as closely spaced, tapering lines below the needle. Although the visualized portion of the needle is centered in the lumen, the disadvantage of the short axis is that the plane of the ultrasound may cut through the needle shaft proximally, underestimating the depth of the tip. (See also Video 1.)

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sion, chest pain, or dyspnea. In patients with trauma, this approach is known as FAST (focused assessment with sonography for trauma). Point-of-care ultrasonography allows immediate, dy-namic, and repeated assessments in these situ-ations and has the potential for detecting conditions such as pneumothorax in which ultra-sonography was traditionally thought to be un-helpful. Here we focus on an integrated point-of-care examination for trauma (FAST), as well as

the use of point-of-care ultrasonography for pul-monary assessment.

FAST ExaminationFAST was a term coined at an international con-sensus conference in 1996 to describe an inte-grated, goal-directed, bedside examination to detect fluid, which is likely to be hemorrhage in cases of trauma.22 The extended FAST (e-FAST) also includes examination of the chest for pneu-mothorax.23

The e-FAST examination combines five fo-cused examinations for the detection of: free intraperitoneal f luid, free f luid in the pelvis, pericardial fluid, pleural effusion, and pneumo-thorax. Peritoneal fluid is detected using views of the hepatorenal space (Morison’s pouch), splenorenal space, and retrovesicular spaces. The thorax is evaluated for fluid at the flanks and for pneumothorax anteriorly. The pericardium may be evaluated for effusion, particularly in cases of penetrating trauma (see Video 2).

A FAST examination may be completed in less than 5 minutes and has been shown to have a sensitivity of 73 to 99%, a specificity of 94 to 98%, and an overall accuracy of 90 to 98% for clinically significant intraabdominal injury in trauma.24 The use of the FAST examination has been shown to reduce the need for CT or diag-nostic peritoneal lavage and to reduce the time to appropriate intervention, resulting in a shorter hospital stay, lower costs, and lower overall mor-tality, although more rigorous study of patient-centered outcomes is recommended.25,26 A com-plete or partial FAST examination may also be helpful in evaluating patients who do not have trauma for ascites, intraperitoneal hemorrhage, pleural effusion, pneumothorax, or pericardial effusion.

Pulmonary UltrasonographyThe use of ultrasound to detect pneumothorax was first described in a horse in 1986, and then in humans shortly afterward.27 In a normal lung, the visceral and parietal pleura are closely associ-ated, and ultrasound shows shimmering or sliding at the pleural interface during respiration (Fig. 3, and Video 3). The absence of sliding indicates a pneumothorax. A small pneumothorax may be missed with the use of ultrasonography, and pa-tients with blebs or scarring may have false positive findings.28 However, for assessing pa-

ARib

Rib Rib

Ribshadow

Ribshadow

Ribshadow

B lines(lung rockets)

Pleuralline

Pleural line

Skin andsubcutaneous

tissue

A line(normal

reverberationartifact)

B

Figure 3. Ultrasound Images of the Pleural Line in a Healthy Patient and in a Patient with Alveolar Interstitial Syndrome.

In Panel A, a high-frequency linear probe is placed with the indicator toward the patient’s head (screen left), in the midclavicular line at approximately the third intercostal space. At the posterior edge of the rib, a hy-perechoic (bright) pleural line is seen, which is the inter-face between the visceral and parietal pleura. In a mov-ing image of a normal lung, shimmering or “sliding” would be seen at the pleural line, indicating that the visceral pleura is closely associated with the parie tal pleura. An “A line” (a normal reverberation artifact) is also seen. In Panel B, a phased-array sector probe is placed at the same anatomical location on a different patient. This sector image is much deeper, but it shows the same structures, as well as pathological “B lines,” artifacts that extend to the bottom of the screen (“lung rockets”). This patient had alveolar interstitial syndrome from congestive heart failure. (See also Video 3.)

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Current Concepts


tients with trauma for pneumothorax, ultrasonog-raphy has been shown to be more than twice as sensitive as conventional supine chest radiogra-phy for detecting occult pneumothorax (pneumo-thorax seen only on CT), with similarly high spec-ificity (>98%).23 The presence of a “lung point” sign, where the visceral pleura intermittently comes in contact with the parietal pleura, is nearly 100% specific for the detection of pneumothorax.

Comet tails are an ultrasound artifact that arises when ultrasound encounters a small air–fluid interface. In 1997, Lichtenstein et al. de-scribed the sonographic identification of alveo-lar interstitial syndrome, diagnosed on the basis of comet tails that extend from the pleural line to the bottom of the screen, also known as “B lines” (Fig. 3B). Alveolar interstitial syndrome is an ultrasonographic finding in several different con-ditions.29 In an acute condition, alveolar inter-stitial syndrome usually represents pulmonary edema, but it may also be seen in the acute re-spiratory distress syndrome and more chronic interstitial diseases and may be a focal finding in infectious or ischemic processes. Characteris-tics of the artifacts may be helpful in distin-guishing these conditions.

Ultrasonography has been shown to be more accurate than auscultation or chest radiography for the detection of pleural effusion, consolida-tion, and alveolar interstitial syndrome in the critical care setting.30 In the emergency care set-ting, the presence of B lines on pleural ultraso-nography predicts fluid overload, adding diag-nostic accuracy to the physical examination and measurement of brain natriuretic peptide.31 The presence of B lines has been shown to be dy-namic, disappearing in patients undergoing he-modialysis.31,32

Screening

Screening with ultrasonography is attractive be-cause it is noninvasive and lacks ionizing radia-tion. Ultrasonography has been described as a screening test for cardiovascular and gynecolog-ic disease, and compact ultrasonography has been incorporated into “mobile screening labs.”33 However, the benefits of screening must be weighed against the harms, particularly false pos-itive findings that lead to unnecessary testing, intervention, or both. The U.S. Preventive Ser-vices Task Force (USPSTF) has specifically rec-ommended that ultrasonography not be used for

routine screening for carotid stenosis, peripheral vascular disease, or ovarian cancer in the general population (class D recommendation — “inef-fective or harms outweigh benefits”), although research is ongoing to determine whether more narrowly defined populations may benefit from such screening.34

In 2005, the USPSTF gave a class B recom-mendation for one-time ultrasound screening for abdominal aortic aneurysm in men between the ages of 65 and 75 years who had ever smoked, leading to the incorporation of screening for abdominal aortic aneurysm into Medicare reim-bursement.35,36 The USPSTF reports that ultraso-nography has a sensitivity of 95% and a specific-ity of nearly 100% when performed in “a setting with adequate quality assurance.”

Imaging of the abdominal aorta is performed with a curvilinear probe of 2 to 5 MHz. With the patient in a supine position, gentle pressure is applied to move bowel gas out of the way. The aorta should be imaged as completely as possi-ble from the proximal (celiac trunk) to the distal bifurcation and should include assessment of the iliac arteries when possible. It should be measured at its maximum diameter from out-side wall to outside wall in two planes, trans-verse and longitudinal. Challenges include en-suring that the aorta is imaged, not the inferior vena cava or another fluid-filled structure, and ensuring that the entire diameter is measured (Fig. 1, and Video 4).

Ultrasonography of the abdominal aorta has been shown to be fairly straightforward to learn as a focused examination, and screening by pri-mary care providers using point-of-care ultraso-nography may provide an economical method for wider screening, although more study is needed in this area.

Point- of- C a r e Ultr asonogr a ph y in O ther Se t tings

Point-of-care ultrasonography is increasingly be-ing used in resource-limited settings. The World Health Organization states that plain radiogra-phy and ultrasonography, singly or in combina-tion, will meet two thirds of all imaging needs in developing countries.37 Ultrasonography has been used at the Mount Everest base camp to diagnose high-altitude pulmonary edema, and ultrasonog-raphy is the only diagnostic imaging technique

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used on the International Space Station, where astronauts obtain images that are interpreted on earth.38,39 The use of hand-carried ultrasono-graphic devices has been described in prehospi-tal settings, including ambulance and disaster settings, as well as in battlefield medicine (the scenario for which hand-carried ultrasonogra-phy was initially developed).40-42 The e-FAST ex-amination for internal bleeding and pneumotho-rax has been the most extensively described application in the prehospital setting (Video 2).

Polic y Consider ations

From 2000 to 2006, physician fees billed for medical imaging in the United States more than doubled, with the proportion of billing for “in-office” imaging rising from 58 to 64%.43 Al-though the rate of imaging increased among both radiologists and nonradiologists, the rate of in-crease was faster among nonradiologists.44,45 Most of this increase was related to “advanced” imaging (CT, magnetic resonance imaging, and nuclear medicine), but certain applications of ultrasonography by nonradiologists (particularly breast and cardiac applications) increased at a very rapid rate.46

With appropriate use, point-of-care ultrasonog-raphy can decrease medical errors, provide more efficient real-time diagnosis, and supplement or replace more advanced imaging in appropriate situations. In addition, point-of-care ultrasonog-raphy may allow more widespread, less-expen-sive screening for defined indications. It may be particularly cost-effective in a reimbursement scheme based on episodes of care (“bundling”),

in some cases obviating the need for more re-source-intensive imaging performed by a consult-ing radiologist.47 However, indiscriminate use of ultrasonography could lead to further unneces-sary testing, unnecessary interventions in the case of false positive findings, or inadequate investigation of false negative findings. More imaging could simply lead to increased expense without added benefit, or might even be harmful.

As a user-dependent technology, point-of-care ultrasonography requires consideration of appro-priate training and quality assurance. In addition, methodologically rigorous studies are needed to assess patient-centered outcomes for point-of-care ultrasonography.25,48-50

Conclusions

The use of point-of-care ultrasonography will continue to diffuse across medical specialties and care situations. Future challenges include gaining a better understanding of when and how point-of-care ultrasonography can be used effec-tively, determining the training and assessment that will be required to ensure competent use of the technology, and structuring policy and re-imbursement to encourage appropriate and effec-tive use.

Dr. Moore reports receiving consulting fees from SonoSite and Philips; and Dr. Copel, speaking fees from Siemens, World Class CME, the Institute for Advanced Medical Education, and Educational Symposia, grant support from Philips, and reim-bursement for travel expenses from Philips and Esaote and serving as a paid member of the editorial board of Contemporary OB/GYN at modernmedicine.com. No other potential conflict of interest relevant to this article was reported.


References

1. Greenbaum LD, Benson CB, Nelson LH III, Bahner DP, Spitz JL, Platt LD. Pro-ceedings of the Compact Ultrasound Conference sponsored by the American Institute of Ultrasound in Medicine. J Ultra-sound Med 2004;23:1249-54.2. Alpert JS, Mladenovic J, Hellmann DB. Should a hand-carried ultrasound ma-chine become standard equipment for every internist? Am J Med 2009;122:1-3.3. AIUM Ultrasound Practice Forum, 2010: point-of-care use of ultrasound. (http://www.aium.org/advertising/2010Forum.pdf.)4. Rao S, van Holsbeeck L, Musial JL, et al. A pilot study of comprehensive ultra-sound education at the Wayne State Uni-

versity School of Medicine: a pioneer year review. J Ultrasound Med 2008;27:745-9.5. Brenner DJ, Hall EJ. Computed tomog-raphy — an increasing source of radiation exposure. N Engl J Med 2007;357:2277-84.6. Barnett SB. Routine ultrasound scan-ning in first trimester: what are the risks? Semin Ultrasound CT MR 2002;23:387-91.7. Filly RA. Is it time for the sonoscope? If so, then let’s do it right! J Ultrasound Med 2003;22:323-5.8. Adler RS. The use of compact ultra-sound in anesthesia: friend or foe. Anesth Analg 2007;105:1530-2.9. Bree RL, Benson CB, Bowie JD, et al.

The role of radiology in the era of com-pact ultrasound systems: SRU Conference, October 14 and 15, 2003. Ultrasound Q 2004;20:19-21.10. Greenbaum LD. It is time for the so-noscope. J Ultrasound Med 2003;22:321-2.11. Dussik KT. On the possibility of us-ing ultrasound waves as a diagnostic aid. Z Neurol Psychiat 1942;174:153-68. (In German.)12. Edler I, Lindström K. The history of echocardiography. Ultrasound Med Biol 2004;30:1565-644.13. Donald I, Macvicar J, Brown TG. Inves-tigation of abdominal masses by pulsed ultrasound. Lancet 1958;1:1188-95.14. Moore C. Current issues with emer-

109

Current Concepts


gency cardiac ultrasound probe and im-age conventions. Acad Emerg Med 2008;15:278-84.15. Gluckman JL, Mann W, Portugal LG, Welkoborsky H-J. Real-time ultrasonog-raphy in the otolaryngology office set-ting. Am J Otolaryngol 1993;14:307-13.16. Nicolaou S, Talsky A, Khashoggi K, Venu V. Ultrasound-guided interventional radiology in critical care. Crit Care Med 2007;35:Suppl:S186-S197.17. Making health care safer: a critical analysis of patient safety practices. Rock-ville, MD: Agency for Healthcare Re-search and Quality. (AHRQ publication no. 01-E058.)18. Randolph AG, Cook DJ, Gonzales CA, Pribble CG. Ultrasound guidance for placement of central venous catheters: a meta-analysis of the literature. Crit Care Med 1996;24:2053-8.19. Hind D, Calvert N, McWilliams R, et al. Ultrasonic locating devices for central ve-nous cannulation: meta-analysis. BMJ 2003;327:361-8.20. Kumar A, Chuan A. Ultrasound guid-ed vascular access: efficacy and safety. Best Pract Res Clin Anaesthesiol 2009;23:299-311.21. Ortega R, Song M, Hansen CJ, Barash P. Ultrasound-guided internal jugular vein cannulation. N Engl J Med 2010;362(16):e57. (Video available at NEJM.org.)22. Scalea TM, Rodriguez A, Chiu WC, et al. Focused Assessment with Sonography for Trauma (FAST): results from an inter-national consensus conference. J Trauma 1999;46:466-72.23. Kirkpatrick AW, Sirois M, Laupland KB, et al. Hand-held thoracic sonography for detecting post-traumatic pneumotho-races: the Extended Focused Assessment with Sonography for Trauma (EFAST). J Trauma 2004;57:288-95.24. Melanson SW. The FAST Exam: a re-view of the literature. In: Jehle D, Heller MB, eds. Ultrasonography in trauma: the FAST Exam. Dallas: American College of Emergency Physicians, 2003:127-45.25. Melniker LA, Leibner E, McKenney MG, Lopez P, Briggs WM, Mancuso CA. Randomized controlled clinical trial of point-of-care, limited ultrasonography for trauma in the emergency department: the first Sonography Outcomes Assessment Program trial. Ann Emerg Med 2006;48:227-35.

26. Hosek WT, McCarthy ML. Trauma ul-trasound and the 2005 Cochrane Review. Ann Emerg Med 2007;50:619-20.27. Rantanen NW. Diseases of the thorax. Vet Clin North Am Equine Pract 1986;2:49-66.28. Dulchavsky SA, Schwarz KL, Kirkpat-rick AW, et al. Prospective evaluation of thoracic ultrasound in the detection of pneumothorax. J Trauma 2001;50:201-5.29. Lichtenstein D, Mézière G, Biderman P, Gepner A, Barré O. The comet-tail arti-fact: an ultrasound sign of alveolar-inter-stitial syndrome. Am J Respir Crit Care Med 1997;156:1640-6.30. Lichtenstein D, Goldstein I, Mour-geon E, Cluzel P, Grenier P, Rouby JJ. Comparative diagnostic performances of auscultation, chest radiography, and lung ultrasonography in acute respiratory dis-tress syndrome. Anesthesiology 2004;100:9-15.31. Liteplo AS, Marill KA, Villen T, et al. Emergency Thoracic Ultrasound in the Differentiation of the Etiology of Short-ness of Breath (ETUDES): sonographic B-lines and N-terminal pro-brain-type na-triuretic peptide in diagnosing congestive heart failure. Acad Emerg Med 2009;16:201-10.32. Noble VE, Murray AF, Capp R, Sylvia-Reardon MH, Steele DJR, Liteplo A. Ultra-sound assessment for extravascular lung water in patients undergoing hemodialy-sis. Chest 2009;135:1433-9.33. Payne JW. Screening with holes in it? Washington Post. July 19, 2005. (http://www.washingtonpost.com/wp-dyn/content/article/2005/07/18/AR2005071801175.html.)34. Screening for carotid artery stenosis. Rockville, MD: U.S. Preventive Services Task Force, December 2007. (http://www.uspreventiveservicestaskforce.org/uspstf/uspsacas.htm.)35. U.S. Preventive Services Task Force. Screening for abdominal aortic aneurysm: recommendation statement. Ann Intern Med 2005;142:198-202.36. Thompson SG, Ashton HA, Gao L, Scott RA. Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the ran-domised Multicentre Aneurysm Screening Study. BMJ 2009;338:2307-18.37. Aide-memoire for diagnostic imaging services. Geneva: World Health Organi-

zation, 2009. (http://whqlibdoc.who.int/aide-memoire/a71903.pdf.)38. Otto C, Hamilton DR, Levine BD, et al. Into thin air: extreme ultrasound on Mt Everest. Wilderness Environ Med 2009;20(3):283-9.39. Sargsyan AE, Hamilton DR, Jones JA, et al. FAST at MACH 20: clinical ultra-sound aboard the International Space Sta-tion. J Trauma 2005;58:35-9.40. Nelson BP, Chason K. Use of ultra-sound by emergency medical services: a review. Int J Emerg Med 2008;1:253-9.41. Brooks AJ, Price V, Simms M. FAST on operational military deployment. Emerg Med J 2005;22:263-5.42. Beck-Razi N, Fischer D, Michaelson M, Engel A, Gaitini D. The utility of fo-cused assessment with sonography for trauma as a triage tool in multiple-casual-ty incidents during the second Lebanon war. J Ultrasound Med 2007;26:1149-56.43. Medicare imaging payments. Wash-ington, DC: Government Accountability Office, 2008. (GAO-08-452.)44. Hillman BJ, Olson GT, Griffith PE, et al. Physicians’ utilization and charges for outpatient diagnostic imaging in a Medi-care population. JAMA 1992;268:2050-4.45. Maitino AJ, Levin DC, Parker L, Rao VM, Sunshine JH. Practice patterns of ra-diologists and nonradiologists in utiliza-tion of noninvasive diagnostic imaging among the Medicare population. Radiol-ogy 2003;228:795-801.46. Miller ME. MedPAC recommenda-tions on imaging services. Washington, DC: Subcommittee on Health Committee on Ways and Means, 2005.47. Schoen C, Guterman S, Shih A, et al. Bending the curve: options for achieving savings and improving value in U.S. health spending. Washington, DC: The Commonwealth Fund, 2007.48. Rose JS. Ultrasonography and out-comes research: one small step for man-kind or another drop in the bucket? Ann Emerg Med 2006;48:237-9.49. Liu SS, Ngeow JE, Yadeau JT. Ultra-sound-guided regional anesthesia and analgesia: a qualitative systematic review. Reg Anesth Pain Med 2009;34:47-59.50. Vance S. The FAST scan: are we im-proving care of the trauma patient? Ann Emerg Med 2007;49:364-6.Copyright © 2011 Massachusetts Medical Society.

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review article

Current Concepts

Myocardial Infarction Due to Percutaneous Coronary Intervention

Abhiram Prasad, M.D., and Joerg Herrmann, M.D.

From the Department of Internal Medi-cine and the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN. Address reprint requests to Dr. Prasad at the Mayo Clinic, 200 First St. SW, Roch-ester, MN 55905, or at [email protected].


Approximately 1.5 million patients undergo percutaneous coro-nary intervention (PCI) in the United States every year.1 Depending on local practices and the diagnostic criteria used, 5 to 30% of these patients (75,000

to 450,000) have evidence of a periprocedural myocardial infarction.2,3 At the higher estimate, the incidence of these events is similar to the annual rate of major spon-taneous myocardial infarction.1 Thus, many cardiologists and internists are likely to encounter patients with coronary artery disease who have sustained a periproce-dural myocardial infarction. However, the clinical significance of these events and their management remain a matter of considerable controversy and uncertainty (Table 1).4-6 Questions that often arise include the following: Do we need to routinely screen patients for periprocedural myocardial infarction? Which patients should be observed in the hospital for a prolonged period after periprocedural myocardial infarction? What are the therapeutic implications, and what should we tell patients who sustained a periprocedural myocardial infarction despite an otherwise suc-cessful procedure? Is a periprocedural myocardial infarction prognostically equiva-lent to a spontaneous myocardial infarction? Is periprocedural myocardial infarc-tion a valid end point in clinical trials? The aim of this review is to address these questions and to provide a current perspective on this issue.

Defini tions a nd Pr edic t or s of PCI-R el ated M yonecrosis

Current PCI guidelines give a class I recommendation for the measurement of car-diac biomarkers (the MB fraction of creatine kinase [CK-MB], cardiac troponin, or both) in patients who have signs or symptoms suggestive of myocardial infarction during or after PCI and for those who have undergone complicated procedures.7 In addition, a class IIa recommendation is given for routine measurements of cardiac biomarkers 8 to 12 hours after the procedure. In either case, “a new CK-MB or tro-ponin I or T rise greater than 5 times the upper limit of normal would constitute a clinically significant periprocedural MI [myocardial infarction].”7 The more recent consensus document on the universal definition of myocardial infarction specifi-cally classifies cardiac-biomarker levels that are more than 3 times the upper refer-ence limit as indicative of a periprocedural myocardial infarction and recommends measurement of cardiac troponin as the preferred biomarker.8 Given the availabil-ity of high-sensitivity cardiac troponin assays, this guideline establishes the thresh-old for a diagnosis of periprocedural myocardial infarction at very low levels of myonecrosis.

The predictors of periprocedural myocardial infarction can be broadly catego-rized as patient-, lesion-, and procedure-related risk factors.2 The major risk factors, in terms of both frequency and potency, are complex lesions (e.g., the presence of thrombus, stenosis of a saphenous-vein graft, or a type C lesion), complex procedures

111



(e.g., treatment of multiple lesions or use of rota-tional atherectomy), and associated complica-tions (e.g., abrupt vessel closure, side-branch occlusion, distal embolization, or no reflow).2,9-12 In contrast, patient-related factors, such as ad-vanced age, diabetes mellitus, renal failure, multivessel disease, and left ventricular dysfunc-tion, are the important determinants of clinical outcomes after PCI.2,9-11 The occurrence of peri-procedural ischemic symptoms, particularly chest pain at the end of the procedure, or electrocardio-graphic evidence of ischemia defines the sub-group of patients most likely to have periproce-dural myocardial infarction.11,13

Mech a nisms of PCI-R el ated M yonecrosis

Large periprocedural myocardial infarcts are usu-ally due to angiographically visible complications; however, this is generally not the case in the vast majority of patients with elevated biomarker lev-els after PCI.6,14,15 Cardiac magnetic resonance imaging (MRI) has confirmed two distinct loca-tions for procedural myonecrosis: adjacent to the site of the intervention, where the injury is most likely due to epicardial side-branch occlusion, and downstream from the intervention site, where it is most likely due to compromise of the micro-vascular circulation (Fig. 1).2,16 Acute myocardial injury occurs with equal frequency at the two lo-cations and is detected on MRI in 25% of pa-tients after PCI, with a mean infarct size of ap-

proximately 5% of the left ventricular mass.3 The size of distal infarcts correlates directly with the extent to which the plaque volume is reduced (em-bolized) by PCI, since more debris is sent down-stream, but this is not so for the proximal type of injury. Moreover, the composition of the plaque influences the extent of periprocedural myonecro-sis. PCI for plaques with large necrotic cores leads to greater degrees of myonecrosis, whereas fibrous plaques are relatively inert in this regard.17,18

Embolization of plaque material has been de-tected on intracoronary Doppler ultrasonography during PCI. Although it occurs at each phase of the intervention, embolization is most pronounced during stent implantation.19 Even though the num-ber of microemboli correlates positively with the severity of myocardial microvascular dysfunction and myonecrosis, there is considerable overlap with regard to the magnitude of plaque micro-embolization between patients with and those without periprocedural myocardial infarction.19,20 This finding suggests that factors other than the burden of plaque microembolization influence the likelihood of periprocedural myocardial infarc-tion, such as the release of vasoactive factors from the atherosclerotic plaque, platelet activation, and preexisting vulnerability of the myocardium.2

Tr a ditiona l Focus on Pos tprocedur a l M yonecrosis

In the CK-MB and early cardiac troponin era, nu-merous studies evaluated the clinical significance

Table 1. Evidence for and against the Clinical Significance of Periprocedural Myocardial Infarction.*

Evidence for Clinical Significance Evidence against Clinical Significance

Patients with elevated cardiac biomarkers after PCI have evidence of focal infarction on cardiac imaging

Virtually all data correlating PMI to adverse clinical outcomes are derived from retrospective studies that have shown associations but not causal relationships

A large number of studies have shown a correlation between PMI and adverse clinical outcomes (see the Supplementary Appendix, available with the full text of this article at NEJM.org), and these studies greatly outnumber those that do not

Retrospective studies are generally limited because they cannot adequately adjust for all possible confounding variables with respect to baseline clinical, angiographic, and procedural char-acteristics that may determine the likelihood of both PMI and adverse outcomes

There is a positive correlation between the magnitude of postproce-dural biomarker elevation and the likelihood of adverse out-comes

Most studies did not use high-sensitivity cardiac troponin assays; when these assays were used, the studies did not apply the cur-rently recommended 99th percentile cutoff value for the upper limit of the normal range

Studies have shown that pre-PCI interventions such as statin ther-apy reduce the frequency of PMI and improve long-term out-comes

In most cases, PMI results in minimal myonecrosis and therefore does not substantially impair cardiac function — one of the most important determinants of outcome in coronary artery disease

* PCI denotes percutaneous coronary intervention, and PMI periprocedural myocardial infarction.

112

current concepts


of cardiac-biomarker elevations after PCI, and these studies have been systematically reviewed in a previous publication.2 The general conclu-sion from the retrospective analyses was that a CK-MB elevation higher than 5 times the upper limit of normal was independently associated with

an increased risk of in-hospital adverse cardiac events, whereas lower levels did not appear to influence in-hospital outcomes significantly (Ta-ble 2).21,26,40-43 Data indicating a relationship be-tween the CK-MB level and long-term survival were less consistent. The results of several studies sug-

Figure 1. Mechanisms Underlying Periprocedural Myocardial Infarction.

Cardiac-biomarker elevation before percutaneous coronary intervention (PCI) is primarily due to spontaneous rupture of vulnerable plaques, epicardial thrombosis, and subsequent myocardial injury. In the absence of abrupt, PCI-related epicardial-artery closure, peri-procedural myocardial infarction is related to either side-branch occlusion or iatrogenic plaque rupture by balloons and stents, which promotes microvascular injury owing to distal embolization, the release of vasoactive peptides, or both.

113



Tabl

e 2.

Lar

ge C

ohor

t Stu

dies

of C

ardi

ac-B

iom

arke

r El

evat

ion

afte

r Pe

rcut

aneo

us C

oron

ary

Inte

rven

tion

(PC

I), a

nd O

utco

mes

.*

Stud

yN

o. o

fPa

tient

sIn

cide

nce

of A

CS

Type

of

Inte

rven

tion

Inci

denc

eIn

-Hos

pita

l Out

com

es†

Leng

th o

f Fo

llow

-up

Mul

tivar

iate

Adj

uste

d Lo

ng-T

erm

O

utco

mes

%%

mo

Ston

e et

al.2

171

4768

.9PC

IIn

crea

sed

risk

of d

eath

(od

ds r

atio

, 8 fo

r C

K-M

B >

8× U

LN; 6

7 fo

r Q

-wav

e M

I)24

Incr

ease

d ris

k of

dea

th (

haza

rd ra

tio, 2

.2 fo

r C

K-M

B >

8× U

LN; 9

.9 fo

r Q-w

ave

MI)

CK

-MB

, >4–

32 n

g/m

l29

.6

CK

-MB

, >32

ng/

ml

7.7

Q-w

ave

MI

0.6

Dan

gas

et a

l.22

4085

67.3

PCI

NA

12In

crea

sed

risk

of d

eath

or

MI (

odds

rat

io,

1.5

for

CK

-MB

>5×

ULN

)

CK

-MB

, 4–2

0 ng

/ml

24.1

CK

-MB

, >20

ng/

ml

12.8

Aja

ni e

t al.2

313

2685

.4PC

IN

A12

Incr

ease

d ri

sk o

f dea

th o

r M

I (od

ds r

atio

, 1.

57 fo

r C

K-M

B >

3× U

LN)

CK

-MB

, 4–1

2 ng

/ml

25

CK

-MB

, >12

ng/

ml

20

Kin

i et a

l.24‡

1675

NA

PCI

Incr

ease

d ri

sks

of c

hest

pai

n (5

8%

vs. 9

–12%

), h

eart

failu

re (

35%

vs

. 6–7

%),

and

incr

ease

d le

ngth

of

sta

y fo

r C

K-M

B >

5× U

LN v

s.

othe

r el

evat

ions

and

nor

mal

leve

ls

13±3

No

asso

ciat

ion

CK

-MB

, 1–3

× U

LN12

.6

CK

-MB

, >3–

5× U

LN3.

7

CK

-MB

, >5×

ULN

2.4

Bre

ner

et a

l.25

3478

64.0

Sten

t pla

cem

ent

NA

15±1

5In

crea

sed

risk

of d

eath

(od

ds r

atio

, 1.8

9 fo

r C

K-M

B >

3× U

LN; 6

.36

for

CK

-MB

>1

0× U

LN)

CK

-MB

, >8.

8–26

.4 n

g/m

l (C

K-M

B, >

1–3×

ULN

)14

.5

CK

-MB

, >26

.4–4

4 ng

/ml

(CK

-MB

, >3–

5× U

LN)

4.5

CK

-MB

, >44

–88

ng/m

l (C

K-M

B, >

5–10

× U

LN)

2.9

CK

-MB

, >88

ng/

ml

(CK

-MB

, >10

× U

LN)

2.4

Ellis

et a

l.26

8409

63.0

PCI

Incr

ease

d le

ngth

of s

tay

for

CK

-MB

>1

× U

LN4

Incr

ease

d ri

sk o

f dea

th (

1.2,

1.9

, and

8.9

%

for

CK

-MB

<1,

1–5

, and

>5×

ULN

, re-

spec

tivel

y)

CK

-MB

, 8.8

–40

ng/m

l13

.6

CK

-MB

, >40

ng/

ml

3.6

48In

crea

sed

risk

of d

eath

(15.

1, 1

6.9,

and

19.

4%

for

CK

-MB

<1,

1–5

, and

>5×

ULN

, re-

spec

tivel

y)

114

current concepts


Bre

ner

et a

l.27

3573

NA

PCI

NA

36In

crea

sed

risk

of d

eath

(ha

zard

ratio

, 1.1

for

CK

-MB

>10

× U

LN)

CK

-MB

, >8.

8–26

.4 n

g/m

l (C

K-M

B, >

1–3×

ULN

)21

CK

-MB

, >26

.4–4

4 ng

/ml

(CK

-MB

, >3–

5× U

LN)

6

CK

-MB

, >44

–88

ng/m

l (C

K-M

B, >

5–10

× U

LN)

6

CK

-MB

, >88

ng/

ml

(CK

-MB

, >10

× U

LN)

5

Hon

g et

al.2

816

9379

.0Sa

phen

ous-

vein

gr

aft P

CI

Incr

ease

d ne

ed fo

r ba

lloon

pum

p (7

.8%

vs

. 1.1

%)

and

repe

at P

CI (

4.2%

vs.

1.

2%)

for

CK

-MB

ele

vatio

n vs

. no

ele-

vatio

n

12In

crea

sed

risk

of d

eath

(ha

zard

ratio

, 3.3

for

CK

-MB

>5×

ULN

)

CK

-MB

, 4–2

0 ng

/ml

32.1

CK

-MB

, >20

ng/

ml

15.2

And

ron

et a

l.29

3864

30.4

PCI

NA

6–42

Incr

ease

d ri

sk o

f dea

th (

haza

rd r

atio

, 1.3

, 1.

76, a

nd 2

.26

for

CK

-MB

1–3

, >3–

5 an

d >5

× U

LN, r

espe

ctiv

ely)

CK

-MB

, 4–1

2 ng

/ml

19.9

CK

-MB

, >12

–20

ng/m

l4.

4

CK

-MB

, >20

ng/

ml

5.1

Jang

et a

l.30

1807

40.9

Dru

g-el

utin

g st

entin

g PC

IN

o as

soci

atio

n13

±7In

crea

sed

risk

of d

eath

(0.

5, 1

.1, a

nd 2

.6%

fo

r C

K-M

B <

1, 1

–5, a

nd >

5× U

LN, r

e-sp

ectiv

ely)

CK

-MB

, 5–2

5 ng

/ml

14.6

CK

-MB

, >25

ng/

ml

6.4

Nat

araj

an e

t al.3

111

2861

.0PC

IIn

crea

sed

risk

of m

ajor

car

diac

eve

nts

(3.8

for

cTnI

≥5×

ULN

)12

No

asso

ciat

ion

cTnI

, 1–4

× U

LN7.

6

cTnI

, ≥5×

ULN

9.1

Nal

lam

othu

et a

l.32

1157

36.5

PCI

NA

11±7

Incr

ease

d ris

k of

dea

th (

haza

rd ra

tio, 2

.4 fo

r cT

nI ≥

8× U

LN, 8

.9 fo

r Q

-wav

e M

I)

cTnI

, 2–5

.9 n

g/m

l16

.0

cTnI

, 6–9

.9 n

g/m

4.6

cTnI

, 10–

15.9

ng/

ml

2.0

cTnI

, ≥16

.0 n

g/m

l6.

5

Q-w

ave

MI

0.3

115



Tabl

e 2.

(Con

tinue

d.)

Stud

yN

o. o

fPa

tient

sIn

cide

nce

of A

CS

Type

of

Inte

rven

tion

Inci

denc

eIn

-Hos

pita

l Out

com

es†

Leng

th o

f Fo

llow

-up

Mul

tivar

iate

Adj

uste

d Lo

ng-T

erm

O

utco

mes

%%

mo

Pras

ad e

t al.3

319

4947

.9PC

IIn

crea

sed

leng

th o

f sta

y26

Incr

ease

d ris

k of

dea

th (

haza

rd ra

tio, 1

.2 p

er

log 2

incr

ease

in c

TnT)

cTnT

, ≥0.

03 n

g/m

l19

.6

Hub

acek

et a

l.34

1208

31.0

PCI

NA

24N

o as

soci

atio

n

Incr

ease

in c

TnT

>0.1

ng/

ml

20

Feld

man

et a

l.35

1601

43.3

PCI

No

asso

ciat

ion

25±8

Incr

ease

d ris

k of

dea

th (

haza

rd ra

tio, 1

.6)

cTnI

, ≥0.

15 n

g/m

l51

.9

De

Labr

iolle

et a

l.36

3200

0.0

PCI

NA

12N

o as

soci

atio

n

cTnI

, >0.

30 n

g/m

l23

.4

Cav

allin

i et a

l.37

2362

45.1

PCI

NA

24N

o as

soci

atio

n

cTnI

, 0.1

5–0.

45 n

g/m

l19

.7

cTnI

, >0.

45 n

g/m

l19

.8

Fuch

s et

al.3

811

2970

.9PC

IIn

crea

sed

risk

of m

ajor

adv

erse

car

dio-

vasc

ular

eve

nts

(odd

s ra

tio, 2

.1 fo

r cT

nI >

3× U

LN)

8N

o as

soci

atio

n

cTnI

, 0.1

5–0.

45 n

g/m

l15

.2

cTnI

, >0.

45 n

g/m

l15

.4

CK

-MB

, >4

ng/m

l40

.8

Cav

allin

i et a

l.39

3494

50.8

PCI

NA

24In

crea

sed

risk

of d

eath

(od

ds ra

tio, 1

.04

per

peak

CK

-MB

rat

io u

nit)

§

cTnI

, >0.

15 n

g/m

l44

.2

CK

-MB

, >5

ng/m

l16

.0

* Pl

us–m

inus

val

ues

are

mea

ns ±

SD. O

nly

data

from

stu

dies

tha

t in

clud

ed a

t le

ast

1000

pat

ient

s, lo

ng-t

erm

out

com

e da

ta, a

nd c

once

ntra

tion-

base

d bi

omar

ker

anal

ysis

are

sho

wn.

H

azar

d ra

tios

wer

e de

term

ined

by

mea

ns o

f a m

ultiv

aria

te C

ox p

ropo

rtio

nal-h

azar

ds r

egre

ssio

n m

odel

, if a

vaila

ble;

oth

erw

ise,

odd

s ra

tios

wer

e de

term

ined

by

mul

tivar

iate

ana

lysi

s.

Acu

te c

oron

ary

synd

rom

es (

AC

S) in

clud

ed a

ngin

a at

res

t an

d ur

gent

pri

ority

inte

rven

tions

. CK

-MB

den

otes

the

MB

frac

tion

of c

reat

ine

kina

se, c

TnI

card

iac

trop

onin

I, c

TnT

card

iac

tro-

poni

n T,

MI

myo

card

ial i

nfar

ctio

n, N

A n

ot a

vaila

ble,

and

ULN

upp

er li

mit

of t

he n

orm

al r

ange

.†

Out

com

es o

ther

tha

n ev

olvi

ng m

yoca

rdia

l inf

arct

ion

are

show

n. P

<0.0

5 fo

r al

l com

pari

sons

.‡

In

this

stu

dy, t

he fi

nal a

naly

sis

was

bas

ed o

n m

ass

imm

unoa

ssay

.§

This

rat

io w

as c

alcu

late

d by

div

idin

g th

e m

axim

um p

ost-

PCI

leve

l by

the

ULN

or

base

line

leve

l of C

K-M

B.

116

current concepts


gested that any elevation in CK-MB was associ-ated with reduced long-term survival and that there was a direct correlation between the mag-nitude of myonecrosis and mortality.26,39,41,42 In contrast, other studies have shown that only large myocardial infarctions, variably defined as a CK-MB level exceeding 5 or 8 times the upper limit of normal or the presence of new Q waves, were predictive of a poor long-term outcome, es-pecially if they were related to an unsuccessful revascularization procedure (Table 2).21,40,43,44

Studies evaluating the relationship between the postprocedural cardiac troponin level and long-term mortality, in general, have not excluded pa-tients with acute coronary syndromes, many of whom would have had abnormal cardiac-biomark-er levels at baseline.31,32,35,39,45-47 Thus, the report-ed frequency of postprocedural elevations in car-diac troponin has been highly variable, and although some studies showed that the serum concentration of cardiac troponin was an inde-pendent predictor of survival, others did not (Ta-ble 2). The inconsistent findings were most likely due to heterogeneity of the inclusion criteria, varia-tions in the sensitivity and specificity of the bio-marker assays, different sample sizes, and dif-ferences in the duration of follow-up. Two recent meta-analyses concluded that an elevated cardiac troponin level after PCI does provide prognostic information.48,49 Both analyses were influenced by studies from our catheterization laboratories on postprocedural cardiac troponin T elevations in which we had reached a similar conclusion.33,50 However, the studies included in the meta-analyses (including our own) had used cardiac troponin cutoff values for normal that were higher than the currently recommended 99th percentile, thereby limiting the accuracy of their conclusions.8

Focus on Pr epro cedur a l R isk

To date, virtually all studies of periprocedural myocardial infarction have been limited by the lack of precision with which they determined preprocedural risk. Contemporary cardiac tropo-nin assays have greatly enhanced our ability to detect myonecrosis before and after PCI.46,51 In a recent analysis, using the currently recommend-ed 99th percentile value as the cutoff for a nor-mal cardiac troponin T level, we found that ap-proximately one third of patients who underwent nonemergency PCI had evidence of preprocedural

myonecrosis.6 These patients had a greater ath-erosclerotic burden and more unstable disease than patients without evidence of preprocedural myonecrosis, a finding that is consistent with previous reports.52 Applying the universal defini-tion of myocardial infarction to patients with normal preprocedural cardiac troponin T levels, another one third of patients sustained a peripro-cedural myocardial infarction after the proce-dure when cardiac troponin T was used to detect myonecrosis, as compared with only 1 in 15 pa-tients when CK-MB was used.6 The preprocedural rather than postprocedural cardiac-biomarker level was a powerful independent predictor of short-term and long-term mortality.6 Similar findings have been reported in two additional recent stud-ies that used cardiac troponin I within the frame-work of the universal definition of myocardial infarction36,37 and in an analysis from the Evalu-ation of Drug Eluting Stents and Ischemic Events (EVENT) registry.53

These observations may seem surprising, since one might argue that the clinical effect of myocardial infarction should be the same re-gardless of its cause. However, most periproce-dural myocardial infarcts are very small in rela-tion to the magnitude of myonecrosis, especially in patients with stable coronary artery disease. Among patients with normal preprocedural car-diac troponin values, less than 5% have CK-MB values that are higher than 5 times the upper reference limit after PCI, and Q-wave infarctions are rare (<0.1%). Instead, CK-MB levels that are higher than 5 times the upper reference limit are generally observed in patients with elevated pre-procedural cardiac troponin T.6 Thus, it is likely that in the older studies that explored the effect of periprocedural myocardial infarction on out-comes, a large proportion of the patients who had been classified as biomarker-negative on the basis of CK or CK-MB levels at the time of PCI actually had non–ST-segment elevation myocar-dial infarction according to contemporary defi-nitions. This conclusion is supported by the high proportion of patients (about 50% on average) who had acute coronary syndromes in the previous studies (Table 2, and the Supplementary Appen-dix, available with the full text of this article at NEJM.org).

In summary, recent studies reveal that the pre-procedural cardiac troponin level is a powerful independent predictor of prognosis after PCI.

117



Moreover, these studies suggest that the associa-tion between postprocedural myonecrosis and outcomes after an otherwise successful PCI is, in general, a reflection of the preprocedural risk, which can be estimated by measuring baseline cardiac troponin levels with the use of contem-porary high-sensitivity assays in conjunction with the clinical and angiographic characteristics of the patient.

Pro gnos tic Signific a nce of Per ipro cedur a l v er sus

Spon ta neous E v en t s

On the basis of the traditional concept of peri-procedural myocardial infarction described above, this complication has often been equated with spontaneous myocardial infarction in clinical tri-als.54 The validity of this assumption has not been examined in detail, and it has been confounded by the variable definitions of periprocedural myocar-dial infarction used in the past. The current uni-versal definition of myocardial infarction attempts to address this issue by introducing a specific category (type 4a) for periprocedural myocardial infarction to distinguish it from spontaneous myocardial infarction (types 1 and 2).8

Akkerhuis and colleagues compared the effect of periprocedural myocardial infarction as detect-ed by CK-MB elevation with that of spontaneous myocardial infarction on 6-month mortality in a heterogeneous group of patients who had acute coronary syndromes without ST-segment eleva-tion; the data were derived from five different clinical-trial databases.55 The authors reported a positive correlation between CK-MB levels and mortality in both groups, although the absolute mortality was significantly higher among patients who had spontaneous myocardial infarction than among those who had periprocedural myocardial infarction. The authors concluded that the clini-cal significance of periprocedural myocardial in-farction should be considered similar to the ad-verse consequences of spontaneous myocardial infarction. However, the study was conducted in the era of balloon angioplasty, before the wide-spread use of stents, and the analysis was not adjusted for confounding clinical variables.

To address these limitations, an analysis was conducted of data from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial (Clinical.Trials.gov number, NCT00093158)

involving 7773 patients with moderate-to-high-risk, non–ST-segment elevation acute coronary syndromes who underwent PCI.15 Periprocedural myocardial infarction and spontaneous myocar-dial infarction during follow-up developed in 6.0% and 2.6% of the cohort, respectively. Among pa-tients with either type of myocardial infarction, as compared with those without myocardial in-farction, unadjusted mortality at 1 year was sig-nificantly higher. After adjustment for differences in baseline and procedural characteristics between the two groups, spontaneous myocardial infarc-tion was a powerful independent predictor of an increased risk of death, whereas periprocedural myocardial infarction was not significantly as-sociated with an increased risk of death. Similar observations have been made among patients with diabetes and stable coronary artery disease in the Bypass Angioplasty Revascularization Investiga-tion 2 Diabetes (BARI 2D) trial (NCT00006305), in which a first spontaneous, symptomatic myo-cardial infarction was associated with higher mor-tality, as compared with myocardial infarction induced by percutaneous or surgical revascular-ization.56

Taken together, contemporary studies indicate that spontaneous myocardial infarction is a pow-erful predictor of mortality. Periprocedural myo-cardial infarction, although frequent, is a marker of atherosclerotic burden and procedural complex-ity, but in most cases, it does not have important independent prognostic significance in stable cor-onary artery disease or in non–ST-elevation acute coronary syndromes. Although large periproce-dural myocardial infarcts may affect prognosis, they rarely occur in the absence of procedural com-plications or in patients with normal baseline cardiac troponin levels.


There is a pressing need for the interventional community and the associated professional or-ganizations to examine the new data and provide more practical guidelines for defining periproce-dural myocardial infarction. This process should include an assessment of the appropriateness of relying on biomarkers alone and of the low thresh-old used for the universal definition, as compared with a definition that includes clinical criteria such as symptoms or evidence of ischemia or infarc-tion on electrocardiography or cardiac imaging.

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Since most of the data on periprocedural myo-cardial infarction are derived from patients with normal levels of cardiac biomarkers before the procedure (predominantly those with stable or unstable angina), clearer guidelines are needed with regard to whether periprocedural myocardial infarction can be diagnosed in patients with non–ST-elevation myocardial infarction in whom bio-markers are rising before PCI and, if so, what di-agnostic criteria should be used. This is probably not feasible in contemporary practice, since PCI is often performed within 24 hours after hospital admission. Another practical issue that needs to be addressed is whether the class IIa recommen-dation to routinely measure biomarkers after PCI is still appropriate and, if so, what the therapeutic implications of an elevated post-PCI level would be. A recent report from the National Cardiovas-cular Data Registry indicates that the majority of hospitals in the United States do not routinely measure cardiac biomarkers at the time of PCI.14

The improved understanding of the clinical significance of periprocedural myocardial infarc-tion has important implications for the design of future randomized trials (i.e., periprocedural myocardial infarction and spontaneous myocar-dial infarction should not be considered equiva-lent clinical end points). This issue has most recently been relevant with respect to the inter-pretation of data from the Cangrelor versus Stan-dard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PLATFORM trial (NCT00385138).54 In that study, the majority of patients had acute coronary syndromes with-out ST-segment elevation and underwent PCI with-in 24 hours after presentation. This did not allow a reliable distinction between spontaneous myo-cardial infarction and periprocedural myocardi-al infarction, and led the investigators to con-clude that the result of the trial “calls into question the definition of periprocedural MI used.” Differentiating spontaneous myocardial infarc-tion from periprocedural myocardial infarction will be increasingly difficult in clinical practice, since most invasively managed cases involve car-diac catheterization during a period when pre-

Figure 2. Recommendations for the Prevention and Management of Periprocedural Myocardial Infarction.

ACS denotes acute coronary syndromes, CK-MB MB fraction of creatine kinase, and GP glycoprotein.

Pre-PCI Troponin Level

PCIIf appropriate, use distal protection

for vein-graft interventions

PCIIf appropriate, use distal protection

for vein-graft interventions

Post-PCI Troponin LevelIf troponin elevated, consider measuring CK-MB

Proceed with PCIRecognize increased risk and

inform patientConsider initiation of antiplatelet

therapy(e.g., GP IIb/IIIa inhibitors, clo-pidogrel) and high-dose statintherapy

Manage ACS according to standardguidelines

Treat decompensated heart failure,if present

Provide optimal care for coexistingconditions such as renal dysfunc-tion, anemia, and diabetes

Provide standard post-PCI careand secondary prevention for

coronary artery disease

CK-MB >5× upper reference limit orequivalent magnitude of tropo-nin elevation or new Q waves

Prolong in-hospital observation(by at least 1 day)

Assess for left ventricular dys-function

If indicated, repeat angiography to identify procedural compli-cations and need for inter-vention

Troponin greater than upper reference limit and CK-MB <5× upper refer-ence limit

Prolong duration of observation onlyif clinically indicated (e.g., proce-dural complication)

Intensify secondary prevention forcoronary artery disease to ensureoptimal management

Observe in hospital according to stan-dard local practice

Consider measuring post-PCI troponinor CK-MB at 8–16 hr (e.g., for thosewith complex PCI)

Allow longer in-hospital observationMeasure post-PCI CK-MB or troponin

at 8–16 hr or as clinically indicated

Normal Elevated

Normal Elevated

No proceduralcomplications

Proceduralcomplicationsor symptomsof ischemia,

or both

119



procedural biomarker levels would generally be rising. Thus, we would caution against including myocardial infarction as a component of the pri-mary composite end point in future clinical tri-als of PCI in acute coronary syndromes or using it as a surrogate for long-term outcomes, although one might reasonably consider it as a secondary efficacy end point or a safety end point.

Implic ations for Pr ac tice

Our recommendation is that cardiac troponin lev-els be routinely measured before PCI is performed (Fig. 2). A normal preprocedural level of cardiac troponin will assist in risk stratification by iden-tifying patients in whom PCI can be performed with very low risk and who may be considered for early discharge from the hospital. In addition, a pre-PCI elevation in cardiac troponin identifies high-risk patients with complex or thrombotic le-sions who may benefit from the preprocedural initiation of potent antiplatelet therapies and statins to improve outcomes.2,57,58 Post-PCI levels should be routinely measured in patients who have undergone complex procedures, who have suboptimal angiographic results, or who have pro-cedural complications, as well as in those who have signs or symptoms of myocardial ischemia, in order to quantify the extent of myocardial in-jury. However, a reasonable case can be made for not routinely measuring postprocedural cardiac troponin levels in uncomplicated, successful PCI, since it is not likely that in such cases relevant additional information can be gained that will be independent of the preprocedural risk and proce-dural outcomes. The role of postprocedural mon-itoring of biomarkers for risk stratification in the secondary prevention of coronary artery disease or as a metric of quality remains to be established.

There are no established cutoff values for car-diac troponin that define a “large” periprocedural myocardial infarct, and until such values can be clearly identified, a CK-MB level that is more than 5 times the upper reference limit, the pres-ence of new Q waves, or both would appear to be reasonable criteria for defining a periproce-

dural myocardial infarction as extensive. We be-lieve that, in general, this definition can reliably be applied only to patients with normal cardiac troponin levels before PCI. In the absence of data that can be used to help direct practice, we rec-ommend that patients with large periprocedural myocardial infarction be monitored in the hospi-tal for an additional day because of the reported risks of arrhythmias, hemodynamic instability, heart failure, and death (Table 2, and the Supple-mentary Appendix). For the purpose of preproce-dural consent, one should discuss the frequency of a large periprocedural myocardial infarction (<5%) with the patient and inform the patient if it occurs after the intervention.

The care of patients with acutely elevated pre-procedural cardiac troponin who sustain major periprocedural myonecrosis should, in general, be based on the guidelines for managing acute coro-nary syndromes. Patients whose condition unex-pectedly deteriorates soon after PCI (e.g., those with recurrent and unrelenting chest pain, par-ticularly in combination with ST-segment shifts or echocardiographic evidence of ischemia or peri-cardial effusion) should undergo repeat coronary angiography. The goal is to identify procedural complications that are amenable to further in-tervention, such as acute stent thrombosis, coro-nary dissection, or perforation, to limit myone-crosis and relieve symptoms. In most cases, this involves repeat PCI; it is rare in current practice for patients to require cardiac surgery.

Perhaps the most important implication for the long-term care of the vast majority of patients with periprocedural myocardial infarction is the realiza-tion that they represent a higher-risk cohort owing to a greater disease burden and more unstable disease. These patients should therefore be target-ed for optimal secondary prevention based on the current guidelines. Occasionally, patients with stable coronary artery disease have extensive peri-procedural myocardial infarction. The long-term care of such patients should be similar to that for patients with spontaneous myocardial infarction.


References

1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics — 2010 update: a report from the Ameri-can Heart Association. Circulation 2010;121(7):e46-e215.2. Herrmann J. Peri-procedural myocar-

dial injury: 2005 update. Eur Heart J 2005;26:2493-519.3. Porto I, Selvanayagam JB, Van Gaal WJ, et al. Plaque volume and occurrence and location of periprocedural myocardi-al necrosis after percutaneous coronary

intervention: insights from delayed-enhancement magnetic resonance imag-ing, Thrombolysis in Myocardial Infarc-tion myocardial perfusion grade analysis, and intravascular ultrasound. Circulation 2006;114:662-9.

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4. Bhatt DL, Topol EJ. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes. Cir-culation 2005;112:906-15.5. Cutlip DE, Kuntz RE. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Cardiac enzyme elevation after successful percutaneous coronary inter-vention is not an independent predictor of adverse outcomes. Circulation 2005;112:916-22.6. Prasad A, Rihal CS, Lennon RJ, Singh M, Jaffe AS, Holmes DR Jr. Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and post-intervention troponin T levels in 5487 pa-tients. Circ Cardiovasc Interv 2008;1:10-9.7. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guide-line update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guide-lines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutane-ous Coronary Intervention). Circulation 2006;113(7):e166-e286.8. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarc-tion. Eur Heart J 2007;28:2525-38.9. Mandadi VR, DeVoe MC, Ambrose JA, et al. Predictors of troponin elevation af-ter percutaneous coronary intervention. Am J Cardiol 2004;93:747-50.10. Blankenship JC, Haldis T, Feit F, et al. Angiographic adverse events, creatine kinase-MB elevation, and ischemic end points complicating percutaneous coro-nary intervention (a REPLACE-2 substudy). Am J Cardiol 2006;97:1591-6.11. Cai Q, Skelding KA, Armstrong AT Jr, Desai D, Wood GC, Blankenship JC. Pre-dictors of periprocedural creatine kinase-myocardial band elevation complicating elective percutaneous coronary interven-tion. Am J Cardiol 2007;99:616-20.12. van Gaal WJ, Ponnuthurai FA, Selva-nayagam J, et al. The Syntax score pre-dicts peri-procedural myocardial necrosis during percutaneous coronary interven-tion. Int J Cardiol 2009;135:60-5.13. Alcock RF, Roy P, Adorini K, et al. In-cidence and determinants of myocardial infarction following percutaneous coro-nary interventions according to the re-vised Joint Task Force definition of tropo-nin T elevation. Int J Cardiol 2010;140:66-72.14. Wang TY, Peterson ED, Dai D, et al. Patterns of cardiac marker surveillance after elective percutaneous coronary in-tervention and implications for the use of periprocedural myocardial infarction as a quality metric: a report from the National Cardiovascular Data Registry (NCDR). J Am Coll Cardiol 2008;51:2068-74.

15. Prasad A, Gersh BJ, Bertrand ME, et al. Prognostic significance of periproce-dural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol 2009;54:477-86.16. Srinivasan M, Rihal C, Holmes DR, Prasad A. Adjunctive thrombectomy and distal protection in primary percutaneous coronary intervention: impact on micro-vascular perfusion and outcomes. Circu-lation 2009;119:1311-9.17. Uetani T, Amano T, Ando H, et al. The correlation between lipid volume in the target lesion, measured by integrated backscatter intravascular ultrasound, and post-procedural myocardial infarction in patients with elective stent implantation. Eur Heart J 2008;29:1714-20.18. Hong YJ, Mintz GS, Kim SW, et al. Im-pact of plaque composition on cardiac troponin elevation after percutaneous cor-onary intervention: an ultrasound analy-sis. JACC Cardiovasc Imaging 2009;2:458-68.19. Bahrmann P, Werner GS, Heusch G, et al. Detection of coronary microemboli-zation by Doppler ultrasound in patients with stable angina pectoris undergoing elective percutaneous coronary interven-tions. Circulation 2007;115:600-8.20. Herrmann J, Haude M, Lerman A, et al. Abnormal coronary flow velocity re-serve after coronary intervention is asso-ciated with cardiac marker elevation. Cir-culation 2001;103:2339-45.21. Stone GW, Mehran R, Dangas G, Lansky AJ, Kornowski R, Leon MB. Dif-ferential impact on survival of electrocar-diographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients. Circulation 2001;104:642-7.22. Dangas G, Mehran R, Feldman D, et al. Postprocedure creatine kinase-MB el-evation and baseline left ventricular dys-function predict one-year mortality after percutaneous coronary intervention. Am J Cardiol 2002;89:586-9.23. Ajani AE, Waksman R, Sharma AK, et al. Usefulness of periprocedural creati-nine phosphokinase-MB release to pre-dict adverse outcomes after intracoronary radiation therapy for in-stent restenosis. Am J Cardiol 2004;93:313-7.24. Kini A, Marmur JD, Kini S, et al. Cre-atine kinase-MB elevation after coronary intervention correlates with diffuse ath-erosclerosis, and low-to-medium level el-evation has a benign clinical course: im-plications for early discharge after coronary intervention. J Am Coll Cardiol 1999;34:663-71.25. Brener SJ, Ellis SG, Schneider J, Topol EJ. Frequency and long-term impact of myonecrosis after coronary stenting. Eur Heart J 2002;23:869-76.

26. Ellis SG, Chew D, Chan A, Whitlow PL, Schneider JP, Topol EJ. Death follow-ing creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of cre-atine kinase-MB level, completeness of re-vascularization, ventricular function, and probable benefit of statin therapy. Circu-lation 2002;106:1205-10.27. Brener SJ, Lytle BW, Schneider JP, Ellis SG, Topol EJ. Association between CK-MB elevation after percutaneous or surgical revascularization and three-year mortali-ty. J Am Coll Cardiol 2002;40:1961-7.28. Hong MK, Mehran R, Dangas G, et al. Creatine kinase-MB enzyme elevation fol-lowing successful saphenous vein graft intervention is associated with late mor-tality. Circulation 1999;100:2400-5.29. Andron M, Stables RH, Egred M, et al. Impact of periprocedural creatine kinase-MB isoenzyme release on long-term mor-tality in contemporary percutaneous cor-onary intervention. J Invasive Cardiol 2008;20:108-12.30. Jang JS, Hong MK, Park DW, et al. Im-pact of periprocedural myonecrosis on clinical events after implantation of drug-eluting stents. Int J Cardiol 2008;129:368-72.31. Natarajan MK, Kreatsoulas C, Ve-lianou JL, Mehta SR, Pericak D, Goodhart DM. Incidence, predictors, and clinical significance of troponin-I elevation with-out creatine kinase elevation following percutaneous coronary interventions. Am J Cardiol 2004;93:750-3.32. Nallamothu BK, Chetcuti S, Mukher-jee D, et al. Prognostic implication of tro-ponin I elevation after percutaneous coro-nary intervention. Am J Cardiol 2003;91:1272-4.33. Prasad A, Singh M, Lerman A, Lennon RJ, Holmes DR Jr, Rihal CS. Isolated ele-vation in troponin T after percutaneous coronary intervention is associated with higher long-term mortality. J Am Coll Cardiol 2006;48:1765-70.34. Hubacek J, Basran RS, Shrive FM, Shewchuk L, Goodhart DM, Anderson TJ. Prognostic implications of C-reactive pro-tein and troponin following percutane-ous coronary intervention. Can J Cardiol 2009;25(2):e42-e47.35. Feldman DN, Minutello RM, Berg-man G, Moussa I, Wong SC. Relation of troponin I levels following nonemergent percutaneous coronary intervention to short- and long-term outcomes. Am J Car-diol 2009;104:1210-5.36. De Labriolle A, Lemesle G, Bonello L, et al. Prognostic significance of small tro-ponin I rise after a successful elective per-cutaneous coronary intervention of a na-tive artery. Am J Cardiol 2009;103:639-45.37. Cavallini C, Verdecchia P, Savonitto S, et al. Prognostic value of isolated tropo-nin I elevation after percutaneous coro-nary intervention. Circ Cardiovasc Interv 2010;3:431-5.

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38. Fuchs S, Kornowski R, Mehran R, et al. Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions. Am J Cardiol 2000;85:1077-82.39. Cavallini C, Savonitto S, Violini R, et al. Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coro-nary intervention: results of the CK-MB and PCI study. Eur Heart J 2005;26:1494-8.40. Kugelmass AD, Cohen DJ, Moscucci M, et al. Elevation of the creatine kinase myocardial isoform following otherwise successful directional coronary atherec-tomy and stenting. Am J Cardiol 1994;74:748-54.41. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-36.42. Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, Bonow RO. Prog-nostic implication of creatine kinase ele-vation following elective coronary artery interventions. JAMA 1997;277:461-6.43. Saucedo JF, Mehran R, Dangas G, et al. Long-term clinical events following creatine kinase–myocardial band isoen-zyme elevation after successful coronary stenting. J Am Coll Cardiol 2000;35:1134-41.44. Jeremias A, Baim DS, Ho KK, et al. Differential mortality risk of postproce-dural creatine kinase-MB elevation fol-lowing successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44:1210-4.45. Cantor WJ, Newby LK, Christenson RH, et al. Prognostic significance of ele-

vated troponin I after percutaneous coro-nary intervention. J Am Coll Cardiol 2002;39:1738-44.46. Kizer JR, Muttrej MR, Matthai WH, et al. Role of cardiac troponin T in the long-term risk stratification of patients under-going percutaneous coronary interven-tion. Eur Heart J 2003;24:1314-22.47. Kini AS, Lee P, Marmur JD, et al. Cor-relation of postpercutaneous coronary intervention creatine kinase-MB and tro-ponin I elevation in predicting mid-term mortality. Am J Cardiol 2004;93:18-23.48. Nienhuis MB, Ottervanger JP, Bilo HJ, Dikkeschei BD, Zijlstra F. Prognostic val-ue of troponin after elective percutaneous coronary intervention: a meta-analysis. Catheter Cardiovasc Interv 2008;71:318-24.49. Testa L, Van Gaal WJ, Biondi Zoccai GG, et al. Myocardial infarction after per-cutaneous coronary intervention: a meta-analysis of troponin elevation applying the new universal definition. QJM 2009;102:369-78.50. Herrmann J, Von Birgelen C, Haude M, et al. Prognostic implication of cardiac troponin T increase following stent im-plantation. Heart 2002;87:549-53.51. Miller WL, Garratt KN, Burritt MF, Lennon RJ, Reeder GS, Jaffe AS. Baseline troponin level: key to understanding the importance of post-PCI troponin eleva-tions. Eur Heart J 2006;27:1061-9.52. Heeschen C, van Den Brand MJ, Hamm CW, Simoons ML. Angiographic findings in patients with refractory unsta-ble angina according to troponin T status. Circulation 1999;100:1509-14.53. Jeremias A, Kleiman NS, Nassif D, et al. Prevalence and prognostic signifi-

cance of preprocedural cardiac troponin elevation among patients with stable cor-onary artery disease undergoing percuta-neous coronary intervention: results from the Evaluation of Drug Eluting Stents and Ischemic Events registry. Circulation 2008;118:632-8.54. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330-41.55. Akkerhuis KM, Alexander JH, Tardiff BE, et al. Minor myocardial damage and prognosis: are spontaneous and percuta-neous coronary intervention-related events different? Circulation 2002;105:554-6.56. Chaitman BR, Hardison RM, Adler D, et al. The Bypass Angioplasty Revascular-ization Investigation 2 Diabetes random-ized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treat-ment strategy on cardiac mortality and myocardial infarction. Circulation 2009;120:2529-40.57. Herrmann J, Lerman A, Baumgart D, et al. Preprocedural statin medication re-duces the extent of periprocedural non-Q-wave myocardial infarction. Circula-tion 2002;106:2180-3.58. Di Sciascio G, Patti G, Pasceri V, Gas-pardone A, Colonna G, Montinaro A. Ef-ficacy of atorvastatin reload in patients on chronic statin therapy undergoing percu-taneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) randomized trial. J Am Coll Cardiol 2009;54:558-65.Copyright © 2011 Massachusetts Medical Society.

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current concepts

MDR Tuberculosis — Critical Steps for Prevention and Control

Eva Nathanson, M.Sc., Paul Nunn, F.R.C.P., Mukund Uplekar, M.D., Katherine Floyd, Ph.D., Ernesto Jaramillo, M.D., Ph.D., Knut Lönnroth, M.D., Ph.D.,

Diana Weil, M.Sc., and Mario Raviglione, M.D.

From the Stop TB Department, World Health Organization, Geneva. Address reprint requests to Dr. Jaramillo at the Stop TB Dept., World Health Organiza-tion, CH-1211 Geneva, Switzerland, or at [email protected].


Multidrug-resistant (MDR) tuberculosis is defined as disease caused by strains of Mycobacterium tuberculosis that are at least resistant to treatment with isoniazid and rifampicin; extensively drug-resistant (XDR)

tuberculosis refers to disease caused by multidrug-resistant strains that are also resistant to treatment with any fluoroquinolone and any of the injectable drugs used in treatment with second-line anti-tuberculosis drugs (amikacin, capreomycin, and kanamycin). MDR tuberculosis and XDR tuberculosis are serious threats to the progress that has been made in the control of tuberculosis worldwide over the past decade.1,2

In 2008, an estimated 440,000 cases of MDR tuberculosis emerged globally.1 India and China carry the greatest estimated burden of MDR tuberculosis, together accounting for almost 50% of the world’s total cases. More than three quarters of the estimated cases of MDR tuberculosis occur in previously untreated patients. The proportion of MDR cases among new cases and previously treated cases of tuberculosis reported globally from 1994 through 2009 ranged from 0 to 28.3% and from 0 to 61.6%, respectively (Fig. 1). The highest proportions of MDR cases, and the most severe drug-resistance patterns, appear in the countries of the former Soviet Union. By 2009, a total of 58 countries had reported at least one case of XDR tuberculosis. In eight countries, reported cases of XDR tuberculosis account for more than 10% of all cases of MDR tuberculosis, and six of these countries were part of the former Soviet Union. By far the largest number of cases of XDR tuberculosis has been reported from South Africa (10.5% of all cases of MDR tuber-culosis in that country), owing to rapid spread among people infected with the human immunodeficiency virus (HIV).

National programs are failing to diagnose and treat MDR tuberculosis. Globally, just under 30,000 cases of MDR tuberculosis were reported to the World Health Organization (WHO) in 2008 (7% of the estimated total), of which less than one fifth were managed according to international guidelines. The vast majority of the remaining cases probably are not diagnosed or, if diagnosed, are mismanaged. This problem remains despite the evidence that management of MDR tuberculosis is cost-effective3 and that treatment of MDR tuberculosis, and even treatment of XDR tuberculosis, is feasible in persons who are not infected with HIV.4,5

In some countries, the incidence of tuberculosis is rising, and the incidence of MDR tuberculosis appears to be rising even faster (e.g., in Botswana and South Korea).6 However, in Estonia, Hong Kong, the United States, and Orel and Tomsk Oblasts (in the Russian Federation), the incidence of tuberculosis is falling, and the incidence of MDR tuberculosis appears to be falling even faster.1,6 This trend is

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the result of high-quality care and control prac-tices that result in high rates of case detection and cure, drug-susceptibility testing for all pa-tients, and the provision of appropriate treat-ment for all patients carrying drug-resistant strains. In short, preventing initial infection with MDR tuberculosis and managing the treat-ment of existing cases appropriately are the keys to containing the spread of this disease.

The WHO-recommended Stop TB Strategy7

provides the framework for treating and caring for those who are sick and controlling the epi-demic of drug-susceptible and drug-resistant dis-ease. The DOTS approach, which underpins the Stop TB Strategy, calls for political commitment to national programs designed to control disease by means of early diagnosis with the use of bacteriologic testing, standardized treatment with supervision and patient support, and provision and management of the drugs used in treatment; the approach also includes the monitoring of treatment and evaluation of its effectiveness. Be-tween 1995 and 2008, a total of 36 million people were treated successfully with the use of the

DOTS approach, and 6 million lives were saved.8

Specific guidelines for controlling drug-suscep-tible and drug-resistant disease already exist,9,10

and the Global Plan to Stop TB, 2006 through 2015, developed by the Stop TB Partnership, specifies the scale at which these interventions need to be funded and implemented to achieve global targets.11 However, to date, planning, funding, and implementation are falling far be-hind the milestones that have been set.

Prompted by concern that political support for the management of MDR tuberculosis is insuf-ficient, WHO, the Bill and Melinda Gates Foun-dation, and the Chinese Ministry of Health orga-nized a ministerial conference in Beijing in April 2009.12 The report from the conference in Beijing and the subsequent resolution (number 62.15) approved by the World Health Assembly in May 2009 state that significant changes in several components of the health care system must be made if MDR tuberculosis is to be eliminated.13,14

This review assesses the critical factors imped-ing control and discusses the solutions required to address them.

0 to <3%3 to <6%6 to <12%12 to <18%≥18%No data available

Figure 1. Distribution of the Proportion of Cases of MDR Tuberculosis among New Cases of Tuberculosis, 1994–2009.

The following 27 countries are responsible for 85% of the world’s estimated cases of MDR tuberculosis and are classified as countries with a high burden of MDR tuberculosis: China, India, Russia, Pakistan, Bangladesh, South Africa, Ukraine, Indonesia, Philippines, Nige-ria, Uzbekistan, Democratic Republic of Congo, Kazakhstan, Vietnam, Ethiopia, Myanmar, Tajikistan, Azerbaijan, Moldova, Kyrgyzstan, Belarus, Georgia, Bulgaria, Lithuania, Armenia, Latvia, and Estonia. Adapted from the 2010 report on MDR and XDR tuberculosis from the WHO.1

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Cr i tic a l W e a k nesses a nd How t o A ddr ess Them

Prevention is better than cure. Thus, the top pri-ority for the control and, ultimately, elimination of MDR tuberculosis is prevention of its emer-gence.15 Once MDR tuberculosis has emerged, however, urgent measures are required to curb its effects on efforts to control the disease. The major obstacles and approaches to controlling MDR tuberculosis are described below and sum-marized in Table 1. Three topics of great impor-tance — the global shortage of health care work-ers,16 the need for improvements in surveillance systems,1 and the urgent need for intensified re-search on new diagnostic tests, drugs, and vac-cines17 — have been well described elsewhere and are beyond the scope of this article.

Financing Control and Care

To achieve the goal of universal access to diagno-sis and treatment described in the Global Plan to Stop TB, 1.3 million cases of MDR tuberculosis in the 27 countries with the highest burden of MDR disease will need to be treated between 2010 and 2015.1 The total estimated cost of such treatment is several billion U.S. dollars, an amount far in excess of the existing level of funding. The national strategic plans in these countries must incorporate the preparation of ambitious budgets for the prevention and control of MDR tuberculo-sis. These plans must be consistent with poli-cies on health care financing, including social-protection schemes (the delivery of commodities to reduce the social vulnerability of poor popu-lations), and with broader planning and financ-ing frameworks. These countries — especially the middle-income countries among them — must mobilize their domestic resources. In 2001, the WHO Commission on Macroeconomics and Health indicated that these middle-income coun-tries could finance all, or almost all, of their health care needs.18 While maximizing the use of domestic resources, they should also target re-sources available from international financing organizations, such as the Global Fund to Fight AIDS (Acquired Immunodeficiency Syndrome), Tuberculosis, and Malaria and UNITAID, an or-ganization that provides grants allowing coun-tries to purchase diagnostic tests and drugs used in the treatment of HIV–AIDS, malaria, and tu-berculosis. The failure to adequately fund a re-

sponse to MDR tuberculosis would have cata-strophic consequences in terms of both human lives and tuberculosis control in general.

Abolishing Financial Barriers

Health expenditures that account for more than 40% of household income (after deducting the cost of basic subsistence) have been defined as catastrophic.19 In virtually all countries with a high burden of MDR tuberculosis, treatment costs (per course of treatment) for one person are more than 100% of the gross national income per cap-ita (the cost of second-line anti-tuberculosis drugs alone is typically $2,000 to $4,000 per patient).1 Collective financing mechanisms are therefore required to guarantee universal access to health care. The main source of funding should be do-mestic resources, such as contributions from tax-es, payroll deductions, or mandatory insurance premiums.20,21 Most countries in Africa, Asia, and the Middle East have not attained universal health coverage,22 although there are exceptions. Lessons need to be drawn from universal health-financing schemes applied in such diverse set-tings as Mexico, Rwanda, and Thailand, where access to care may facilitate early detection and treatment of all tuberculosis cases.

Even before universal health coverage is achieved, immediate steps can be taken to reduce catastrophic health expenditures for patients with tuberculosis and their households.23 These steps include decentralization of services to reduce the indirect costs that patients seeking care incur, provision of patient incentives and social support to promote adherence to treatment, and subsidi-zation of care provided in the private sector that is in line with guidelines from national tubercu-losis programs.

Engaging All Care Providers

A substantial proportion of patients with tuber-culosis or MDR tuberculosis seek care with pro-viders who are not linked to national tuberculo-sis programs.24,25 In five countries with a high burden of MDR tuberculosis, more than half of all sales of first-line anti-tuberculosis drugs oc-cur in the private sector, and the proportion is even higher for sales of second-line drugs.26 Many physicians in the private sector and some in the public sector do not follow internationally recommended treatment regimens for tuberculo-sis, use medicines of questionable quality, and ne-

125

current concepts


Tabl

e 1.

Cri

tical

Cha

lleng

es in

the

Con

trol

of M

DR

Tub

ercu

losi

s an

d X

DR

Tub

ercu

losi

s an

d Po

tent

ial S

olut

ions

Sup

port

ed b

y th

e W

HO

.*

Goa

lPr

oble

mPr

opos

ed S

olut

ion

Fina

nce

cont

rol a

nd tr

eatm

ent

for

MD

R-T

B a

nd X

DR

-TB

Estim

ated

cos

t for

201

0–20

15 is

$16

.2 b

illio

n (i

n U

.S $

), in

crea

sing

an

nual

ly fr

om <

$1.3

bill

ion

in 2

010

to $

4.4

billi

on in

201

5; fu

nd-

ing

need

ed is

alr

eady

in e

xces

s of

the

plan

ned

natio

nal M

DR

-TB

bu

dget

s fo

r 20

10

Max

imiz

e us

e of

dom

estic

res

ourc

es w

hile

targ

etin

g re

sour

ces

from

the

Glo

bal F

und

to F

ight

AID

S, T

uber

culo

sis,

and

Mal

aria

, UN

ITA

ID, a

nd

othe

r ex

tern

al fu

ndin

g m

echa

nism

s

Abo

lish

finan

cial

bar

rier

sIn

cou

ntri

es w

ith a

hig

h bu

rden

of M

DR

-TB

, tre

atm

ent c

osts

for

a si

ngle

pat

ient

con

stitu

te m

ore

than

100

% o

f the

gro

ss n

atio

nal

inco

me

per

capi

ta

Impr

ove

heal

th c

are

finan

cing

sch

emes

to s

triv

e fo

r un

iver

sal a

cces

s to

pr

even

tion

and

cont

rol;

dece

ntra

lize

serv

ices

to r

educ

e in

dire

ct c

osts

; pr

omot

e pa

tient

adh

eren

ce to

trea

tmen

t; an

d su

bsid

ize

care

pro

vide

d in

the

priv

ate

sect

or

Enga

ge a

ll ca

re p

rovi

ders

in a

ppro

-pr

iate

MD

R-T

B p

reve

ntio

n an

d co

ntro

l

A s

ubst

antia

l pro

port

ion

of p

atie

nts

seek

car

e fr

om p

rovi

ders

who

do

not f

ollo

w in

tern

atio

nally

reco

mm

ende

d st

anda

rds

of tr

eatm

ent

Enga

ge d

iver

se p

rovi

ders

(pu

blic

, vol

unta

ry, p

rivat

e, a

nd c

orpo

rate

) to

alig

n TB

-man

agem

ent p

ract

ices

with

WH

O In

tern

atio

nal S

tand

ards

for T

B C

are

Opt

imiz

e M

DR

-TB

and

XD

R-T

B

man

agem

ent a

nd c

are

Pers

ons

with

infe

ctio

us M

DR

-TB

and

XD

R-T

B re

mai

n in

the

com

-m

unity

for l

ong

perio

ds o

f tim

e be

caus

e of

del

ayed

dia

gnos

is a

nd

initi

atio

n of

trea

tmen

t with

sec

ond-

line

anti-

TB d

rugs

; hos

pita

liza-

tion

of p

atie

nts

with

MD

R-T

B o

r XD

R-T

B p

oses

pro

blem

of n

oso-

com

ial t

rans

mis

sion

and

is c

ostly

and

inco

nven

ient

for p

atie

nts

Ensu

re ti

mel

y di

agno

sis

and

trea

tmen

t ini

tiatio

n fo

r pa

tient

s w

ith M

DR

-TB

or

XD

R-T

B; i

mpl

emen

t app

ropr

iate

mod

els

of c

are,

pre

fera

bly

outp

a-tie

nt, t

o en

sure

pat

ient

-cen

tere

d ca

re, a

void

dis

ease

tran

smis

sion

in

heal

th c

are

faci

litie

s, a

nd m

ake

ratio

nal u

se o

f fin

anci

al r

esou

rces

Add

ress

labo

rato

ry c

risi

sIn

200

8, in

27

coun

trie

s w

ith th

e hi

ghes

t bur

den

of M

DR

-TB

, onl

y 1%

of p

atie

nts

with

new

ly d

iagn

osed

TB

and

3%

of p

atie

nts

with

pr

evio

usly

trea

ted

TB u

nder

wen

t dru

g-su

scep

tibili

ty te

stin

g

Stre

ngth

en la

bora

tory

ser

vice

s by

usi

ng n

ew m

olec

ular

tech

nolo

gies

Ensu

re a

cces

s to

qua

lity-

assu

red

anti-

TB d

rugs

Use

of c

ount

erfe

it an

d po

or-q

ualit

y an

ti-TB

dru

gs, w

hich

can

lead

to

deve

lopm

ent a

nd a

mpl

ifica

tion

of d

rug

resi

stan

ce, i

s w

ell d

ocu-

men

ted,

but

ther

e is

no

accu

rate

est

imat

e of

the

scal

e of

the

prob

lem

Secu

re a

fford

able

, qua

lity-

assu

red

anti-

TB d

rugs

usi

ng n

atio

nal p

rocu

re-

men

t mec

hani

sms

whi

le b

uild

ing

up a

rel

iabl

e se

cond

-line

ant

i-TB

dr

ug m

arke

t, w

ith m

anuf

actu

rers

inve

stin

g in

incr

ease

d vo

lum

es a

nd

impr

oved

qua

lity

Res

tric

t ava

ilabi

lity

of a

nti-T

B

drug

sW

ide

avai

labi

lity

of a

nti-T

B d

rugs

ove

r th

e co

unte

r in

ret

ail p

harm

a-ci

es e

ncou

rage

s se

lf-tr

eatm

ent a

nd th

e pu

rcha

se o

f ina

dequ

ate

quan

titie

s an

d co

mbi

natio

ns o

f med

icin

es

Res

tric

t dru

g av

aila

bilit

y to

acc

redi

ted

prov

ider

s by

com

bini

ng g

over

nmen

t po

licy,

agr

eem

ent w

ith p

rovi

ders

and

indu

stry

on

impr

oved

mar

ketin

g pr

actic

es, a

nd o

ptim

izat

ion

of th

e pr

otoc

ol fo

r dr

ug m

anag

emen

t and

su

pply

spe

cifie

d by

the

natio

nal T

B p

rogr

am

Prio

ritiz

e TB

infe

ctio

n co

ntro

lO

ngoi

ng tr

ansm

issi

on o

f MD

R-T

B a

nd X

DR

-TB

occ

urs

in h

ealth

ca

re fa

cilit

ies

and

cong

rega

te s

ettin

gs b

ecau

se o

f ina

dequ

ate

in-

fect

ion

cont

rol

Enga

ge w

ide

rang

e of

sta

keho

lder

s ac

ross

the

heal

th s

yste

m (

e.g.

, hos

pita

l ad

min

istr

ator

s, a

rchi

tect

s, e

ngin

eers

, and

hea

lth c

are

wor

kers

), in

clud

-in

g th

ose

conc

erne

d w

ith c

ontr

ol o

f oth

er in

fect

ions

with

air

born

e po

-te

ntia

l, su

ch a

s in

fluen

za, t

o im

plem

ent i

nfec

tion-

cont

rol p

olic

ies

Add

ress

glo

bal h

ealth

wor

kfor

ce

cris

isSh

orta

ge o

f tra

ined

sta

ff to

effe

ctiv

ely

man

age

the

1.6

mill

ion

MD

R-

TB c

ases

exp

ecte

d by

201

5 is

exa

cerb

ated

in m

any

low

-inco

me

coun

trie

s by

act

ive

recr

uitm

ent o

f sta

ff by

indu

stria

lized

cou

ntrie

s

Rev

ise

or u

pdat

e st

rate

gic

plan

s fo

r in

crea

sing

the

TB h

ealth

car

e w

ork-

forc

e (i

nclu

ding

pri

vate

hea

lth c

are

prov

ider

s) to

impr

ove

basi

c TB

co

ntro

l and

to s

cale

up

MD

R-T

B c

ontr

ol

Impr

ove

surv

eilla

nce

syst

ems

Estim

ates

of t

he b

urde

n of

dru

g-re

sist

ant T

B g

loba

lly a

nd b

y co

untr

y re

mai

n in

com

plet

e an

d le

ss th

an a

ccur

ate

Esta

blis

h or

str

engt

hen

cont

inuo

us s

urve

illan

ce s

yste

ms

for d

rug-

resi

stan

t TB

Inve

st in

res

earc

h an

d de

velo

p-m

ent o

f new

dia

gnos

tic te

sts,

dr

ugs,

and

vac

cine

s

Tool

s fo

r pr

even

tion,

dia

gnos

is, a

nd tr

eatm

ent o

f TB

and

dru

g-re

sis-

tant

TB

are

obs

olet

eEn

sure

col

labo

ratio

n be

twee

n de

velo

pmen

t and

tech

nica

l age

ncie

s to

fa-

cilit

ate

deve

lopm

ent a

nd fi

eld

test

ing

of n

ew to

ols

for

prev

entio

n, d

iag-

nosi

s, a

nd tr

eatm

ent o

f TB

* Th

e in

tern

atio

nal g

roup

kno

wn

as U

NIT

AID

pur

chas

es a

nd d

istr

ibut

es d

iagn

ostic

tes

ts a

nd d

rugs

use

d in

the

tre

atm

ent

of H

IV–A

IDS,

mal

aria

, and

tub

ercu

losi

s. A

IDS

deno

tes

acqu

ired

im

mun

odef

icie

ncy

synd

rom

e, M

DR

-TB

mul

tidru

g-re

sist

ant

tube

rcul

osis

, TB

tub

ercu

losi

s, W

HO

Wor

ld H

ealth

Org

aniz

atio

n, a

nd X

DR

-TB

ext

ensi

vely

dru

g-re

sist

ant

tube

rcul

osis

.

126



glect essential principles of case management.27,28 Such practices lead to the development, amplifi-cation, and spread of drug resistance. In addi-tion, collaboration with public and private hospi-tals warrants special attention.29

Guidance on implementing a mix of public and private approaches to tuberculosis care is available,30 and many national tuberculosis pro-grams have begun to incorporate diverse sources of care, including public, voluntary, private, and corporate providers. Nonetheless, only a fraction of the tuberculosis cases diagnosed by practitioners outside the public sector are registered with or referred to national tuberculosis programs.31,32 These approaches should therefore be scaled up and applied to the prevention and management of MDR tuberculosis as well. National tubercu-losis programs need to play a stewardship role and provide guidelines, training, technical and finan-cial support, and the supervision needed to align the practices of private providers with the Inter-national Standards for TB Care.33 Effective en-gagement of diverse care providers will require national tuberculosis programs to both augment their own capacities and strengthen private pro-vider networks to enable them to shoulder their responsibility for managing tuberculosis and MDR tuberculosis. Professional associations need to act as intermediaries between national tuberculosis programs and private providers. Nongovernmen-tal organizations have introduced successful pro-grams for the management of MDR tuberculosis in a number of countries and are key players in scaling up diagnosis and treatment.34,35

But collaborative approaches and appropriate incentives alone may not enlist the support of all relevant care providers — some regulation may be necessary. In some countries with a high bur-den of tuberculosis, providers are not required to notify the government when a new case of tuber-culosis has been diagnosed. And even in coun-tries where notification is required, systems have not been established to ensure that the require-ment is met. Case notification for both tubercu-losis and MDR tuberculosis must be made man-datory; providers who follow best practices should be certified and accredited and should be offered access to free supplies of quality-assured anti-tuberculosis drugs for their patients.30 Sustain-able engagement of all care providers will require national tuberculosis programs to work in close

partnership with health professionals, represen-tatives of the pharmaceutical industry, pharma-cists, and drug regulatory authorities, in addition to consumer and patient associations.

Optimizing Disease Management and Care

Transmission of drug-resistant tuberculosis oc-curs in the community,36 as indicated by the high frequencies of MDR tuberculosis among previ-ously untreated patients in some countries. In most countries with limited resources, patients with MDR or XDR tuberculosis must complete two unsuccessful courses of treatment with first-line anti-tuberculosis drugs before being eligible for treatment with second-line drugs.37 Moreover, in many countries, treatment of MDR tuberculo-sis is started only after the diagnosis has been confirmed, a process that takes months when conventional methods are used. As a result, per-sons with infectious MDR or XDR tuberculosis remain in the community for long periods of time. Prompt diagnosis and treatment of tuber-culosis and MDR tuberculosis can keep the case reproduction number of MDR strains below their replacement rate — and perhaps even below that of non-MDR strains.6

Outbreaks of MDR tuberculosis have occurred in hospitals, and patients with tuberculosis who are hospitalized have a higher risk of acquiring MDR tuberculosis than do those who are treated as outpatients.38,39 Treating MDR tuberculosis in a hospital is more expensive than doing so on an ambulatory basis. Hospital treatment is also more socially and economically disruptive for most patients.40 In addition, the number of hospital beds may become insufficient as countries ex-pand treatment for MDR tuberculosis. Despite the complexities involved in caring for patients with MDR tuberculosis, including lengthy ther-apy with poorly tolerated drugs, clinic-based or community-based care has proved to be feasible and effective in several countries, including Ne-pal41 and Peru.42 However, the effectiveness of outpatient care depends on the availability of pri-mary care facilities, qualified health care work-ers, and social support networks to promote ad-herence to treatment. Countries need to select the model of care that is right for them, taking into account the personal rights and needs of patients and communities,43 the numbers of pa-tients who have both MDR tuberculosis and

127

current concepts


HIV–AIDS, the social circumstances of patients,44 the health care infrastructure, and the ability of the country to mobilize resources.

Responding to the Laboratory Crisis

Weak laboratory capacity remains a serious im-pediment to prompt diagnosis and better control of MDR tuberculosis.1 The goal of universal ac-cess to drug-susceptibility testing has not yet been achieved. In 2008, drug-susceptibility testing was performed in only 1% of new tuberculosis cases and 3% of previously treated cases in the 27 countries with the highest burden of MDR tuber-culosis.

Today, rapid molecular tests for MDR tubercu-losis are available.45 For instance, one new auto-mated rapid test for rifampicin resistance holds promise for easier detection of MDR tuberculosis even in community settings.46 The implementa-tion of this and other rapid tests, especially in countries with a high prevalence of concurrent HIV infection and MDR tuberculosis, can prevent fatal delays in detection.47 The establishment of quality-assured diagnostic capacity, including rapid diagnostic technologies to identify MDR tubercu-losis, is feasible in resource-limited settings.48 Use of the new molecular technologies offers one of the best avenues for improving overall diagnostic capacity in the laboratory.49 At present, however, the adoption of the new rapid tests will not elimi-nate the need for conventional drug-susceptibility testing with the use of solid or liquid culture. Con-ventional susceptibility testing is required to de-termine susceptibility to drugs other than rifam-picin and isoniazid.9 While countries expand laboratory capacity and introduce the new rapid tests, targeted drug-susceptibility testing should be performed in specific groups of patients at risk for drug resistance. Expansion of diagnostic capacity for MDR tuberculosis must be coupled with ac-cess to second-line anti-tuberculosis drugs. Efforts to shorten the time required for diagnosis must occur in tandem with measures that minimize or-ganizational delay to ensure prompt initiation of treatment.

Ensuring Access to Quality-Assured Drugs

In 2007, only 15% of reported new cases of tuber-culosis were treated with fixed-dose combina-tions of anti-tuberculosis drugs,50 despite their logistic advantages and potential to reduce the

risk of the development of drug resistance.51 The use of counterfeit and poor-quality anti-tubercu-losis drugs, which can lead to the development and amplification of drug resistance, is well doc-umented, but there is no accurate estimate of the scale of the problem.52,53 International quality standards have been developed but are often ig-nored, and an insufficient number of manufac-turers have been approved under the WHO Pre-qualification Programme.54

To effectively prevent and manage MDR tu-berculosis, countries need to secure affordable, quality-assured, anti-tuberculosis drugs through national procurement mechanisms. Affordable and quality-assured, second-line anti-tuberculo-sis drugs can also be accessed through the WHO Green Light Committee, which ensures manage-ment of MDR tuberculosis that is in line with international quality standards in 70 countries.1 However, of particular concern for efforts to in-crease the scale of MDR tuberculosis manage-ment is the insufficient supply of quality-assured, second-line anti-tuberculosis drugs.13 As of April 2010, only two manufacturers that produce three of the seven second-line anti-tuberculosis drugs on the WHO Model List of Essential Medicines had been approved by the WHO Prequalification Programme.54 Building up a reliable market of second-line anti-tuberculosis drugs, with manu-facturers investing in increased volumes and im-proved quality, requires more accurate forecast-ing of demand. In addition, national authorities need to expedite the enrollment of many more patients under proper management conditions.

Restricting Drug Availability

Anti-tuberculosis drugs are widely available over the counter in retail pharmacies in many coun-tries.55 This encourages self-treatment and the purchase of inadequate quantities and combina-tions of medicines. Even when the drugs are pre-scribed, those prescribing the drugs outside na-tional tuberculosis programs may not abide by recommended regimens, and some patients may purchase only part of the prescription because of financial constraints.56 Prescription and dispens-ing of medicines in general, and of antibiotics in particular, are poorly monitored and regulated in most countries.57 Even when regulations exist, their enforcement is often insufficient.

An essential step toward improved prevention

128



of MDR tuberculosis is to encourage the engage-ment of private and public providers with nation-al tuberculosis programs on a voluntary basis.30 A more forceful approach would be to restrict the right to prescribe and dispense the drugs to the national tuberculosis program itself or to pro-viders that have been accredited by the program. Either approach would require a combination of new government policy and dialogue with care providers, including pharmacists, and the phar-maceutical industry. Such measures undertaken by national tuberculosis programs to optimize drug management and supply have been success-ful in some countries, including Brazil, Ghana, Syria, and Tanzania. Consumers also need to be aware of the risks of poor prescribing prac-tices and, as discussed above, the clinical and public health threats posed by substandard medi-cines.52,57 Demand-driven efforts to push for more accountability and enforcement of regulations by national authorities may be highly effective. Further advances in social responsibility and im-proved marketing practices on the part of drug manufacturers are also essential, along with supportive government measures.

Prioritizing Control of Tuberculosis Infection

As a result of inadequate measures of infection control, there is ongoing transmission of MDR tuberculosis and XDR tuberculosis in health care facilities and congregate settings (e.g., prisons).38 To date, virtually no country with a high burden of tuberculosis has implemented systematic mea-sures to reduce the risk of tuberculosis transmis-sion in health facilities.1 Health care workers, especially those working in tuberculosis hospi-tals and in resource-limited settings, are at sub-stantially higher risk of contracting tuberculosis and MDR tuberculosis than the general popula-tion.58,59

All health care facilities that admit patients with tuberculosis or patients suspected of having tuberculosis should implement tuberculosis-con-trol measures that complement general measures of infection control, especially those which tar-get other airborne infections.60 Home-based and community treatment of MDR tuberculosis should be promoted. To curb the increased risk of noso-comial tuberculosis and MDR tuberculosis among health care workers, some countries have added

tuberculosis to the list of recognized occupa-tional hazards.59 Infection control requires en-gagement with a wide range of stakeholders across the health care system, including hospital administrators, architects, engineers, doctors, nurses, and laboratory staff. On the policy level, infection control requires collaborative action among those concerned with infections with airborne potential, such as influenza.

The Urgen t Need for Ac tion

Critical weaknesses in current approaches to the treatment and control of MDR tuberculosis and XDR tuberculosis have been identified and are being addressed at the global level. In 2009, the Beijing Call for Action13 and the passage of World Health Assembly Resolution 62.1514 signaled a major step forward in coordinated planning for the treatment and control of MDR tuberculosis and in the commitment to achieve universal ac-cess to diagnosis and treatment by 2015 for pa-tients who have the disease. Resolutions, however, are useful only insofar as they stimulate the ap-propriate policymakers in governments to act on them. By October 2009, 20 of the 27 countries with the highest burden of MDR tuberculosis were updating their national tuberculosis-control plans to include a component addressing MDR tuber-culosis, in compliance with the World Health As-sembly resolution. Furthermore, for the countries that have received grants from the Global Fund in its ninth round of grants, funding requested for the management of MDR tuberculosis was by far the largest requested for all aspects of tuber-culosis control: more than $500 million (in U.S. dollars) was requested for the management of MDR tuberculosis in 28 countries over a period of 5 years.

Every one of the recommendations in this ar-ticle for improving the treatment and control of MDR tuberculosis requires action beyond national tuberculosis control programs, sometimes in the political environment outside the health care sys-tem. This is a highly ambitious but necessary agenda for health authorities in the affected countries and for the global health community. The steps involved in controlling MDR tubercu-losis are also important steps toward strengthen-ing health care systems, including progress in achieving universal health care coverage. If this

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References

1. World Health Organization. Multi-drug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on sur-veillance and response. 2010. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf.)2. Raviglione MC, Smith IM. XDR tuber-culosis — implications for global public health. N Engl J Med 2007;356:656-9.3. Tupasi TE, Gupta R, Quelapio MI, et al. Feasibility and cost-effectiveness of treat-ing multidrug-resistant tuberculosis: a co-hort study in the Philippines. PLoS Med 2006;3(9):e352.4. Orenstein EW, Basu S, Shah NS, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: system-atic review and meta-analysis. Lancet In-fect Dis 2009;9:153-61.5. Sotgiu G, Ferrara G, Matteelli A, et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009;33:871-81.6. Dye C. Doomsday postponed? Prevent-ing and reversing epidemics of drug resis-tant tuberculosis. Nat Rev Microbiol 2009;7:81-7.7. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952-5.8. Lönnroth K, Castro KG, Chakaya JM, et al. Tuberculosis control and elimina-tion 2010-50: cure, care, and social devel-opment. Lancet 2010;375:1814-29.9. World Health Organization. Treat-ment of tuberculosis: guidelines. 4th ed. 2009 (WHO/HTM/TB/2009.420). Geneva, 2010.10. World Health Organization. Guide-lines for the programmatic management of drug-resistant tuberculosis: emergency update 2008. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf.)11. Stop TB. Partnership: global plan to stop TB, 2006-2015. (Accessed August 16, 2010, at http://www.stoptb.org/global/plan/default.asp.)12. Cheng MH. Ministerial meeting agrees plan for tuberculosis control. Lancet 2009;373:1328.13. World Health Organization. Global tu-berculosis control and patient care: a min-isterial meeting of high M/XDR-TB burden countries. (Accessed August 16, 2010, at

http://www.who.int/tb_beijingmeeting/en/index.html.) 14. Idem. Prevention and control of multi-drug-resistant tuberculosis and extensive-ly drug-resistant tuberculosis. World Health Assembly resolution 62.15. May 2009. (Accessed August 16, 2010, at http://apps.who.int/gb/ebwha/pdf_files/A62/A62_R15-en.pdf.)15. Reichman LB. Unsexy tuberculosis. Lancet 2009;373:28.16. The world health report 2006: work-ing together for health. Geneva: World Health Organization, 2006. (Accessed Au-gust 16, 2010, at http://www.who.int/whr/2006/whr06_en.pdf.)17. Fauci AS. Opinion: fighting TB should be priority. New York: Msnbc.com, 2009. (Accessed August 16, 2010, at http://www.msnbc.msn.com/id/33890464/ns/health-infectious_diseases/.)18. Macroeconomics and health: investing in health for economic development. Re-port of the Commission on Macroeco-nomics and Health. Geneva: World Health Organization, 2001. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/2001/924154550X.pdf.)19. Xu K, Evans DB, Kawabata K, Zeram-dini R, Klavus J, Murray CJL. Household catastrophic health expenditure: a multi-country analysis. Lancet 2003;362:111-7.20. Social health protection: an ILO strat-egy towards universal access to health care. Social security policy briefings. Paper 1. Geneva: International Labour Organiza-tion, 2008. (Accessed August 16, 2010, at http://www.ilo.org/public/english/protection/secsoc/downloads/policy/policy1e.pdf.)21. World Health Organization. Social health insurance: sustainable health fi-nancing, universal coverage and social health insurance. April 2005. (Accessed August 16, 2010, at http://apps.who.int/gb/ebwha/pdf_files/WHA58/A58_20-en.pdf.)22. Garrett L, Chowdhury AM, Pablos-Méndez A. All for universal health cover-age. Lancet 2009;374:1294-9.23. Hanson C, Floyd K, Weil D. Tubercu-losis in the poverty alleviation agenda. In: Raviglione M, ed. TB: a comprehensive international approach. New York: Infor-ma Healthcare, 2006:1097-114.24. Pantoja A, Floyd K, Unnikrishnan KP, et al. Economic evaluation of public-pri-

vate mix for tuberculosis care and con-trol, India. I. Socio-economic profile and costs among tuberculosis patients. Int J Tuberc Lung Dis 2009;13:698-704.25. Lönnroth K, Aung T, Maung W, Kluge H, Uplekar M. Social franchising of TB care through private GPs in Myanmar: an assessment of treatment results, access, equity and financial protection. Health Policy Plan 2007;22:156-66.26. Pathway to patients: charting the dy-namics of the global TB drug market. New York: TB Alliance, 2007. (Accessed August 16, 2010, at http://www.tballiance.org/downloads/publications/Pathway_to_Patients_Compendium_FINAL.pdf.)27. Loveday M, Thomson L, Chopra M, Ndlela Z. A health systems assessment of the KwaZulu-Natal tuberculosis pro-gramme in the context of increasing drug resistance. Int J Tuberc Lung Dis 2008;12:1042-7.28. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912-6.29. Uplekar M. Stopping tuberculosis: time to turn urgent attention to hospitals. Int J Tuberc Lung Dis 2008;12:986.30. World Health Organization. Engaging all health care providers in TB control: guidance on implementing public-private mix approaches. 2006. (Accessed August 16, 2010, at http://whqlibdoc.who.int/hq/2006/WHO_HTM_TB_2006.360_eng.pdf.)31. Lönnroth K, Uplekar M, Blanc L. Hard gains through soft contracts: productive engagement of private providers in tuber-culosis control. Bull World Health Organ 2006;84:876-83.32. Irawati SR, Basri C, Arias MS, et al. Hospital DOTS linkage in Indonesia: a model for DOTS expansion into govern-ment and private hospitals. Int J Tuberc Lung Dis 2007;11:33-9.33. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International stan-dards for tuberculosis care. Lancet Infect Dis 2006;6:710-25.34. Van Deun A, Maug AK, Salim MA, et al. Short, highly effective and inexpensive standardized treatment of multidrug-resis-tant tuberculosis. Am J Respir Crit Care Med 2010 May 4 (Epub ahead of print).35. Cox HS, Kalon S, Allamuratova S, et al. Multidrug-resistant tuberculosis treatment

policy agenda is not pursued with urgency, the human and financial costs to societies will be profound.

Supported by a grant from the Bill and Melinda Gates Foun-dation.

No potential conflict of interest relevant to this article was reported.


We thank Karin Bergström, Léopold Blanc, Robert Matiru, Andrea Pantoja, Fabio Scano, Karin Weyer, and Matteo Zignol for their support in developing the background documents for the ministerial meeting in Beijing in April 2009 and for review-ing earlier versions of the manuscript.

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outcomes in Karakalpakstan, Uzbekistan: treatment complexity and XDR-TB among treatment failures. PLoS ONE 2007;2(11):e1126.36. Marais BJ, Victor TC, Hesseling AC, et al. Beijing and Haarlem genotypes are overrepresented among children with drug-resistant tuberculosis in the Western Cape Province of South Africa. J Clin Microbiol 2006;44:3539-43.37. Basu S, Friedland GH, Medlock J, et al. Averting epidemics of extensively drug-resistant tuberculosis. Proc Natl Acad Sci U S A 2009;106:7672-7.38. Nodieva A, Jansone I, Broka L, Pole I, Skenders G, Baumanis V. Recent nosoco-mial transmission and genotypes of multi-drug-resistant Mycobacterium tuberculo-sis. Int J Tuberc Lung Dis 2010;14:427-33.39. Gelmanova IY, Keshavjee S, Golub-chikova VT, et al. Barriers to successful tuberculosis treatment in Tomsk, Russian Federation: non-adherence, default and the acquisition of multidrug resistance. Bull World Health Organ 2007;85:703-11.40. Heller T, Lessells RJ, Wallrauch CG, et al. Community-based treatment for multidrug-resistant tuberculosis in rural KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2010;14:420-6.41. Malla P, Kanitz EE, Akhtar M, et al. Ambulatory-based standardized therapy for multi-drug resistant tuberculosis: ex-perience from Nepal, 2005-2006. PLoS ONE 2009;4:e8313.42. Shin S, Furin J, Bayona J, Mate K, Kim JY, Farmer P. Community-based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med 2004;59:1529-39.43. Singh JA, Upshur R, Padayatchi N. XDR-TB in South Africa: no time for de-

nial or complacency. PLoS Med 2007;4(1):e50.44. Floyd K, Hutubessy R, Samyshkin Y, et al. Health-systems efficiency in the Russian Federation: tuberculosis control. Bull World Health Organ 2006;84:43-51.45. World Health Organization. Molecu-lar line probe assays for rapid screening of patients at risk of multidrug-resistant tuberculosis (MDR-TB). Policy statement. June 27, 2008. (Accessed August 16, 2010, at http://www.who.int/tb/dots/laboratory/lpa_policy.pdf.)46. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuber-culosis and rifampin resistance. N Engl J Med 2010;363:1005-15.47. Gandhi NR, Shah NS, Andrews JR, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis re-sults in high early mortality. Am J Respir Crit Care Med 2009;181:80-6.48. Paramasivan CN, Lee E, Kao K, et al. Experience establishing tuberculosis lab-oratory capacity in a developing country setting. Int J Tuberc Lung Dis 2010;14:59-64.49. Birx D, de Souza M, Nkengasong JN. Laboratory challenges in the scaling up of HIV, TB, and malaria programs: the inter-action of health and laboratory systems, clinical research, and service delivery. Am J Clin Pathol 2009;131:849-51.50. Global tuberculosis control: epidemi-ology, strategy, financing. WHO report 2009. Geneva: World Health Organization, 2009. (WHO/HTM/TB/2009.411.) (Accessed August 16, 2010, at http://www.who.int/tb/publications/global_report/en/index.html.)51. Blomberg B, Fourie B. Fixed-dose com-bination drugs for tuberculosis: applica-tion in standardised treatment regimens. Drugs 2003;63:535-53.

52. Caudron JM, Ford N, Henkens M, Macé C, Kiddle-Monroe R, Pinel J. Sub-standard medicines in resource-poor set-tings: a problem that can no longer be ignored. Trop Med Int Health 2008;13:1062-72.53. Newton PN, Green MD, Fernández FM, Day NP, White NJ. Counterfeit anti-infective drugs. Lancet Infect Dis 2006;6:602-13.54. World Health Organization. Prequali-fication programme. (Accessed August 16, 2010, at http://apps.who.int/prequal/.)55. Kobaidze K, Salakaia A, Blumberg HM. Over the counter availability of anti-tuberculosis drugs in Tbilisi, Georgia, in the setting of a high prevalence of MDR-TB. Interdiscip Perspect Infect Dis 2009; 2009:513-609.56. Uplekar M, Juvekar S, Morankar S, Rangan S, Nunn P. Tuberculosis patients and practitioners in private clinics in In-dia. Int J Tuberc Lung Dis 1998;2:324-9.57. Cars O, Högberg LD, Murray M, et al. Meeting the challenge of antibiotic resis-tance. BMJ 2008;337:a1438.58. Skodric-Trifunovic V, Markovic-Denic L, Nagorni-Obradovic L, Vlajinac H, Woeltje KF. The risk of occupational tuberculosis in Serbian health care workers. Int J Tu-berc Lung Dis 2009;13:640-4.59. Naidoo S, Jinabhai CC. TB in health care workers in KwaZulu-Natal, South Af-rica. Int J Tuberc Lung Dis 2006;10:676-82.60. WHO policy on TB infection control in health-care facilities, congregate set-tings and households. Geneva: World Health Organization, 2009. (Accessed August 16, 2010, at http://whqlibdoc.who.int/publications/2009/9789241598323_eng.pdf.)Copyright © 2010 Massachusetts Medical Society.

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Clinical Evaluation of the KneeTeresa L. Schraeder, M.D., Richard M. Terek, M.D., and C. Christopher Smith, M.D.

From Mt. Auburn Hospital, Cambridge, MA (T.L.S.); Warren Alpert Medical School (T.L.S.) and the Department of Ortho-paedics (R.M.T.), Brown University, Prov-idence, RI; and the Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, and Harvard Medical School (C.C.S.) — both in Bos-ton. Address reprint requests to Dr. Terek at the Department of Orthopaedic Sur-gery, Brown University, 2 Dudley St., Suite 200, Providence, RI 02905, or at [email protected].

N Engl J Med 2010;363(4):e5.Copyright © 2010 Massachusetts Medical Society.

The knee is one of the most complex joints in the body. Not surprisingly, knee problems are one of the most common musculoskeletal symptoms evaluated by the primary care physician.1

Anatomy

The knee joint consists of three bones — the femur, tibia, and patella — with three areas of articulation. The important soft-tissue structures of the knee include the four major ligaments — the anterior cruciate, posterior cruciate, and medial and lateral collateral ligaments — the joint capsule, the medial and lateral menisci, the quadriceps tendon, and the patellar tendon. The menisci are fibrocartilaginous structures located between the tibiofemoral articulations; they increase stability and distribute contact forces on the articular cartilage (Fig. 1 and 2).

Common Knee Injuries

All the bones and soft tissues of the knee are subject to injury. The most common problems that are reported in a physician’s office are related to soft-tissue inflam-mation, injury, or arthritis. Injuries to soft tissue and injuries resulting from over-use are often caused by reproducible mechanisms of physical trauma or forces. Fractures are less common and include fractures of the tibial plateau, the femoral condyles, or the patella.

Knowledge of the mechanisms of knee injury can be essential to making an accurate diagnosis. An injury caused by valgus stress to the knee can result in medial collateral ligament strain or rupture, and an injury caused by varus stress can result in lateral collateral ligament strain or rupture. Abrupt noncontact decel-eration or twisting and pivoting with simultaneous valgus stress to the knee can cause rupture of the anterior cruciate ligament, whereas abrupt posterior translation of the tibia can result in rupture of the posterior cruciate ligament. Twisting and pivoting of the knee while it is bearing weight can cause a meniscal tear.

Overuse injuries are often manifested as pain in the structure subject to repetitive stress. For example, repetitive jumping can lead to patellar tendonitis, also called jumper’s knee, whereas repeated application of direct pressure to the patella through kneeling can cause prepatellar bursitis, sometimes referred to as housemaid’s knee.

History

Obtaining a complete history is the first step in determining the cause of knee pain. The key elements include location and characterization of pain, mechanism of in-jury, sound of a “pop” at the time of injury (which can indicate a ligamentous tear or fracture), immediate or delayed swelling, recent infections, ability to bear weight, locking sensation or instability (or incidents of subluxation), and prior injuries to the joint.

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To assess nontraumatic causes of subacute or chronic knee pain (in addition to questions about location and characterization of pain), the clinician should inquire about fever, morning stiffness, pain after exercise, tick bites (to assess risk of Lyme disease), infections (including sexually transmitted diseases, such as gonorrhea), his-tory of gout or psoriasis, and activities contributing to long-term overuse.

General Examination of the Knee

Gait is an important element of the physical examination of the knee. The clinician should always evaluate the patient’s gait and weight-bearing abilities, since the findings can help distinguish knee pathology from pain referred from the hip, lower back, or foot.

When clinically appropriate, a useful part of the clinical evaluation of knee pain is observing the patient execute a duckwalk, which requires the patient to squat and attempt to walk in that position. The duckwalk requires an intact ligamentous system and a knee free of significant meniscal pathology, effusions, and bony abnormalities, such as arthritis. Thus, if a patient can perform a duckwalk, he or she probably has no ligamentous instability, large effusions, or meniscal tears.

The alignment of the knees should also be evaluated, with the patient standing with feet together. Look for a varus (bow-legged) or valgus (knock-kneed) defor-mity. Such deformities can predispose the patient to osteoarthritis or indicate the presence of significant osteoarthritis.2

Quadriceps atrophy can indicate disuse after an injury. If there is any suspicion of quadriceps atrophy the circumference of each thigh should be measured to confirm or rule out any changes to the underlying musculature.

It is also important to carefully assess the skin around the knee. Abnormalities such as hematoma, rash (e.g., psoriasis), abrasions or lacerations, and cellulitis provide important diagnostic clues.

Palpation of the Knee

Always examine both knees, beginning with the unaffected knee. This approach will reassure the patient and limit any apprehension about the examination, and it will also establish a baseline against which the affected knee can be compared.

Using the back of the hand, assess for warmth as an indicator of inflammation. Next, with the knee at a 90-degree angle, palpate the knee, beginning with the anterior structures. Start by placing your thumbs on the tibial tuberosity and move superiorly. As you move superiorly, palpate the patellar tendon and its insertion at the inferior pole of the patella; pain in this area, especially in an athlete, might indicate patellar tendonitis.

In a patient with a direct trauma to the knee, carefully palpate for areas of tenderness that might indicate a fracture. In such patients, five specific findings or factors should prompt consideration of radiographic imaging to rule out a trau-matic fracture: an age of 55 years or older, tenderness at the head of the fibula, isolated patellar tenderness, inability to flex the knee to 90 degrees, or inability to bear weight and complete at least four steps. These five factors constitute the Ottawa knee rules, a validated decision-making tool with a sensitivity of 100%.3,4 Radiography should also be considered if an injury to the anterior cruciate liga-ment is suspected; such an injury can be associated with avulsion fractures of the lateral tibial plateau.

In a patient with focal tenderness, erythema, and warmth and swelling anterior to the patella, acute prepatellar bursitis should be considered. Patients with this condition, which can be septic and may require aspiration or drainage, typically have a history of recurrent kneeling or of direct trauma.

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n engl j med 363;4 nejm.org july 22, 2010

Figure 1. Anatomy of the Right Knee, Anterior View.

Figure 2. Anatomy of the Right Knee, Posterior View.

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Pain, swelling, and a palpable defect at the insertion of the quadriceps tendon into the superior aspect of the patella suggests rupture of a quadriceps tendon. This injury may be accompanied by a “pop” when it occurs, followed by dimin-ished or complete absence of extensor strength.

The clinician should identify the inferior pole of the patella and move medially to examine the medial joint line. Pain along the medial joint line might represent medial compartment osteoarthritis, injury to the medial collateral ligament, or a medial meniscal tear.

Tenderness at the midpoint between the anterior aspect of the medial joint line and the tibial tuberosity may indicate pes anserine bursitis (located at the insertion of the hamstring tendons into the tibia). Pes anserine bursitis is often found in runners with tight hamstrings and in patients with valgus deformity; in the latter case, it is often associated with osteoarthritis of the knee.

The clinician should also examine the lateral joint line for tenderness, which can be caused by lateral compartment osteoarthritis, injury to the lateral collateral ligament, or a lateral meniscal tear. Focal pain at the lateral femoral condyle is suggestive of iliotibial band syndrome.

Palpation of the popliteal fossa can reveal a tender, fluid-filled mass called a Baker’s cyst. This results from a posterior extension of knee-joint effusions and often accompanies osteoarthritis.

Assessment of Effusion

The absence of the normal indentations on the peripatellar grooves on either side of the patella may indicate the presence of a large intraarticular effusion. Two ma-neuvers can help confirm the presence of an intraarticular effusion.

In the first maneuver, with the knee extended, use the nondominant hand to squeeze the intraarticular fluid from the suprapatellar region into the space be-tween the patella and femur. With the dominant hand, exert pressure superiorly from the tibia while using your index finger to push the patella against the patel-lofemoral groove. When an effusion is present, you can easily ballot the patella.

The second maneuver used to assess for an effusion should also be performed with the knee in extension. Gently milk the fluid into the suprapatellar pouch by moving your hand proximally along the medial aspect of the patella. Next milk or compress the fluid from the suprapatellar pouch to the medial knee by moving your hand from the superior lateral region to the inferior lateral region; if there is an effusion, compressing the lateral regions will cause a bulge to appear medial to the patella in the areas that are naturally concave.

Comparison with the unaffected knee is essential. If an effusion is present, arthrocentesis may be necessary for diagnostic or therapeutic reasons.5

Range of Motion

Both active and passive range of motion of the knee should be tested. The normal range of extension is 0 to −10 degrees, and the normal range of flexion is 130 to 150 degrees. The location and movement of the patella should be noted: watch for any signs of abnormal tracking, crepitus, or pain. If retropatellar pain and crepitus occur while the patella is being compressed against the trochlea during active ex-tension, patellofemoral syndrome or patellofemoral arthritis (chondromalacia) should be considered. Pain with active range of motion but painfree passive range of motion suggest a soft-tissue disorder such as tendonitis. Pain that is equal on both passive and active range of motion is more likely to suggest an intraarticular process.

Clinical Evaluation of the Knee


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Assessment of the Medial Collateral and Lateral Collateral Ligaments

Injury to the medial or lateral collateral ligaments typically involves direct trauma to the contralateral side of the knee — for example, a direct blow to the lateral side results in valgus stress and injury to the medial collateral ligament. To assess the medial collateral ligament, apply valgus stress to the knee. With the knee flexed to 25 degrees, place one hand on the outer aspect of the knee to apply medial pressure, and the other hand on the inner aspect of the distal tibia to apply lateral pressure; you are testing for tenderness or laxity along the medial collateral ligament.6,7 Simi-larly, the lateral collateral ligament can be tested by applying lateral pressure to the inner knee and medial pressure to the outer ankle or lower leg, which causes varus stress to the knee.

When assessing the medial or lateral collateral ligaments, tenderness along the ligament, but less than 5 mm of laxity and a solid end point, indicates a first-degree sprain. In a second-degree sprain, a solid end point is maintained but there is increased laxity when the knee is tested at 25 degrees of flexion and no laxity in full extension. In a third-degree sprain or a complete tear of the ligament, there will be a soft end point and more than 10 mm of laxity when the knee is at 25 degrees of flexion; if there is also laxity with full extension, there may be additional dam-age to the cruciate ligament.6

Assessment of the Anterial Cruciate Ligament

The anterior drawer test and the Lachman test provide information about the integ-rity of the anterior cruciate ligament.

In the anterior drawer test, the patient should be supine, with the knee flexed to 90 degrees and the foot placed flat on the table. Stabilize the foot (you can sit on the end of the patient’s foot) and place your thumbs on the tibial plateau and your fingers around the calf, relaxing the hamstrings; pull forward to test the anterior cruciate ligament. If the ligament is intact, it should abruptly stop the anterior mo-tion of the tibia with a solid end point. The affected and unaffected legs should have similar degrees of anterior translation.

The Lachman test is a more sensitive and specific test for assessment of the anterior cruciate ligament.7,8 In this maneuver, the patient is supine and asked to relax the hamstrings. Use one hand to stabilize the femur while placing the knee at 20 degrees of flexion. With the other hand, grasp the proximal tibia and briskly pull the tibia forward. If there is more than 6 to 8 mm of laxity, more laxity than in the unaffected knee, or a soft end point, the ligament may be torn.9 If you are unable to firmly grasp and stabilize the femur, you can modify the Lachman maneu-ver by placing your knee under the patient’s knee, firmly pressing down on the distal femur with one hand, and pulling the tibia anteriorly with your other hand.

A large hemorrhagic effusion of rapid onset frequently accompanies anterior cruciate ligament tears and bony fractures and contributes to the patient’s discom-fort. Arthrocentesis can be of both diagnostic and therapeutic benefit and can also facilitate a more accurate examination.

Assessment of the Posterior Cruciate Ligament

To test the integrity of the posterior cruciate ligament, perform the posterior drawer test and assess for evidence of a tibial sag.

As in the anterior drawer test, the patient should be supine and the knee flexed to 90 degrees. The foot should be flat on the table. Stabilize the foot (you can sit on the end of the patient’s foot) and place your thumbs on the tibial tubercle and your fingers around the calf, then briskly push the tibia posteriorly to test the posterior cruciate ligament. If the ligament is intact, there should be a solid end point and little posterior translation of the tibia.

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Clinical Evaluation of the Knee

The tibial sag test is another test of the integrity of this ligament.6 Have the patient flex both knees at 90 degrees and place both feet flat on the table; then observe the alignment of the tibial plateau. Normally, the tibial plateau extends 1 cm beyond the femoral condyle. If the affected tibia is displaced posteriorly on the femur, or sags, as compared with the unaffected tibial plateau, the posterior cruci-ate ligament may be ruptured.

Assessment of the Meniscus

Patients with meniscal injuries may report clicking, catching, or locking of the knee. In addition, they frequently have an effusion of delayed onset, appearing hours or even days after the injury.

In addition to assessment of the knee for joint-line tenderness, there are two common maneuvers that can be used to assess for possible meniscal tears. In the McMurray test, the patient is supine. To test the medial meniscus, place one hand over the anterior aspect of the knee, with fingers and thumb on the medial and lateral joint lines. Grasp the patient’s heel with the other hand and externally ro-tate the tibia, using the first hand to apply valgus force at the knee during passive flexion and extension. The maneuver is repeated when applying internal rotation and varus stress to test the lateral meniscus. Clicking, catching, or popping at the joint line during early extension or midextension may indicate a meniscal tear.10

In the Apley compression test, or grind test, the patient lies prone and the knee is flexed to 90 degrees. Stabilize the thigh by placing your knee or hand firmly on top of the patient’s posterior thigh. Grasp the foot and apply a downward com-pressive force while rotating the tibia internally and externally. Pain on compres-sion is considered positive for a meniscal tear.7,11

Suspicion of a meniscal tear should prompt a careful assessment of the ante-rior cruciate ligament; likewise, suspicion of a torn anterior cruciate ligament should prompt a careful assessment of the meniscus. Injuries to these two struc-tures often occur together.

Summary

In summary, a thorough history and physical examination are the first steps in evaluating knee pain and making an accurate diagnosis, after which decisions about imaging studies (radiography, magnetic resonance imaging, and ultrasonog-raphy), treatment, and referral to specialists can be made.


References

1. Cherry DK, Woodwell DA, Rechstein-er EA. National Ambulatory Medical Care Survey: 2005 summary. Advance data from Vital and Health Statistics. No. 387. (Accessed June 28, 2010, at http://www.cdc.gov/nchs/data/ad/ad387.pdf.)2. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286:188-95. [Erratum, JAMA 2001;286:792.]3. Stiell IG, Greenberg GH, Wells GA, et al. Derivation of a decision rule for the use of radiography in acute knee injuries. Ann Emerg Med 1995;26:405-13.4. Stiell IG, Greenberg GH, Wells GA, et al. Prospective validation of a decision rule for the use of radiography in acute knee injuries. JAMA 1996;275:611-5.5. Thomsen TW, Shen S, Shaffer RW, Setnik GS. Arthrocentesis of the knee. N Engl J Med 2006;354(19):e19. (Available at NEJM.org.)6. Malanga GA, Andrus S, Nadler SF, McLean J. Physical examination of the knee: a review of the original test descrip-tion and scientific validity of common orthopedic tests. Arch Phys Med Rehabil 2003;84:592-603.7. Solomon DH, Simel DL, Bates DW, Katz JN, Schaffer JL. Does this patient have a torn meniscus or ligament of the knee? JAMA 2001;286:1610-20.8. Jackson JL, O’Malley PG, Kroenke K. Evaluation of acute knee pain in primary care. Ann Intern Med 2003;139:575-88.9. Torg JS, Conrad W, Kalen V. Clinical diagnosis of anterior cruciate ligament instability in the athlete. Am J Sports Med 1976;4:84-93.10. McMurray TP. The semilunar carti-lages. Br J Surg 1942;29:407-14.11. Apley AG. The diagnosis of meniscus injuries: some new clinical methods. J Bone Joint Surg Am 1947;29:78-84.Copyright © 2010 Massachusetts Medical Society.

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Lying LowJohn J. Ross, M.D., Anand Vaidya, M.D., and Ursula B. Kaiser, M.D.

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INTERACTIVE MEDICAL CASE

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Lying LowJohn J. Ross, M.D., Anand Vaidya, M.D., and Ursula B. Kaiser, M.D.

N Engl J Med 2011; 364:e10 February 10, 2011

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