ACE inhibitors

14 © 2011 Future Medicine1414 www.futuremedicine.com

About the Authors

Giorgio GentileGiorgio Gentile is a PhD Attendant at the Department of Internal Medicine, University of Perugia, Italy. His research activity is in cardio vascular and renal diseases and clinical epidemiology. He is a member of the American Society of Nephrology and other scientific societies.

Gianpaolo ReboldiGianpaolo Reboldi is Senior Lecturer, Consultant Physician, Adjunct Professor, Department of Internal Medicine, University of Perugia, Italy. His research activity is in cardiovascular, metabolic and renal diseases, geriatric endocrinology, clinical pharmacology, biostatistics and clinical epidemiology.

Fabio AngeliFabio Angeli is a cardiologist and biomedical researcher at the Hos-pital ‘Media Valle del Tevere’, Perugia, Italy. He is an investigator and is co-responsible for planning and management of single and multi-center clinical studies on cardiovascular drugs (in connection with Hospitals and Universities).

Giovanni MazzottaGiovanni Mazzotta is a graduate in Medicine at the University of Perugia, Italy. He is attending the postgraduate Specialization in Cardiology and is involved in clinical research activities in cardiology. He currently holds a position of visiting doctor at the McMaster University, ON, Canada.

Paolo VerdecchiaPaolo Verdecchia is Chief, Department of Medicine, Hospital of Assisi, Italy. His research activity is in cardiovascular medicine. He is a co-ordinator of national and international clinical trials. He is a Fellow of the American College of Cardiology and member of other scientific societies.

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15© 2012 Future Medicine

doi:10.2217/EBO.11.186

Chapter 2Angiotensin-converting enzyme inhibitors

Giorgio Gentile, Gianpaolo Reboldi, Fabio Angeli, Giovanni Mazzotta & Paolo Verdecchia

More than 30 years since their discovery, angiotensin-converting enzyme (ACE) inhibitors still represent one of the most commonly prescribed medications for treating hypertension and one of the favored first-line agents, particularly in the presence of high-risk conditions, such as diabetes. Even if the primary importance of blood pressure lowering in reducing cardiovascular and renal outcomes is unquestionable, ACE inhibitors remain a cornerstone among the different classes of antihypertensive drugs, as available evidence from several randomized controlled trials and meta-analyses highlights their beneficial effects in controlling blood pressure, treating heart failure, improving survival after heart attacks and preventing renal damage. ACE inhibitors are still unsurpassed in terms of efficacy in reducing clinical events, safety and costs. Given clinicians’ favorable experience with ACE inhibitors, the increasing prevalence of Type 2 diabetes worldwide and the fact that most hypertensive

History of angiotensin-converting enzyme inhibitors 16

Pharmacokinetics of ACE inhibitors 17

Safety 22

Drug interactions 22

ACE inhibitors in clinical studies 23

Conclusion 26

Gentile, Reboldi, Angeli, Mazzotta & Verdecchia

16 www.futuremedicine.com

patients need two or more drugs for blood pressure control and concomitant reduction of the risk of cardiovascular (CV) and renal outcomes, it is very likely that ACE inhibitors will maintain an important role in the treatment of hypertension and other CV disorders in the future.

History of angiotensin-converting enzyme inhibitorsThe origins of the renin–angiotensin system (RAS) can be traced back to the 19th century, with the landmark publication of Tigerstedt and Bergman on renin in 1898. More than 50 years later, Skeggs and colleagues reported that the decapeptide angiotensin I (Ang-I) was converted to the active vasoconstrictor peptide angiotensin II (Ang-II) by a previously unknown factor, that was called angiotensin-converting enzyme (ACE) [1]. The same protein, acting as a peptidyl-dipeptidase, releases the C-terminal Phe8-Arg9 from bradykinin (BK), a powerful vasodilator, leading to its inactivation. After ACE was discovered, it became clear that its inhibition would have dual beneficial effects: the reduction of Ang II and the increase in circulating BK. The conversion from Ang I to Ang II was first thought to take place in the plasma, but subsequent investigations highlighted the role of pulmonary circulation instead.

In the 1960s, Brazilian scientist Sergio Ferreira isolated a pentapeptide BK-potentiating factor (BPF) from the venom of the viper Bothrops jararaca.

The synthesis of the nine-amino acid teprotide soon followed. Ferreira then went to John Vane’s laboratory in London (UK) for a postdoctoral fellowship. BPF traveled back to the western hemisphere when Vane persuaded his old mentor AD Welch, president of Squibb Company’s research institute, to investigate its potential usefulness in clinical medicine as an ACE inhibitor. Unfortunately, BPFs had limited clinical value due to their peptide nature and lack of activity when given orally. In the early 1970s, David Cushman, Miguel Ondetti and colleagues used peptide analogs to study the structure of ACE, and their discoveries led to the development of captopril, the first orally active ACE inhibitor, in 1975. Captopril was approved by the US FDA in 1981, followed by enalapril 2 years later. Several ACE inhibitors have since then

Angiotensin II: eight-amino acid active peptide cleaved from angiotensin I by angiotensin-

converting enzyme. Angiotensin II has hemodynamic and nonhemodynamic effects. Hemodynamic effects include increase in systemic and glomerular pressures, proteinuria and vasoconstriction. Nonhemodynamic effects include cell proliferation, hypertrophy and matrix expansion. Angiotensin II stimulates the release of aldosterone from the adrenal cortex, increases thirst, stimulates release of adrenocorticotropin or corticotropin and antidiuretic hormone and increase sodium reabsorption.

Bradykinin: nine-amino acid active peptide cleaved from kininogen by kallikrein. Bradykinin is a potent endothelium-dependent vasodilator, causes relaxation of vascular smooth muscle (vasodilation) and intense contractions of visceral smooth muscle, increases vascular permeability and natriuresis, contributing to a reduction in blood pressure, and is also involved in the mechanism of pain. In some patients treated with ACE inhibitors, the increased amount of bradykinin causes a chronic cough.

Angiotensin-converting enzyme inhibitors

17www.futuremedicine.com

been marketed. Their main mechanisms of action are reported in Box 2.1.

Pharmacokinetics of ACE inhibitorsThe active moiety of most ACE inhibitors (with the exception of fosinopril) is mainly eliminated by the kidneys and to a minor extent through the liver (Table 2.1). Many ACE inhibitors elicit large, unpredictable increases in AUC in patients with severe renal dysfunction, particularly in patients with glomerular filtration rate (GFR) <30 ml/min [2]. In contrast to renally excreted ACE inhibitors, there is relatively little increase in AUC for ACE inhibitors with dual routes of elimination (renal and hepatic), as when the renal route is altered there is a compensatory rise in the fractional excretion of drug through the liver. Lisinopril and captopril do not require hepatic activation, and may be better suited for patients with severe liver dysfunction [3]. The reduced clearance of ACE inhibitors in the elderly is mainly explained by the concomitant renal impairment. Some ACE inhibitors show increased bioavailability, with a functional increase of effective dose, a greater decrease of blood pressure and a longer duration of action [2]. ACE inhibitors usually have a relatively long half-life and an overall duration of action of 24 h or more (Table 2.2), resulting in less frequent dosing and improved patient compliance. However, between commercially available once-a-day ACE inhibitors, only delapril, fosinopril, enalapril, ramipril, spirapril, trandolapril and zofenopril comply

Box 2.1. Mechanisms of action of ACE inhibitors.

� Antihypertensive (decrease arteriolar resistance, increase venous capacity, increase bradykinin)

� Decrease aldosterone (increase natriuresis, decrease kaliuresis) � Decrease renovascular resistance � Slow progression of renal disease � Increase cardiac output, cardiac index and volume � Reverse left ventricular hypertrophy and vascular disease � Slow progression of heart failure � Prevent remodeling after myocardial infarction � Inhibit collagen deposition � Inhibit fibroblast proliferation � Anti-inflammatory effect � Prevent diabetes

AUC: area under the curve, corresponding to the integral of the plasma concentration versus

an interval of definite time. The AUC represents the most reliable measure of a drug’s bioavailability, and it is directly proportional to the total amount of unchanged drug that reaches systemic circulation. In practice, the approximation is used: AUC = ƒ ([C] x Dt), where [C] is the measured concentration and Dt the interval of time between two measurements. The precision of the AUC grows with the number of measurements of concentration taken. AUC is expressed in units of mg × h/ml.



Table 2

.1. P

harm

aco

kinet

ics

of angiote

nsin-c

onv

erting e

nzym

e inhibito

rs.

Age

ntPr

odru

g/bi

otra

ns.

site

Acti

ve d

rug

Prod

rug

oral

ab

sorp

tion

(%

)

Prod

rug

prot

ein

bind

ing

(%)

Prod

rug

onse

t of

acti

on

Prod

rug

tim

e to

pe

ak

plas

ma

conc

.

Acti

ve

drug

tim

e to

pea

k pl

asm

a co

nc.

Prod

rug

half

-lif

eA

ctive

dr

ug

eff.

half

-lif

e

Elim

inati

on

rout

es

Bena

zepr

ilYe

s/liv

erBe

naze

prila

tA

t lea

st 3

7 96

.7W

ithi

n 1

h0.

5–1

h1–

2 h

0.6

h10

–11

hN

on-r

enal

cl

eara

nce

(ben

azep

rila

t (1

1–12

%);

hepa

tic

(unc

hang

ed

bena

zepr

il)

Capt

opri

lN

o –

At l

east

75

25–3

015

–60

min

30–9

0 m

in –

<2 h

–Ki

dney

(>

95%

)

Cila

zapr

ilYe

s/liv

erCi

laza

prila

t57

20–3

0W

ithi

n 1

h1.

1 h

Wit

hin

2 h

1-1.

5 h

9 h

Kidn

ey

(cila

zapr

ilat)

Del

apri

lYe

s/liv

erM

-1M

-3A

t lea

st 9

5A

t lea

st

961

h1.

1 h

1.4

h

(M-1

)1.

7 h

(M

-3)

0.4

h1.

2 h

(M-1

)0.

8 h

(M-3

)

Kidn

ey (5

5-58

%, m

ainl

y M

-1 a

nd

M-3

), fe

ces

Enal

apri

lYe

s/liv

erEn

alap

rila

t60

50–6

01

h1

h3-

4 h

1.3

h11

hM

ainl

y ki

dney

(e

nala

prila

t an

d en

alap

ril),

Fosi

nopr

ilYe

s/liv

erFo

sino

prila

t36

97–9

8W

ithi

n 1

h2.

8 h

2-4

h0.

1 h

11.5

hKi

dney

(5

0%),

fece

s (5

0%)

biot

rans

.: Bi

otra

nsfo

rmati

on; c

onc.

: Con

cent

ratio

n; e

ff.: E

ffec

tive

.



Table 2

.1. P

harm

aco

kinet

ics

of angiote

nsin-c

onv

erting e

nzym

e inhibito

rs (cont.).

Age

ntPr

odru

g/bi

otra

ns.

site

Acti

ve d

rug

Prod

rug

oral

ab

sorp

tion

(%

)

Prod

rug

prot

ein

bind

ing

(%)

Prod

rug

onse

t of

acti

on

Prod

rug

tim

e to

pe

ak

plas

ma

conc

.

Acti

ve

drug

tim

e to

pea

k pl

asm

a co

nc.

Prod

rug

half

-lif

eA

ctive

dr

ug

eff.

half

-lif

e

Elim

inati

on

rout

es

Lisi

nopr

ilN

o–

25N

one

1 h

7 h

–12

h–

Kidn

ey

Moe

xipr

ilYe

s/liv

erM

oexi

prila

t13

501

hW

ithi

n 0.

8 h

1.5

h1.

3 h

12 h

Kidn

ey

(moe

xipr

ilat,

m

oexi

pril,

m

etab

olite

s),

fece

s (m

oexi

prila

t)

Peri

ndop

ril

Yes/

liver

Peri

ndop

rila

t65

–75

60W

ithi

n 1–

2 h

1 h

3–7

h0.

8–1

h3-

10 h

Kidn

ey

(75%

), fe

ces

(25%

)

Qui

napr

ilYe

s/liv

erQ

uina

prila

t60

10–2

0W

ithi

n 1

hW

ithi

n 1

hW

ithi

n 2

h1–

2 h

3 h

Kidn

ey

(60%

), fe

ces

(40%

)

Ram

ipri

lYe

s/liv

erRa

mip

rila

t50

–60

73%

Wit

hin

1–2

hW

ithi

n 1

h2–

4 h

5.1

h13

–17

hKi

dney

(6

0%),

fece

s (4

0%)

Spir

apri

lYe

s/liv

erSp

irap

rila

t50

–60

Not

kn

own

Wit

hin

1 h

1 h

2.4

h0.

9–1.

6 h

1.7–

1.9

hKi

dney

, fec

es

Tran

dola

pril

Yes/

liver

Tran

dola

prila

t10

802

h0.

5–1

h4–

10 h

6 h

22.5

hKi

dney

(3

3%),

fece

s (6

6%)

Zofe

nopr

ilYe

s/liv

erZo

feno

prila

tA

t lea

st 9

388

1 h

0.4–

0.6

h0.

9 h

0.7–

0.9

h3.

6–6.

6 h

Kidn

ey, f

eces

biot

rans

.: Bi

otra

nsfo

rmati

on; c

onc.

: Con

cent

ratio

n; e

ff.: E

ffec

tive

.



Table 2

.2. Clin

ical ind

icatio

ns a

nd d

osing in

form

atio

ns for ora

lly a

vaila

ble A

CE in

hibito

rs in

adult patie

nts.

Age

ntLa

bele

d in

dica

tion

s U

sual

sta

rting

do

se (a

ll in

dica

tion

s)

Usu

al m

aint

enan

ce

dosi

ng r

ange

(adu

lts

only

, all

indi

cati

ons)

Max

imum

re

com

men

ded

daily

dos

e (a

dult

s)

Ora

l dai

ly

dose

s (n

)Tr

ough

-to

-pea

k ra

tio

(%)†

Dos

e ad

just

men

t in

live

r/re

nal

impa

irm

ent

Bena

zepr

ilH

YP (F

DA

)D

N, N

DN

, CH

F, L

VH

(n

on-F

DA

)

5–10

mg/

day

10–4

0 m

g/da

y20

–80

1–2

40N

o/Ye

s

Capt

opri

lH

YP, C

HF,

DN

, LV

D a

fter

M

I (FD

A)

ND

N (n

on-F

DA

)

6.25

–75

mg/

day

50–1

50 m

g/da

y15

0–45

01–

325

No/

Yes

Cila

zapr

ilH

YP, C

HF

(non

-FD

A)

0.5–

1 m

g/da

y1–

2.5

mg/

day

51

10–8

0Ye

s/Ye

s

Del

apri

lH

YP, C

HF

(non

-FD

A)

15–3

0 m

g/da

y30

–60

mg/

day

60–1

201–

2>

50Ye

s/Ye

s

Enal

apri

lH

YP, C

HF,

asy

mpt

omati

c LV

D (F

DA

)D

N, N

DN

, MI (

non-

FDA

)

2.5–

5 m

g/da

y2.

5–40

mg/

day

20–4

01–

240

–64

Yes/

Yes

Fosi

nopr

ilH

YP, C

HF

(FD

A)

DN

, ND

N, M

I (no

n-FD

A)

5–10

mg/

day

5–40

mg/

day

20–8

01–

264

Yes/

Yes

Lisi

nopr

ilH

YP, C

HF,

MI (

FDA

)D

N, N

DN

(non

-FD

A)

5–10

mg/

day

5–40

mg/

day

10–8

01

30–7

0N

o/Ye

s

Moe

xipr

ilH

YP (F

DA

and

non

-FD

A)

7.5

mg/

day

7.5–

30 m

g/da

y60

1–2

0–9

Yes/

Yes

Peri

ndop

ril

HYP

, CA

D (F

DA

)CH

F, M

I, st

roke

, pa

roxy

smal

AF

(non

-FD

A)

4 m

g/da

y4–

8 m

g/da

y8–

161–

235

Yes/

Yes

AF:

Atr

ial fi

brill

ation

; CA

D: C

oron

ary

arte

ry d

isea

se; C

HF:

Con

gesti

ve h

eart

failu

re; D

N: D

iabe

tic n

ephr

opat

hy; H

YP: H

yper

tens

ion;

LV

D: L

eft v

entr

icul

ar

dysf

uncti

on; L

VH

: Left

ven

tric

ular

hyp

ertr

ophy

; MI:

Myo

card

ial i

nfar

ction

; ND

N: N

ondi

abeti

c ne

phro

path

y.† A

dapt

ed fr

om [3

2].



Table 2

.2. Clin

ical ind

icatio

ns a

nd d

osing in

form

atio

ns for ora

lly a

vaila

ble A

CE in

hibito

rs in

adult patie

nts

(cont

.).

Age

ntLa

bele

d in

dica

tion

s U

sual

sta

rting

do

se (a

ll in

dica

tion

s)

Usu

al m

aint

enan

ce

dosi

ng r

ange

(adu

lts

only

, all

indi

cati

ons)

Max

imum

re

com

men

ded

daily

dos

e (a

dult

s)

Ora

l dai

ly

dose

s (n

)Tr

ough

-to

-pea

k ra

tio

(%)†

Dos

e ad

just

men

t in

live

r/re

nal

impa

irm

ent

Qui

napr

ilH

YP, C

HF

(FD

A)

DN

(non

- FD

A)

10–2

0 m

g/da

y10

–40

mg/

day

40–8

01–

210

–40

Yes/

Yes

Ram

ipri

lH

YP, H

igh-

CV r

isk,

CH

F aft

er M

I (FD

A)

DN

, ND

N, M

I, CH

F

(non

-FD

A)

1.25

–2.5

mg/

day

2.5–

10 m

g/da

y5–

201–

250

–63

Yes/

Yes

Spir

apri

lH

YP (n

on-F

DA

)6

mg/

day

6 m

g/da

y6

160

–90

No/

Yes

Tran

dola

pril

HYP

, CH

F po

st-M

I, LV

D

post

-MI (

FDA

)D

N, N

DN

(non

-FD

A)

1–2

mg/

day

2–4

mg/

day

4–8

1–2

50–1

00Ye

s/Ye

s

Zofe

nopr

ilH

YP, M

I (no

n-FD

A)

15 m

g/da

y30

mg/

day

601–

255

–75

Yes/

Yes

AF:

Atr

ial fi

brill

ation

; CA

D: C

oron

ary

arte

ry d

isea

se; C

HF:

Con

gesti

ve h

eart

failu

re; D

N: D

iabe

tic n

ephr

opat

hy; H

YP: H

yper

tens

ion;

LV

D: L

eft v

entr

icul

ar

dysf

uncti

on; L

VH

: Left

ven

tric

ular

hyp

ertr

ophy

; MI:

Myo

card

ial i

nfar

ction

; ND

N: N

ondi

abeti

c ne

phro

path

y.† A

dapt

ed fr

om [3

2].



with the FDA recommendation of an average trough–peak ratio greater than 50%, which protects against the possible deleterious consequences of a trough effect (i.e., the decrease in effect observed at the end of the dosing interval).

SafetyACE inhibitors are generally well tolerated [3]. They can cause a dose-dependent hypotension, particularly in renin-dependent states (i.e., low sodium intake and diuretic use). Angioedema, a serious hypersensitivity reaction characterized by the swelling of the lips, tongue and throat among others, has been associated with ACE inhibitors (0.1–0.2% of the treated subjects). ACE inhibitors may also cause a dry and persistent cough in 10% or more of the treated patients, which may lead to the discontinuation of the medication. Patients with bilateral renal artery stenosis may experience renal failure if ACE inhibitors are administered, because the preferential vasoconstriction of the renal efferent arteriole in this condition allows the maintainance of glomerular capillary pressure and filtration, and ACE inhibition may cause a fall in GFR by blocking circulating and intrarenal Ang II formation. ACE inhibitors may also cause hyperkalemia, particularly when associated with potassium supplements or potassium-sparing diuretics. This side effect is most common in patients with underlying renal impairment, and rarely reported in subjects with normal renal function. ACE inhibitors containing a sulfhydryl binding group (e.g., captopril) are more commonly associated with neutropenia, nephritic syndrome, taste disturbances and skin rashes, compared with those with a carboxyl (benazepril, enalapril, perindopril, lisinopril and ramipril) or phosphinil (fosinopril) binding group. There is strong evidence to indicate that the use of ACE inhibitors during pregnancy may cause human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension and

hyperkalemia) [4]. ACE inhibitors should not be initiated during pregnancy or in patients planning pregnancy. Treatment with ACE inhibitors should be stopped immediately when pregnancy is diagnosed and alternative therapy should be started as appropriate.

Drug interactionsACE inhibitors may present specific drug interactions with a number of compounds, including NSAIDs [5,6], lithium [7], tetracyclines and allopurinol [8].

Angiotensin-converting enzyme inhibitors are well tolerated by most individuals.

Angiotensin-converting enzyme inhibitors should not be used during pregnancy because they may cause birth defects.

Angiotensin-converting enzyme inhibitors may cause acute renal failure in patients with bilateral renal artery stenosis.

Angiotensin-converting enzyme inhibitors have proven efficacy in reducing cardiovascular and renal outcomes in patients with uncomplicated hypertension or other high-risk conditions (e.g., diabetes).



ACE inhibitors in clinical studiesHypertensionACE inhibitors are one of the most commonly prescribed medications for treating hypertension, and they were cited in a recent survey of primary-care supervisors in Australia as the favored first-line agent, particularly in the presence of high-risk conditions, such as diabetes [9]. A Cochrane systematic review aimed to assess how effective ACE inhibitors actually are in reducing blood pressure [10]. The review included 92 trials comparing ACE inhibitors and placebo with a total of 12,954 patients with primary hypertension (mean baseline blood pressure: 157/101 mmHg). The studies covered 14 ACE inhibitors. Overall, ACE inhibitors reduced systolic and diastolic blood pressure (BP) by 6–9 mmHg and 4–5 mmHg, respectively. Doses lower than the manufacturer’s maximum recommended dosage had nearly the same blood pressure-lowering effect as the maximum dose. For example, half of the maximum dose achieved the blood pressure-lowering effect of the maximum dose 90% of the time. Therefore, the use of the maximum dosage of ACE inhibitors to achieve greater blood pressure control in subjects with primary hypertension and no other high-risk conditions is usually unnecessary. Only half of the included trials provided data on withdrawal due to adverse events. Remarkably, there was no difference between ACE inhibitors and placebo in this critical outcome.

Post myocardial infarctionA 100,000-patient overview of the Fourth International Study of Infarct Survival (ISIS-4), the Chinese Cardiac Study (CCS-1), the Cooperative New Scandinavian Enalapril Survival Study 2 (CONSENSUS 2) and the Third Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI-3) showed a 7% reduction in overall mortality in patients treated with ACE inhibitors (captopril, enalapril and lisinopril) within 36 h after the onset of chest pain, compared with placebo [11]. An 18–27% reduction in overall mortality was also evident in the SAVE, AIRE and TRACE trials (captopril, ramipril and trandolapril, respectively) [12]. Available evidence does not conclusively show which patients with an acute myocardial infarction should be offered ACE inhibitors, nor how long after an acute myocardial infarction it remains beneficial to start treatment. A recent systematic review showed that ACE inhibitors are more effective at reducing sudden cardiac death and overall mortality after 2–42 months when started within 14 days of an acute myocardial infarction (overall mortality: 14% with ACE inhibitors vs 17% with placebo; overall response [OR]: 0.83, 95% CI: 0.71–0.97; sudden cardiac death: 5 vs 7%; OR: 0.80, 95% CI: 0.70–0.92). ACE inhibitors significantly increased



persistent hypotension and renal dysfunction at 6 weeks compared with placebo (hypotension: 18 vs 9%; p < 0.01; renal dysfunction: 1.3 vs 0.6%; p < 0.01) [44]. The relative and absolute risks of these adverse effects were uniformly distributed across both the high and lower CV risk groups [13].

Congestive heart failureACE inhibitors delay the onset of symptomatic congestive heart failure (CHF), reduce CV events and improve long-term survival in patients with asymptomatic left ventricular systolic dysfunction (LVSD). ACE inhibitors reduce the risk of CHF by 21% compared with placebo, while their beneficial effects on CHF are comparable to those of b-blocker/diuretic therapy [14]. ACE inhibitors also seem more effective at reducing nonfatal or fatal myocardial infarction, CV mortality and all-cause mortality in patients with asymptomatic or symptomatic LVSD, as well as at reducing heart failure, CV- and all-cause hospital admissions in people with CHF, asymptomatic LVSD or other risk factors for CHF, compared with placebo [15]. Combination therapy with angiotensin receptor blockers (ARBs) and ACE inhibitors reduces admissions for CHF when compared with ACE inhibitors alone, but does not reduce overall mortality or all-cause hospitalizations, and is associated with more adverse events. Based on current evidence, combination therapy with ARBs and ACE inhibitors may be reserved for CHF patients who remain symptomatic on therapy with ACE inhibitors under strict monitoring for any signs of worsening renal function and/or symptomatic hypotension [16].

StrokeUntil recent times, evidence for the beneficial role of ACE inhibitors in preventing stroke was controversial. Several prospective randomized trials, including PROGRESS, the Post-stroke PATS and HOPE, demonstrated that ACE inhibitors (plus indapamide in PROGRESS) reduce the incidence of stroke by 5–32%. Conversely, ACE inhibitors increased the risk of stroke by 15–25% in the ALLHAT trial and the CAPPP trial, while the ANBP and DIABHYCAR studies showed no difference between ACE inhibitors and the comparator. A recent systematic review showed that the beneficial effects of ACE inhibitors on the risk of stroke are similar to those of other drug classes, and entirely or largely due to BP reduction [17]. Only calcium channel blockers showed a minor additional effect in preventing stroke [18].

NephropathyDiabetic nephropathyDiabetic nephropathy occurs in 25–40% of subjects with Type 1 or Type 2 diabetes within 20–25 years from the onset of disease. Hypertension and



proteinuria may accelerate the decline in the glomerular filtration rate and the progression to end-stage kidney disease (ESKD). The Collaborative Study Group trial [19] was the first large-scale clinical study of an ACE inhibitor (captopril) for preventing or delaying progression of chronic kidney disease (CKD) and ESKD in subjects with Type 1 diabetes and established nephropathy (proteinuria ≥500 mg/day). During a median follow-up of 3 years, the captopril-treated group had a 50% reduction in the number of patients with doubling of serum creatinine, and a 50% reduction in the number of patients who died or reached ESKD. The favorable effects on kidney function were independent of the degree of blood pressure control, which was essentially the same in the two groups. Similarly, the diabetes substudy of the HOPE trial [20] showed that at similar blood pressure values, an ACE inhibitor (ramipril) allowed a 24% greater decrease in the rate of progression to overt nephropathy than placebo in patients with Type 2 diabetes and normo- or micro-albuminuria. ACE inhibitors significantly reduce the risk of all-cause mortality (mainly CV) and progression from micro- to macro-albuminuria by 20 and 55%, respectively; they also increase the rate of regression from macro- to micro-albuminuria by 3.4-fold. These beneficial effects were not related to baseline blood pressure values, type of diabetes, stage of diabetic nephropathy and duration of treatment [21].

Nondiabetic nephropathyThe Collaborative Study Group trial [19] clearly established the benefits of captopril in diabetic nephropathy, but generated two additional questions. First, were the benefits seen with captopril specific for that drug, or was there an ACE inhibitor class effect? Second, could renal protection be obtained in non-diabetic nephropathies? Two of the larger, randomized studies that affirmatively answered these questions are the AIPRI study (benazepril) [22] and the REIN study (ramipril) [23]. Both trials showed a renoprotective effect of ACE inhibitors in patients with nondiabetic nephropathy. These studies and two meta-analyses on this topic [24,25] established that the beneficial effects of ACE inhibitors were clearly independent of blood pressure control per se, as demonstrated either by equivalent blood pressure control in the ACE- and non-ACE-inhibitor groups, by adjusting for treated blood pressure in the statistical analyses, or by both approaches. In addition, the benefits were more evident in subjects with proteinuria greater than 1–3 g/day (i.e., the risk reduction increases as baseline proteinuria increases). On the other hand, patients with little or no proteinuria may not experience any protective effect of ACE inhibitors. Despite the clear relationship between proteinuria and



the magnitude of benefit, statistical analyses also suggest that the benefit of ACE inhibitors may be achieved by additional mechanisms, as the risk reduction with ACE inhibitors is significant even after adjustment for the degree of reduction in proteinuria. Finally, the subgroup of patients with polycystic kidney disease of the AIPRI study did not receive any specific protection against progression of chronic kidney disease with ACE inhibitors.

ConclusionThe primary importance of BP-lowering in reducing CV and renal outcomes is unquestionable [17]. Among the different classes of antihypertensive agents, ACE inhibitors remain a cornerstone for controlling blood pressure, treating heart failure, improving survival after heart attacks and preventing renal damage in people with uncomplicated hypertension or in high-CV risk subjects, as highlighted by HOPE [26]. More than 30 after from the discovery of captopril, ACE inhibitors are still unsurpassed in terms of evidence for efficacy in reducing clinical events, safety, most patient factors and costs. In addition, ONTARGET showed that dual RAS blockade is no more beneficial than monotherapy with an ACE inhibitor or an ARB in preventing serious CV outcomes in patients with known vascular disease or diabetes with end-organ damage, but not heart failure at entry, at cost of higher rates of renal insufficiency, hyperkalemia and hypotension [27]. The only benefit was a greater reduction of proteinuria with combination therapy [28], that is consistent with a recent meta-analysis showing that ACE inhibitors have similar effectiveness as ARBs in reducing urinary protein excretion in both diabetic and nondiabetic nephropathy, while combination therapy leads to a greater reduction in proteinuria than monotherapy [29]. In patients with heart failure and depressed ejection fraction, the combination of ARBs and ACE inhibitors may offer advantages over ACE inhibitors alone [30,31].

In conclusion, in the light of the fact that most hypertensive patients need two or more drugs for BP control and concomitant reduction of the risk of CV and renal outcomes, ACE inhibitors are most likely to have a bright future.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.



Summary.

� With few exceptions, angiotensin-converting enzyme (ACE) inhibitors have a relatively long half-life. This factor may be an advantage, resulting in less frequent dosing and improved patient compliance.

� ACE inhibitors reduce systolic blood pressure by 6–9 mmHg and diastolic blood pressure by 4–5 mmHg. Doses lower than the manufacturer’s maximum recommended dosage have the same blood pressure-lowering effect as the maximum dose.

� ACE inhibitors are more effective at reducing sudden cardiac death and overall mortality after 2–42 months when started within 14 days of an acute myocardial infarction.

� ACE inhibitors reduce the risk of congestive heart failure by 21% compared with placebo, while the benefits of ACE inhibitors on congestive heart failure are comparable to those of b-blocker/diuretic therapy.

� In patients with diabetic nephropathy, ACE inhibitors significantly reduced the risk of all-cause mortality (mainly cardiovascular) by 20% and progression from micro- to macro-albuminuria by 55%. These beneficial effects were not related to baseline blood pressure values, type of diabetes, stage of diabetic nephropathy and duration of treatment.

� AIPRI (benazepril), REIN (ramipril) and two meta-analyses showed a renal protective effect of ACE inhibitors in patients with nondiabetic nephropathy and established that the beneficial effects of ACE inhibitors are clearly independent of blood pressure control per se.

� ACE inhibitors remain unsurpassed in terms of evidence for reduction of cardiovascular and renal outcomes, safety, most patient factors and costs.

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