AHA guideline BB

A

ACFAA(CD

JKHEK

*RO

CJEDVJ

*

BA

rKEPPoCth

Journal of the American College of Cardiology Vol. 47, No. x, 2006© 2006 by the American College of Cardiology Foundation and the American Heart Association ISSN 0735-1097/06/$32.00P

CC/AHA PRACTICE GUIDELINES

CC/AHA 2006 Guideline Update on Perioperativeardiovascular Evaluation for Noncardiac Surgery:ocused Update on Perioperative Beta-Blocker TherapyReport of the American College of Cardiology/

merican Heart Association Task Force on Practice GuidelinesWriting Committee to Update the 2002 Guidelines on Perioperativeardiovascular Evaluation for Noncardiac Surgery)

ublished by Elsevier Inc. doi:10.1016/j.jacc.2006.02.028

eveloped in Collaboration With (organizations to be added post approval)

WRITING COMMITTEE MEMBERS

Lee A. Fleisher, MD, FACC, Chair

WJEJ

oshua A. Beckman, MD, FACC*enneth A. Brown, MD, FACC, FAHA†ugh Calkins, MD, FACC, FAHA‡lliott Chaikof, MD§

Alice K. Jacobs, MD, FAC

LSBRR

ion for Noncardiac Surgery). American College of Cardiology Web site. Available at:ttp://www.acc.org/clinical/guidelines/perio_betablocker.pdf.

C(1srn1p

tAc

illiam K. Freeman, MD, FACC�ames B. Froehlich, MD, MPH, FACCdward K. Kasper, MD, FACC

udy R. Kersten, MD, FACC¶
irsten E. Fleischmann, MD, MPH, FACC Barbara Riegel, DNSC, RN, FAHA
John F. Robb, MD, FACC#

Society for Vascular Medicine and Biology Official Representative; †American Society of Nuclear Cardiology Official Representative; ‡Heart Rhythm Society Officialepresentative; §Society for Vascular Surgery Official Representative; �American Society of Echocardiography Official Representative; ¶Society of Cardiovascular Anesthesiologists
fficial Representative; #Society for Cardiovascular Angiography and Interventions Official Representative
TASK FORCE MEMBERS

Sidney C. Smith, JR., MD, FACC, FAHA, Chair
C, FAHA, Vice-Chair
ynthia D. Adams, MSN, APRN-BC, FAHAeffrey L. Anderson, MD, FACC, FAHAlliott M. Antman, MD, FACC, FAHA**avid P. Faxon, MD, FACC, FAHA††alentin Fuster, MD, PHD, FACC, FAHA, FESC††

oren F. Hiratzka, MD, FACC, FAHA††haron A. Hunt, MD, FACC, FAHAruce W. Lytle, MD, FACC, FAHAick Nishimura, MD, FACC, FAHAichard L. Page, MD, FACC, FAHA

onathan L. Halperin, MD, FACC, FAHA Barbara Riegel, DNSC, RN, FAHA

*Immediate Past Chair; ††Former Task Force member during this writing effort

Copies: This document is available on the World Wide Web sites of the Americanollege of Cardiology (www.acc.org) and the American Heart Association

www.my.americanheart.org). Single copies of this document are available by calling-800-253-4636 or writing the American College of Cardiology Foundation, Re-ource Center, at 9111 Old Georgetown Road, Bethesda, MD 20814-1699. Ask foreprint number 71-0362. To purchase bulk reprints specify version and reprintumber: Up to 999 copies, call 1-800-611-6083 (U.S. only) or fax 413-665-2671;,000 or more copies, call 214-706-1789, fax 214-691-6342, or [email protected]: Multiple copies, modification, alteration, enhancement, and/or dis-

ribution of this document are not permitted without the express permission of the

This document was approved by the American College of Cardiology Foundationoard of Trustees in March 2006 and by the American Heart Association Sciencedvisory and Coordinating Committee in February 2006.When citing this document, the American College of Cardiology Foundation

equests that the following citation format be used: Fleisher LA, Beckman JA, BrownA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, KasperK, Kersten JR, Riegel B, Robb JF. ACC/AHA 2006 Guideline Update onerioperative Cardiovascular Evaluation for Noncardiac Surgery: Focused Update onerioperative Beta-Blocker Therapy. A Report of the American College of Cardiol-gy/American Heart Association Task Force on Practice Guidelines (Writingommittee to Update the 2002 Guidelines on Perioperative Cardiovascular Evalua-

merican College of Cardiology Foundation. Please direct requests [email protected]

http://www.acc.org/clinical/guidelines/perio_betablocker.pdf

http://www.acc.org

http://www.my.americanheart.org

http://[email protected]

http://[email protected]

P

TcmcrSpscamuoii

nrtaugTmaSC

EIP

1

1

StthCCbtpttebuAdmd

Fc

CuebbegPiu

1

TacttswhcFo

ateAu

c

•

•

•

Ir

•

•

2 Fleisher et al. JACC Vol. 47, No. x, 2006ACC/AHA Perioperative Guideline—Update on Beta-Blocker Therapy Month 2006:000–000

REAMBLE

he American College of Cardiology/American Heart Asso-iation (ACC/AHA) Task Force on Practice Guidelinesakes every effort to avoid any actual, potential, or perceived

onflict of interest that might arise as a result of an industryelationship or personal interest of the writing committee.pecifically, all members of the writing committee, as well aseer reviewers of the document, were asked to provide disclo-ure statements of all such relationships that might be per-eived as real or potential conflicts of interest. These statementsre reviewed by the parent task force, reported orally to allembers of the writing committee at each meeting, and

pdated and reviewed by the writing committee as changesccur. Please see Appendix 1 for author relationships withndustry and Appendix 2 for peer reviewer relationships withndustry.

These guidelines attempt to define practices that meet theeeds of most patients in most circumstances. These guidelineecommendations reflect a consensus of expert opinion after ahorough review of the available, current scientific evidence andre intended to improve patient care. If these guidelines aresed as the basis for regulatory/payer decisions, the ultimateoal is quality of care and serving the patient’s best interests.he ultimate judgment regarding care of a particular patientust be made by the healthcare provider and patient in light of

ll the cirucumstances presented by that patient.idney C. Smith Jr., MD, FACC, FAHAhair, ACC/AHA Task Force on Practice Guidelines

lliot M. Antman, MD, FACC, FAHAmmediate Past-Chair, ACC/AHA Task Force onractice Guidelines

. INTRODUCTION

.1. Purpose of the Expedited Update

ince the publication of the previous guidelines on periopera-ive cardiovascular evaluation for noncardiac surgery in 2002,he issue of perioperative beta blockade for non-cardiac surgeryas taken on increased importance. Specifically, the Physiciansonsortium for Performance Improvement and the Surgicalare Improvement Project have both identified perioperativeeta blockade as a quality measure. Given the importance ofhese quality measures for both public reporting and eventualay-for-performance, and the recent series of publications onhe subject, it became imperative to update the recommenda-ions related to beta blockade. Therefore, we have chosen toxpedite the review of the literature on perioperative betalockade in order to produce recommendations that can besed in these national quality initiatives. In general, ACC/HA Class I and III indications for therapy identify potentialimensions of care and processes for performance measure-ent; however, not all Class I and III guidelines recommen-

ations should be selected for performance measurement (1).

urthermore, Class IIa and Class IIb recommendations are notonsidered for stand-alone measures.

Please note that the full 2002 Guideline on Perioperativeardiovascular Evaluation for Noncardiac Surgery is beingpdated and represents current ACC/AHA policy, with thexception of the text and tables in the perioperative beta-locker therapy section. This focused update replaces theeta-blocker section in the 2002 Guideline and is consid-red current ACC/AHA policy until the update of the fulluideline is published. Please note that Table 2, “Clinicalredictors of Increased Perioperative Cardiovascular Risk,”

s currently under review and may be modified as part of thepdate of the full guideline.

.2. Organization of Committee and Evidence Review

he Committee to Update the 2002 Guidelines on Perioper-tive Cardiovascular Evaluation for Noncardiac Surgery: Fo-used Update on Perioperative Beta-Blocker Therapy reviewedhe literature relevant to perioperative cardiac evaluation sincehe last publication of these guidelines in 2002. Literatureearches were conducted in PubMed/MEDLINE. Searchesere limited to the English language, 2002 through 2006, anduman subjects. In addition, related-article searches wereonducted in MEDLINE to find further relevant articles.inally, committee members recommended applicable articlesutside the scope of the formal searches.

As a result of these searches, 23 published articles and 1bstract were identified and reviewed by the committee forhe expedited update of the Beta-Blocker section. Usingvidence-based methodologies developed by the ACC/HA Task Force on Practice Guidelines, the committeepdated the guideline text and recommendations.

These classes summarize the recommendations for pro-edures or treatments as follows:

Class I: Conditions for which there is evidence forand/or general agreement that the procedure or treat-ment is beneficial, useful, and effective.Class II: Conditions for which there is conflictingevidence and/or a divergence of opinion about theusefulness/efficacy of a procedure or treatment.

Class IIa: Weight of evidence/opinion is in favor ofusefulness/efficacy.Class IIb: Usefulness/efficacy is less well established byevidence/opinion.

Class III: Conditions for which there is evidence and/orgeneral agreement that the procedure/treatment is notuseful/effective, and in some cases may be harmful.

n addition, the weight of evidence in support of theecommendation is listed as follows:

Level of Evidence A: Data derived from multiple,randomized, clinical trials.Level of Evidence B: Data derived from a single-
randomized trial or non-randomized studies.

•

icsapcssa

geciissMdgCd

ntFSoS

recom

3JACC Vol. 47, No. x, 2006 Fleisher et al.Month 2006:000–000 ACC/AHA Perioperative Guideline—Update on Beta-Blocker Therapy

Level of Evidence C: Only consensus opinion of experts,case studies, or standard-of-care.

A recommendation with Level of Evidence B or C does notmply that the recommendation is weak. Many importantlinical questions addressed in guidelines do not lend them-elves to clinical trials. Although randomized trials are notvailable, there may be a very clear clinical consensus that aarticular test or therapy is useful and effective. The schema forlassification of recommendations and level of evidence isummarized in Figure 1, which also illustrates how the gradingystem provides an estimate of the size of the treatment effectnd an estimate of the certainty of the treatment effect.

Please note the use of bold-faced type in the recommen-dations shows where the intent of the recommendationhas changed from the 2002 ACC/AHA GuidelineUpdate on Perioperative Cardiovascular Evaluation forNoncardiac Surgery. The bold-faced type only high-lights changes to the recommendations; it does not show

Figure 1. Applying classification of

changes to supporting text, tables, and figures. A

The Committee consisted of acknowledged experts ineneral cardiology as well as persons with recognizedxpertise in more specialized areas including anesthesiology,ardiovascular surgery, echocardiography, electrophysiology,nterventional cardiology, nuclear cardiology, vascular med-cine, and vascular surgery; both academic and privateectors were represented. The following organizations as-igned official representatives: the Society for Vascular

edicine and Biology, American Society of Nuclear Car-iology, Heart Rhythm Society, Society for Vascular Sur-ery, American Society of Echocardiography, Society ofardiovascular Anesthesiologists, and the Society for Car-iovascular Angiography and Interventions.This document was reviewed by 2 official reviewers

ominated by the ACC; 2 official reviewers nominated byhe AHA; 1 official reviewer from the ACC/AHA Taskorce on Practice Guidelines as well as reviewers from theociety for Vascular Medicine and Biology, American Societyf Nuclear Cardiology, Heart Rhythm Society, Americanociety of Echocardiography, Society of Cardiovascular

mendations and level of evidence.

nesthesiologists, and the Society for Cardiovascular An-

giFACcooCsd

2

2

R(

C

1

2

C

1

2

3

C

1

2

C

1

*ecmttca

2asnchrhih(p

T

V

H

L

*f


iography and Interventions; and 20 content reviewers,ncluding members from American College of Cardiologyoundation (ACCF) Cardiac Catheterization Committee,CCF Peripheral Vascular Disease Committee, ACCFardiovascular Clinical Imaging Committee, ACCF Echo-

ardiography Committee, ACCF Clinical Electrophysiol-gy Committee, AHA Council on Cardiopulmonary Peri-perative and Critical Care Leadership Committee, AHAouncil on Cardiovascular Surgery and Anesthesia Leader-

hip Committee, and the AHA Council on Clinical Car-iology, Electrocardiography, and Arrhythmias Committee.

. PERIOPERATIVE MEDICAL THERAPY

.1. Perioperative Beta-Blocker Therapy

ecommendations for Beta-Blocker Medical TherapyTable 1):

lass I

. Beta blockers should be continued in patients undergo-ing surgery who are receiving beta-blockers to treatangina, symptomatic arrhythmias, hypertension, orother ACC/AHA Class I guideline indications.(Level of Evidence: C)

. Beta blockers should be given to patients undergoingvascular surgery at high cardiac risk owing to the findingof ischemia on preoperative testing. (Level of Evidence: B)

lass IIa

. Beta blockers are probably recommended for patientsundergoing vascular surgery in whom preoperative as-sessment identifies coronary heart disease. (Level ofEvidence: B)

. Beta blockers are probably recommended for patientsin whom preoperative assessment for vascular surgeryidentifies high cardiac risk as defined by the presenceof multiple clinical risk factors.* (Level of Evidence: B)

. Beta blockers are probably recommended for patientsin whom preoperative assessment identifies coronaryheart disease or high cardiac risk as defined by the

able 1. Recommendations for Perioperative Beta-Blocker Thera

Low CardiacPatient Risk

ascular Surgery Class IIbLevel of Evidence: C

igh-/Intermediate-RiskSurgery

‡

ow-Risk Surgery ‡

Applies to patients found to have coronary ischemia on preoperative testing. †Applieurther discussion.

CHD � coronary heart disease.

presence of multiple clinical risk factors* and who are m

undergoing intermediate- or high-risk procedures asdefined in these guidelines. (Level of Evidence: B)

lass IIb

. Beta blockers may be considered for patients who areundergoing intermediate- or high-risk procedures asdefined in these guidelines, including vascular sur-gery, in whom preoperative assessment identifiesintermediate cardiac risk as defined by the presence ofa single clinical risk factor.* (Level of Evidence: C)

. Beta blockers may be considered in patients under-going vascular surgery with low cardiac risk (asdefined in these guidelines) who are not currently onbeta blockers. (Level of Evidence: C)

lass III

. Beta blockers should not be given to patients undergo-ing surgery who have absolute contraindications to betablockade. (Level of Evidence: C)

Please see Table 2, Clinical Predictors of Increased Periop-rative Cardiovascular Risk, for an explanation of thelinical risk factors. High cardiac risk includes patients with

ajor and intermediate clinical predictors. Care should beaken in applying recommendations on beta-blocker therapyo patients with decompensated heart failure, nonischemicardiomyopathy, or severe valvular heart disease in thebsence of coronary heart disease.

.1.1. Summary of evidence. Despite several meta-nalyses, some reaching conflicting conclusions, there aretill very few randomized trials of medical therapy beforeoncardiac surgery to prevent perioperative cardiac compli-ations. The studies that have been conducted in this areaave largely focused on beta-blocker therapy; however, thereemain many limitations to the available data. Few studiesave compared different beta-blocker agents or character-

zed their dose effect in the perioperative setting. Even fewerave included a protocol for the titration of therapy to effecte.g., target heart rate), or examined regimens that include areoperative trial of beta-blocker therapy. Studies to deter-

ased on Published Randomized Clinical Trials

Intermediate CardiacPatient Risk

CHD or High CardiacPatient Risk

Patients found to have myocardialischemia on preoperative testing

Class IIbLevel of Evidence: C

Class ILevel of Evidence: B*Class IIaLevel of Evidence: B†

Class IIbLevel of Evidence: C

Class IIaLevel of Evidence: B

‡ ‡

atients found to have coronary heart disease. ‡Indicates insufficient data. See text for

py B

s to p

ine the ideal target population, ideal dose, and route are

lwtdea(wtiaoc

••

•

•

•

•

•

bebheMabehtaemulbPb

tPphfcraw(biotptvopbtu

oato

TCD

MU●

●

DS●

●

●

SIMPCDRMAA

RL

HU

*g7‡


acking. In addition, the practical limitations such as how,hen, how long, and by whom perioperative beta-blocker

herapy is ideally or practically implemented remain unad-ressed. Randomized, controlled trials are still needed toxplore the observation that there may be some harmssociated with beta-blocker therapy in low-risk patients3). Moreover, there is currently a lack of data regardinghich beta blocker to use perioperatively. Some observa-

ional data suggest that perioperative death or myocardialnfarction (MI) rates may differ when different beta-blockersre given perioperatively (4). In summary, the best approachn how to medically protect patients from cardiovascularomplications during noncardiac surgery is still unknown.

Limitations in the Perioperative Beta-Blocker Literature:

Most trials are inadequately powered.Few randomized trials of medical therapy to preventperioperative major adverse cardiac events have beenperformed.Few randomized trials have examined titration of therapyto effect (e.g., target heart rate).Few randomized trials have examined the role of periop-erative beta-blocker therapy.Studies to determine the role of beta blockers in

able 2. Clinical Predictors of Increased Perioperativeardiovascular Risk (Myocardial Infarction, Heart Failure,eath)

ajornstable coronary syndromesAcute or recent MI* with evidence of important ischemic risk byclinical symptoms or noninvasive studyUnstable or severe† angina (Canadian Class III or IV)‡ecompensated heart failure

ignificant arrhythmiasHigh-grade atrioventricular blockSymptomatic ventricular arrhythmias in the presence of underlyingheart diseaseSupraventricular arrhythmias with uncontrolled ventricular rateevere valvular diseasentermediate

ild angina pectoris (Canadian Class I or II)revious MI by history or pathological Q wavesompensated or prior heart failureiabetes mellitus (particularly insulin-dependent)enal insufficiencyinordvanced agebnormal ECG (left ventricular hypertrophy, left bundle-branch block,ST-T abnormalities)

hythm other than sinus (e.g., atrial fibrillation)ow functional capacity (e.g., inability to climb one flight of stairs witha bag of groceries)istory of strokencontrolled systemic hypertension

The American College of Cardiology National Database Library defines recent MI asreater than 7 days but less than or equal to 1 month (30 days); acute MI is within

days. †May include “stable” angina in patients who are unusually sedentary.Campeau et al. (2).

ECG � electrocardiogram; MI � myocardial infarction.

intermediate- and low-risk populations are lacking. A

Studies to determine the optimal type of beta blockers arelacking.No studies have addressed care-delivery mechanisms inthe perioperative setting, identifying how, when, and bywhom perioperative beta-blocker therapy should be im-plemented and monitored.

Although many of the randomized, controlled trials ofeta-blocker therapy are small, the weight of evidence—specially in aggregate—suggests a benefit to perioperativeeta blockade during noncardiac surgery, particularly inigh-risk patients. Current studies suggest that beta block-rs reduce perioperative ischemia and may reduce the risk of

I and death in high-risk patients. When possible, avail-ble evidence suggests, but does not definitively prove thateta blockers should be started several days or weeks beforelective surgery, with the dose titrated to achieve a restingeart rate between 50 and 60 beats per min, to assure thathe patient is indeed receiving the benefit of beta blockadend should continue during the intraoperative and postop-rative period to maintain a heart rate less than 80 beats perin (5). Several prospective, randomized trials are either

nderway or soon to be presented. These will hopefully shedight on some of the questions regarding perioperativeeta-blocker therapy. Per the ACC/AHA Task Force onractice Guidelines methodology, unpublished data cannote used to formulate guideline recommendations.

Two randomized trials examined the effect of periopera-ive beta blockers on cardiac events surrounding surgery.oldermans et al. (5) examined the effect of bisoprolol onatients undergoing vascular surgery and in patients atigh-risk for perioperative cardiac complications scheduledor vascular surgery. Of 846 patients with risk factors forardiac disease, 173 patients were found to have newegional wall motion abnormalities (RWMA) on dobut-mine stress echocardiogram (DSE). Of these patients, 61ere excluded from further study owing to large areas

greater than or equal to 5 segments) of RWMA on DSE orecause they were already taking beta blockers. The remain-ng 112 high-risk patients were randomized to standard carer bisoprolol started at least 7 days preoperatively anditrated to maintain heart rate less than 60 beats per minreoperatively and less than 80 beats per min intraopera-ively and postoperatively. The rates of cardiac death (3.4%s. 17%; p � 0.02) and nonfatal MI (0% vs. 17%; p less thanr equal to 0.001) were lower for the bisoprolol versuslacebo groups, respectively. Importantly, due to the un-linded design and inclusion of only high-risk patients inhis study, the results cannot be generalized to all patientsndergoing noncardiac surgery.Boersma et al. (6) subsequently re-analyzed the total cohort

f 1,351 consecutive patients considered for enrollment in theforementioned randomized trial of bisoprolol. Forty-five pa-ients had perioperative cardiac death or nonfatal MI. A totalf 83% of patients had fewer than three clinical risk factors.
mong this subgroup, patients receiving beta blockers had a

lntwwoneidtbbNf

rgatrmppaptnsbs

bopnbfm(oea1rtccdeaMiist

(nategTsprimhivupdarp

sstlititolm

lipbariwwaababrinnbtr


ower risk of cardiac complications (0.8% [2 of 263]) than thoseot receiving beta blockers (2.3% [20 of 855]). In patients withhree or more risk factors (17%), those taking beta blockersho had a DSE demonstrating four or fewer segments of newall-motion abnormalities had a significantly lower incidencef cardiac complications (2.3% [2 of 86]) compared with thoseot receiving beta-blocker therapy (9.9% [12 of 121]). How-ver, among the small group of patients with more extensiveschemia on DSE (five or more segments), there was noifference in the incidence of cardiac events (4 of 11 for thoseaking beta blockers versus 5 of 15 for those not taking betalockers). Therefore, beta-blocker therapy was beneficial in allut the subset of patients with more extensive ischemia.evertheless, one must be cautious about inferring a class effect

rom this observation about bisoprolol and treatment protocol.The Multicenter Study of Perioperative Ischemia (McSPI)

esearch group (7,8) reported on 200 patients undergoingeneral surgery randomized to a combination of intravenousnd oral atenolol versus placebo for seven days. Althoughhey found no difference in perioperative MI or death, theyeported significantly fewer episodes of ischemia by Holteronitoring (24% vs. 39%; p � 0.03) in the atenolol versus

lacebo groups, respectively. They then followed theseatients after discharge and documented fewer deaths in thetenolol group over the subsequent 6 months (1% vs. 10%;less than 0.001). It is not clear why such a brief course of

herapy could exert such a delayed effect, and the study didot control for other medications given either before or afterurgery. Angiotensin-converting enzyme inhibitor and beta-locker use preoperatively differed significantly between thetudy groups.

Additional studies have examined the use of perioperativeeta blockers, but are limited in power to detect cardiac eventsr are not randomized. Stone et al. (9) randomized a group ofatients with mild hypertension who underwent predomi-antly (58%) vascular surgery to oral beta blockers 2 hoursefore surgery or standard care. Control subjects had a higherrequency (28%) of ST-segment depression (on intraoperativeonitoring, as reported by the authors) than treated patients

2%). In a nonrandomized study, Pasternack et al. (10) gaveral metoprolol immediately before surgery, followed postop-ratively by intravenous metoprolol during abdominal aorticneurysm repair. Only 3% suffered an acute MI compared with8% for matched controls. Pasternack et al. (11) subsequentlyeported fewer episodes of intraoperative ischemia in patientsreated with oral metoprolol before peripheral vascular surgeryompared to untreated patients. Yeager et al. (12) reported aase-control analysis of their experience with perioperative MIuring vascular surgery, comparing 53 index cases of periop-rative MI with 106 matched controls. They found a strongssociation of beta-blocker use with a decreased likelihood of

I (odds ratio 0.43; p � 0.01). Raby et al. (13) demonstratedn 26 vascular surgery patients with documented preoperativeschemia and randomized to a protocol of heart rate suppres-ion with intravenous esmolol compared to standard care that
he esmolol group had fewer episodes of ischemia than controls t
33% vs. 72%; p � 0.055). Zaugg et al. (14) randomized elderlyoncardiac surgery patients to preoperative and postoperativetenolol titrated to heart rate and intraoperative atenololitrated to heart rate or no beta blockers, and detected nopisodes of intraoperative myocardial ischemia, electrocardio-raphic changes consistent with MI, or death in any group.hree (of 19) patients in the no beta-blocker group developed

ignificant elevations of cardiac troponin-I consistent with aerioperative MI compared with 0 (of 40) patients whoeceived one of the atenolol groups. Brady et al. (15) random-zed patients undergoing elective vascular surgery to either

etoprolol 50 mg twice per day or placebo, from admission toospital, until 7 days postoperatively. They found no difference

n cardiovascular events, which included MI, unstable angina,entricular tachycardia, and stroke. This trial may have beennderpowered (n � 103) to identify a difference in outcomes,articularly hard outcomes of death and MI. Also, by trialesign, therapy was initiated the day before vascular surgery,nd it is quite possible that those randomized to metoprololeceived incomplete beta-blockade in the early perioperativeeriod.Perioperative beta-blocker therapy has been reviewed in

everal meta-analyses, and in a very large cohort populationtudy. Auerbach and Goldman (16) undertook a review of thisopic in 2002. They reported on a MEDLINE search anditerature review of only five studies. (All five studies arencluded in Table 3). They calculated a number needed toreat, on the basis of these studies, of only 2.5 to 6.7 to seemprovement in measures of myocardial ischemia, and only 3.2o 8.3 in studies reporting a significant impact of beta blockersn cardiac or all-cause mortality. They concluded that theiterature supports a benefit of beta blockers on cardiac

orbidity.A systematic review of the perioperative medical therapy

iterature by Stevens et al. (17) for noncardiac surgeryncluded the results of 11 trials using beta blockers forerioperative therapy. These authors concluded that beta-lockers significantly decreased ischemic episodes duringnd after surgery. Beta blockers significantly reduced theisk of nonfatal MI; however, the results became nonsignif-cant if the two most positive trials were eliminated. Like-ise, the risk of cardiac death was significantly decreasedith beta-blocker usage. It should be noted that these

uthors incorporated studies not considered in other meta-nalyses, including studies that were not blinded. Results toe quantified were limited to those in the 30-day perioper-tive period. The authors also reported a direct relationshipetween the prevalence of prior MI and the magnitude ofisk reduction observed with beta-blocker therapy, suggest-ng that higher risk confers greater benefit. The numbereeded to prevent perioperative ischemia was 8 patients, theumber needed to prevent MI was 23, and 32 subjects muste treated to prevent cardiac death. These authors point outhat, given the observation that high-risk patients seem toeceive all the benefit, the target population for beta-blocker
herapy is not clear. They also highlighted that schedules of

le3.

Ran

dom

ized

Tri

als

ofP

erio

pera

tive

Pro

phyl

actic

Bet

aB

lock

ers

and

Car

diac

Mor

bidi

ty

Isch

emia

*M

ID

eath

thor

,Y

ear

(Ref

.)P

roce

dure

nC

ontr

olD

rug

Con

trol

Dru

gC

ontr

olD

rug

Con

trol

Dru

g

ne,

988

(9)

Non

card

iac

128

Pla

cebo

Lab

etal

olA

teno

lol

Olp

reno

lol

PO

preo

pera

tivel

y

11/3

92/

89†

0/39

0/89

(28%

)(2

%)

(0)

(0)

Mild

hype

rten

sion

derm

ans,

999

(5)

Vas

cula

r11

2U

nblin

ded

5to

10m

gP

Obi

sopr

olol

9/53

0/59

†9/

532/

59†

(17%

)(0

)(1

7%)

(3%

)

y, 999

(13)

Vas

cula

r26

Pla

cebo

IVes

mol

ol8/

115/

15†

(73%

)(3

3%)

llace

,99

8(8

)ng

ano,

996

(7)

Non

card

iac

200

Pla

cebo

10to

20m

gIV

or50

to10

0m

gP

Oat

enol

ol39

/101

24/9

9†(a

t6m

onth

s)(3

9%)

(24%

)10

/101

(10%

)1/

99†

(1%

)

gg,

999

(14)

Non

card

iac

63(5

9an

alyz

ed)

No

peri

oper

ativ

ebe

tabl

ocke

rsA

teno

lolt

arge

ted

tom

aint

ain

HR

eith

er1)

pre-

and

post

oper

ativ

ely

or2)

intr

aope

rativ

ely

0/20

0/43

3/19

0/40

(0%

)(0

%)

(16%

)(0

%)

an,

000

(25)

Non

card

iac

107

Pla

cebo

IVes

mol

olon

the

day

ofsu

rger

y,fo

llow

edby

met

opro

lols

tart

ing

at25

mg

PO

BID

and

incr

ease

dto

mai

ntai

na

HR

less

than

80be

ats/

min

,and

cont

inue

dfo

rth

ene

xt48

h

8/55

3/52

3/55

1/52

(15%

)(6

%)

(5%

)(2

%)

dy,

005

(15)

Vas

cula

r10

3P

lace

bo50

mg

PO

met

opro

lol

twic

eda

ilypr

eope

rativ

ely

until

7da

yspo

stsu

rger

y

4/44

5/53

5/44

3/53

1/44

3/53

(9%

)(9

%)

(11%

)(6

%)

(2%

)(6

%)

yoca

rdia

lisc

hem

ia.†

ple

ssth

an0.

05fo

rdr

ugve

rsus

cont

rol.

ID�

twic

epe

rda

y;H

R�

hear

tra

te;I

V�

intr

aven

ous;

MI

�m

yoca

rdia

linf

arct

ion;

PO

�by

mou

th.


Tab

Au

Sto 1

Pol 1

Rab 1

Wa 1

Ma 1

Zau 1

Urb 2

Bra 2

*MB

brp

ptpTobpadc(tnicMwcmsMoMaolaactabpoYnt

dtpmafo1(upfi

f

3sqnbthtt(cabT0ihateohab

qmddtomsda(efatso

R


eta-blocker administration varied significantly among theeported studies and the potential for a single large stronglyositive study to skew the results of this meta-analysis.In contrast, Devereaux et al. (18) published their opinion

aper on the clinical evidence regarding the use of beta-blockerherapy in patients undergoing noncardiac surgery for theurpose of preventing perioperative cardiac complications.hey expressed the opinion that the literature supporting usef beta blockers during noncardiac surgery is modest at best,ased on a few small, unblinded studies with a focused patientopulation. In a review of the literature in 2005, Devereaux etl. (19) discussed 22 studies randomizing 2,437 patients un-ergoing noncardiac surgery to beta-blocker therapy or pla-ebo. The POBBLE study was not included in this review14). They found no statistically significant benefit on any ofhe individual outcomes, and a “nominally” statistically sig-ificant benefit (relative risk of 0.44 with 95% confidence

nterval [CI] 0.20 to 0.97, 99% CI 0.16 to 1.24) for theomposite outcome of cardiovascular mortality, nonfatal

I, and nonfatal cardiac arrest. The authors felt these dataere inadequate to draw conclusions, and that a larger,

ontrolled study is indicated before conclusions can beade. This review, however, included a wide variety of

tudies, patient populations, and beta-blocker regimens.any of the studies described only a single or double dose

f beta blocker preoperatively or at induction of anesthesia.uch of the data, therefore, does not pertain to perioper-

tive beta blockade for the purpose of cardiac risk reductionr focused on a low-risk population. Additionally, theargest studies included—those reported by Miller et al. (20)nd preliminary data from Yang et al. (21), which togetherccount for almost as many subjects as all other studiesombined—may not have been appropriate to include inhis analysis. The first, by Miller et al. (20), was a study ofsingle intravenous dose of beta blocker for the purpose oflood pressure control during intubation, not reduction oferioperative events. It included follow-up only to the pointf discharge from the recovery room. The second, that ofang et al. (21), has yet to be published and, therefore, hasot undergone formal peer review. The studies included inhis review also vary widely in length of follow-up.

McGory et al. (22) performed a meta-analysis of six ran-omized trials of perioperative beta-blockade and concludedhat therapy was associated with significant reductions inerioperative myocardial ischemia (33% to 15%), MI, cardiacortality, and long-term cardiac mortality (12% to 2%). These

uthors used the combined data to derive odds ratios and CIsor several outcomes. For perioperative overall mortality thedds ratio for beta-blocker therapy was 0.52 (95% CI 0.20 to.35) and for perioperative cardiac mortality odds ratio 0.2595% CI 0.07 to 0.87). Neither the POBBLE study nor thenpublished findings included in the Devereaux et al. (19)aper were included, explaining the marked difference inndings from the other meta-analysis.A cohort study by Lindenauer et al. (23) reviewed records

rom over 700,000 patients undergoing noncardiac surgery at

29 hospitals in the U.S. Participant hospitals in this cohorttudy were members of a consortium database measuringuality and health care use. These authors evaluated alloncardiac surgical cases, and compared those who receivedeta blockers within the first two days of hospitalization withhose who did not receive beta blockers during the first twoospital days. The authors used propensity score matchingechniques in an attempt to reduce bias. These authors foundhat for a revised cardiac risk index score (24) of three or morebased on the presence of history of ischemic heart disease,erebrovascular disease, renal insufficiency, diabetes mellitus, orpatient undergoing high-risk surgery), patients who receivedeta blockers were significantly less likely to die in hospital.his was not true for those with a revised risk index of 2, l, or. Those with a risk index of 0 were more likely to dien-hospital if given a beta blocker on day 1 or day 2 ofospitalization. This study is retrospective and not randomizednd, therefore, is subject to potential bias. This is particularlyrue in terms of reporting bias as the documentation was basedntirely on administrative datasets, using arbitrary definitionsf “on” or “off” perioperative beta blockers, based solely onospital day of use. Nonetheless, there appears to be anssociation between improved outcomes and the use of betalockers in clinically high-risk patients.

Finally, one recent observational cohort study examined theuestion of which beta blocker may be best for perioperativeedical therapy. Redelmeier et al. (4) reviewed administrative

ata related to elective surgery in Ontario, Canada, andocumented perioperative beta-blocker usage from April 1992o April 2002 (10 years). They limited their analysis to patientsver the age of 65 years, who were receiving either atenolol oretoprolol before and after surgery and identified 37,151

ubjects. A total of 1,038 suffered either a perioperative MI oreath, and the rate of MI or death was significantly lowermong those patients receiving atenolol versus metoprolol2.5% vs. 3.2%, p less than 0.001). This difference persistedven after adjusting for demographic, clinical, and surgicalactors. The inclusion of other long-acting beta blockers in thenalysis yielded an identical risk reduction. These data suggesthat long-acting beta blockade (when therapy is initiated beforeurgery), may be superior to short-acting beta blockade. Thesebservations await clinical trial evaluation.

EFERENCES

1. Spertus JA, Eagle KA, Krumholz HM, et al. American College ofCardiology and American Heart Association methodology for theselection and creation of performance measures for quantifying thequality of cardiovascular care. J Am Coll Cardiol 2005;45:1147–56.

2. Campeau L. Grading of angina pectoris (letter). Circulation 1976;54:522–3.

3. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B,Benjamin EM. Perioperative beta-blocker therapy and mortality aftermajor noncardiac surgery. N Engl J Med 2005;353:349–61.

4. Redelmeier D, Scales D, Kopp A. Beta-blockers for elective surgery inelderly patients: population based, retrospective cohort study. BMJ2005;331:932.

5. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on
perioperative mortality and myocardial infarction in high-risk patientsundergoing vascular surgery. Dutch Echocardiographic Cardiac Risk

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

AC

J

K

H

E

K

L

W

J

E

J

B

J


Evaluation Applying Stress Echocardiography Study Group (seecomments). N Engl J Med 1999;341:1789–94.

6. Boersma E, Poldermans D, Bax JJ, et al. Predictors of cardiacevents after major vascular surgery: role of clinical characteristics,dobutamine echocardiography, and beta-blocker therapy. JAMA2001;285:1865–73.

7. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol onmortality and cardiovascular morbidity after noncardiac surgery. Mul-ticenter Study of Perioperative Ischemia Research Group (see com-ments) (published erratum appears in N Engl J Med 1997;336:1039).N Engl J Med 1996;335:1713–20.

8. Wallace A, Layug B, Tateo I, et al. Prophylactic atenolol reducespostoperative myocardial ischemia. McSPI Research Group (see com-ments). Anesthesiology 1998;88:7–17.

9. Stone JG, Foex P, Sear JW, Johnson LL, Khambatta HJ, Triner L.Myocardial ischemia in untreated hypertensive patients: effect of asingle small oral dose of a beta-adrenergic blocking agent. Anesthesi-ology 1988;68:495–500.

0. Pasternack PF, Imparato AM, Baumann FG, et al. The hemodynam-ics of beta-blockade in patients undergoing abdominal aortic aneurysmrepair. Circulation 1987;76:III1–7.

1. Pasternack PF, Grossi EA, Baumann FG, et al. Beta-blockade todecrease silent myocardial ischemia during peripheral vascular surgery.Am J Surg 1989;158:113–6.

2. Yeager RA, Moneta GL, Edwards JM, Taylor LM Jr., McConnellDB, Porter JM. Reducing perioperative myocardial infarction follow-ing vascular surgery. The potential role of beta-blockade. Arch Surg1995;130:869–72.

3. Raby KE, Brull SJ, Timimi F, et al. The effect of heart rate control onmyocardial ischemia among high-risk patients after vascular surgery(see comments). Anesth Analg 1999;88:477–82.

4. Zaugg M, Tagliente T, Lucchinetti E, et al. Beneficial effects frombeta-adrenergic blockade in elderly patients undergoing noncardiacsurgery. Anesthesiology 1999;91:1674–86.

5. Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR.

ohn F. Robb, MD None None

frarenal vascular surgery: results of a randomized double-blindcontrolled trial. J Vasc Surg 2005;41:602–9.

6. Auerbach AD, Goldman L. Beta-blockers and reduction of cardiacevents in noncardiac surgery: scientific review. JAMA 2002; 87:1435– 44.

7. Stevens RD, Burri H, Tramer MR. Pharmacologic myocardial pro-tection in patients undergoing noncardiac surgery: a quantitativesystematic review. Anesth Analg 2003; 7:623–33.

8. Devereaux PJ, Yusuf S, Yang H, Choi PT, Guyatt GH. Are therecommendations to use perioperative beta-blocker therapy in patientsundergoing noncardiac surgery based on reliable evidence? CMAJ2004;171:245–7.

9. Devereaux PJ, Beattie WS, Choi PT, et al. How strong is the evidencefor the use of perioperative beta-blockers in non-cardiac surgery?Systematic review and meta-analysis of randomised controlled trials.BMJ 2005;331:313–21.

0. Miller DR, Martineau RJ, Wynands JE, Hill J. Bolus administration ofesmolol for controlling the haemodynamic response to tracheal intubation: theCanadian Multicentre Trial. Can J Anaesth 1991;38:849–58.

1. Yang H, Raymer K, Butler R, Parlow J, Roberts R, Tech M. Metoprololafter Vascular Surgery (MaVS) (abstr). Can J Anaesth 2004;51:A7.

2. McGory ML, Maggard MA, Ko CY. A meta-analysis of perioperativebeta-blockade: what is the actual risk reduction? Surgery 2005;138:171–9.

3. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B,Benjamin EM. Perioperative beta-blocker therapy and mortality aftermajor noncardiac surgery. N Engl J Med 2005;353:349–61.

4. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation andprospective validation of a simple index for prediction of cardiac risk ofmajor noncardiac surgery. Circulation 1999;100:1043–9.

5. Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P.Postoperative prophylactic administration of beta-adrenergic blockersin patients at risk for myocardial ischemia. Anesth Analg 2000;90:

Perioperative beta-blockade (POBBLE) for patients undergoing in- 1257–61.

PPENDIX 1. Author Relationships With Industry for the ACC/AHA Guideline Update on Perioperativeardiovascular Evaluation for Noncardiac Surgery: Focused Update on Perioperative Beta-Blocker Therapy

Committee Member Consultant Research GrantScientific

Advisory Board Speakers’ Bureau Other

oshua A. Beckman, MD ● Bristol-Myers Squibb None ● Sanofi-Aventis ● Bristol-Myers Squibb● Merck● Eli Lilly● Sanofi-Aventis

None

enneth A. Brown, MD None None None None None

ugh Calkins, MD None None None None None

lliott Chaikof, MD None None None None None

irsten E. Fleischmann,MD, MPH

None None None None ● Pfizer (QI/CMEInitiatives)

ee A. Fleisher, MD None None None None None

illiam K. Freeman, MD None None None None None

ames B. Froehlich, MD,MPH

● Pfizer None ● Sanofi-Aventis ● Sanofi-Aventis● Otsuka● Pfizer● Merck

None

dward K. Kasper, MD None None None None None

udy R. Kersten, MD ● Abbott Laboratories ● Abbott Laboratories None ● Abbott Laboratories

arbara Riegel, DNSc, RN None None None None None

None None None

APB

D

D

D

D

D

D

D

D

D

D

D


PPENDIX 2. External Peer Reviewer Relationships With Industry for the ACC/AHA Guideline Update onerioperative Cardiovascular Evaluation for Noncardiac Surgery: Focused Update on Perioperative Beta-
locker Therapy*
Peer Reviewer† Representation Research GrantSpeakers

Bureau/Honoraria Stock OwnershipConsultant/

Advisory Board Other

r. Peter Alagona ● Official Reviewer–Board of Trustees(BOT)

None None None None None

r. Joseph Alpert ● Official Reviewer–AHA Reviewer


r. Vincent Carr ● Official Reviewer–Board ofGovernors (BOG)


r. Ray Gibbons ● Official Reviewer–AHA Reviewer

● Radiant Medical● Boston Scientific● Boehringer Ingelheim● Spectranetrics● KAI Pharmaceuticals● TargeGen● TherOx● King Pharmaceuticals

None None ● Hawaii Biotech● Cardiovascular

Clinical Studies(WOMENstudy, TIMI37 A)

● ConsumersUnion

None

r. Bruce Lytle ● Official Reviewer–ACCF/AHATask ForcePractice Guidelines

None None ● Johnson & Johnson None None

r. SusanBegelman

● OrganizationalReviewer–Societyfor VascularMedicine andBiology (SVMB)

None ● Bristol-Myers Squibb● Sanofi-Aventis● GlaxoSmithKline

None ● Bristol-MyersSquibb

● Sanofi-Aventis● GlaxoSmithKline

None

r. Simon Body ● OrganizationalReviewer–Societyof CardiovascularAnesthesiologists(SCA)

● Content Reviewer–AHA Council onCardiopulmonary,Perioperative andCritical care


r. Bengt Herweg ● OrganizationalReviewer–HeartRhythm Society(HRS)


r. Scott Kinlay ● OrganizationalReviewer–Societyfor VascularMedicine andBiology (SVMB)

● Pfizer ● Pfizer● Merck

None ● Pfizer None

r. Richard Page ● OrganizationalReviewer–HeartRhythm Society(HRS)

● Content Reviewer-ACCF ClinicalElectrophysiologyCommittee

● Content Reviewer–AHA Council onClinical CardiologyElectrocardiographyand ArrhythmiasCommittee

None None None ● Procter andGamblePharmaceuticals

None

r. Mark Turco ● OrganizationalReviewer–Societyfor CardiovascularAngiography andInterventions(SCAI)

None ● Boston ScientificCorp.

● Medtronic

None ● BostonScientific Corp.

● Medtronic

None

Continued on next page

A

D

D

D

D

D

D

D

D

D

D

D


PPENDIX 2 Continued




r. Neil Weissman ● OrganizationalReviewer–AmericanSociety ofEchocardiography(ASE)

● Edwards LifeSciences

● Carbomedics● Wyeth● Bristol-Myers Squibb

Medical Imaging● Cook Corp.● Boston Scientific● Arbor Surgical● Arena Pharmaceutical● Mitsubishi

None None ● Wyeth● Pfizer● Bristol-Myers

Squibb MedicalImaging

● BostonScientific

None

r. Kim Williams ● OrganizationalReviewer–AmericanSociety of NuclearCardiology(ASNC)

● Content Reviewer–ACCFCardiovascularClinical ImagingCommittee

● Bristol-Myers Squibb● CV Therapeutics

● GE Healthcare● Astellas Pharma

None ● GE Healthcare ● KingPharmaceuticals(Expert Reader)

r. Mazen Abu-Fadel

● Content Reviewer–ACCF CardiacCatheterizationCommittee


r. Ralph Bolman ● Content Reviewer–AHA Council onCardiovascularSurgery andAnesthesia


r. Mark Carlson ● Content Reviewer–ACCF ClinicalElectrophysiologyCommittee

None ● Medtronic ● AtriCure, Inc. ● St. Jude● Guidant

None

r. Leslie Cho ● Content Reviewer–ACCF PeripheralVascular DiseaseCommittee

● Bristol-Myers Squibb● Aventis-Sanofi

● Bristol-Myers Squibb● Aventis-Sanofi

None None None

r. Jose Diez ● Content Reviewer–ACCF CardiacCatheterizationCommittee


r. J. KevinDonahue



r. LeonardDreifus

● Content Reviewer–ACCF ClinicalElectrophysiologyCommittee

None None None ● Merck None

r. N.A. MarkEstes


None ● Medtronic● Guidant● St. Jude Medical

None ● Medtronic None

r. A. MarcGillinov

● Content Reviewer–AHA Council onCardiovascularSurgery andAnesthesia

None ● Edwards LifeSciences

None ● AtriCure, Inc. None

Continued on next page

A

D

D

D

D

D

D

D

D

D

D

D

D

Twc


PPENDIX 2 Continued




r. Loren Hiratzka ● Content Reviewer–AHA Council onCardiovascularSurgery andAnesthesia


r. Lawrence Katz ● Content Reviewer–ACCFEchocardiographyCommittee


r. Smadar Kort ● Content Reviewer–ACCFEchocardiographyCommittee


r. Peter Kowey ● Content Reviewer–ACCF ClinicalElectrophysiologyCommittee


r. Fred Krainin ● Content Reviewer–ACCF CardiacCatheterizationCommittee

None None ● Boston Scientific● Johnson & Johnson● Medtronic

None None

r. ChristopherKramer

● Content Reviewer–ACCFCardiovascularClinical ImagingCommittee

● Astellas● Novartis

● GE Healthcare None ● GE Healthcare● Novartis

● SiemensMedicalSolutions(ResearchSupport)

r. Jerrold Levy ● Content Reviewer–AHA Council onCardiovascularSurgery andAnesthesia

None None None ● Bayer● Dyax

● AlexionPharmaceuticals(SteeringCommittee forpexellizumab)

● Novo NordiskFXIII (SteeringCommittee forFXIII)

r. M. SeanMcMurry

● Content Reviewer–AHA Council onCardiopulmonary,Perioperative andCritical Care


r. Charanjit Rihal ● Content Reviewer–ACCF CardiacCatheterizationCommittee

● Cardiac Dimensions None None ● Millennium None

r. Carlos Ruiz ● Content Reviewer–ACCF CardiacCatheterizationCommittee


r. Frank Sellke ● Content Reviewer–AHA Council onCardiovascularSurgery andAnesthesia

None ● Bayer Corporation None ● CereMedix● Inotek

Corporation

None

r. Janet Wyman ● Content Reviewer–ACCF CardiacCatheterizationCommittee


his table represents the relationships of peer reviewers with industry that were disclosed at the time of peer review of this guideline. It does not necessarily reflect relationshipsith industry at the time of publication. *Participation in the peer review process does not imply endorsement of the document. †Names are listed in alphabetical order within

ategory of review.

Documents

AHA guideline BB