The clinical use of angiotensin-converting enzyme inhibitors

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he Clinical Use of Angiotensin-Convertingnzyme Inhibitors

oseph Wong, Rajiv A. Patel, and Peter R. Kowey

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hrough an integrative understanding of cardiovas-ular pathophysiologic characteristics at the multi-rgan level, significant achievements in cardiovas-ular therapeutics have been achieved and en-bled the rationale design and development ofrugs such as the angiotensin-converting enzyme

ACE) inhibitors and angiotensin receptor blockersARBs). In this article, we present a detailed reviewf the physiologic features of the renin-angioten-in-aldosterone system (RAAS), ACE inhibitors andRB clinical pharmacologic characteristics, andpecific diseases in which they are considered toe the standard of the care as supported by im-ortant clinical trial data. It is envisioned that anpdated and detailed understanding of ACE inhib-

tors and ARBs will facilitate their successful use inhe treatment of heart failure, myocardial infarction,ypertension, renal failure, and diabetic nephropa-hy.

2004 Elsevier Inc. All rights reserved.

he success of cardiovascular pharmacothera-peutics can be attributed in part to achieve-

ents made in molecular biology that havellowed the precise identification and character-zation of novel targets for drug action. Classicalxamples include the angiotensin-converting en-yme (ACE) inhibitors, which decrease the forma-

From the Cardiovascular Division, Brigham and Wom-n’s Hospital, Harvard Medical School, Boston, Massa-husetts; the Department of Cardiology, Lankenau Hos-ital, Main Line Health Heart Center, Philadelphia,ennsylvania; and the Thomas Jefferson University, Phil-delphia, Pennsylvania.Address reprint requests to Peter R. Kowey, MD, Main

ine Health Heart Center, 556 Lenkenau MOB East, 100ancaster Ane, Wynnewood, PA 19096. E-mail:[email protected]/$ - see front matter© 2004 Elsevier Inc. All rights reserved.

idoi:10.1016/j.pcad.2004.04.003

16 Progress in Cardiovascular Diseases

ion of angiotensin II (AG-II) by competitivelyntagonizing ACE, the rate-limiting enzyme inormation of AG-II, and angiotensin receptorlockers (ARBs), which block the binding ofG-II to its receptor in the renin-angiotensin-ldosterone neurohormonal system (RAAS) (Fig). It is through an understanding of the RAAShat ACE inhibitors and ARBs have been devel-ped. Their efficacy, proven in numerous largeandomized clinical trials highlights their impor-ance in the therapy of patients with hypertension,eft ventricular dysfunction, post–myocardial in-arction, diabetes mellitus, and renal disease. It ishe purpose of this article to present an updatednd concise review of ACE inhibitors for the prac-icing physician.

Physiology of the RAAS

he RAAS has two components—circulating andissue. Whereas the former component partici-ates acutely in maintaining adequate systemicemoperfusion, the latter component is chroni-ally operative at the local tissue level. Despitehese differences, both components share path-ays for synthesis and degradation.1 Upon initialAAS activation, renin synthesized from both re-al and extra-renal tissues is released in responseo stimuli such as glomerular hypoperfusion,ympathetic stimulation, and decreased deliveryf chloride anion to the juxtaglomerular cells ofhe renal macula densa2 (see Fig 1). In the firstynthetic step, renin catalyzes the rate-limitingormation of AG-II, in which hepatically synthe-ized �2-globulin angiotensinogen is converted tohe decapeptide angiotensin I. In the second step,he zinc metallopeptidase ACE (also known asininase II in the bradykinin system) catalyzes theonversion of angiotensin I to AG-II (see Fig 1).

The angiotensin-converting enzyme identified
n lung tissue, neuroepithelium, plasma, and vas-
, Vol. 47, No. 2, (September/October) 2004: pp 116-130

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117THE CLINICAL USE OF ACE INHIBITORS

ular endothelium is expressed as one of threeenotypes: DD, II, and ID.3 In patients expressinghe double-deletion phenotype (DD), plasma andardiac ACE levels may be up to 300% greaterhan in those patients expressing other geno-ypes.4 Knowledge of a specific ACE genotypeay have important pharmacogenetic implica-

ions. For example, the DD genotype is also asso-iated with higher aldosterone levels, increasedradykinin degradation, and greater resistance toCE inhibitor therapy and potentially decreased

urvival, although this is unproven. It thereforeay be argued that prior knowledge of a specificCE genotype may help in defining an optimalose. More recently, a functionally related en-yme termed angiotensin-converting enzyme 2ACE2) has been identified in coronary endothe-ium and renal tubular epithelium. This proteinatalyzes the conversion of angiotensin I to angio-

Fig 1. The renin-angiotensin-aldosterone system. Aangiotensin-converting enzyme; BP, blood pressure

Fig 2. Members of the an

ensin 1-9, which is subsequently converted tongiotensin 1-7 by ACE instead of the traditionalngiotensin 1-8 (Fig 2). Although the function ofngiotensin 1-9 is not fully understood, angioten-in 1-7 is a vasodilator (see Fig 2). Furthermore,CE2 differs from ACE in by its inability to me-

abolize bradykinin and immunity from ACE in-ibitor activity. Additional independent pathways

or AG-II formation include conversion of angio-ensin-I to AG-II catalyzed by chymase or by ca-hepsin G (a chymostatin-sensitive AG-II–gener-ting system).5 The clinical significance of theseathways, however, is currently not known.AG-II may exhibit both systemic and local tis-

ue activity mediated by binding to AT1 and AT2eceptors in a concentration-dependent (first-or-er kinetics) manner with a variable response de-ending on the receptor subtype stimulated. AT1eceptors have been isolated in cardiovascular, re-

k, Site of action of ACE inhibitors. Abbreviations: AC

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118 WONG, PATEL, AND KOWEY

al, hepatic, neurologic, and adrenal tissue andediate peripheral vasoconstriction, release of al-

osterone from the zona glomerulosa of adrenalland, renal sodium and water reabsorption, in-rease of sympathetic tone, and release of vaso-ressin from the posterior pituitary gland. Collec-ively, these actions attempt to maintain adequatergan perfusion by increasing systemic vascularesistance and plasma volume expansion in con-unction with other hormones such as norepi-ephrine, vasopressin, and endothelin6 and coun-erregulatory to nitric oxide (NO),7 natriureticeptides, and prostaglandins. In comparison, AT2eceptors are expressed in fetal tissue, vascularndothelium, uterus, ovary, brain, pancreas, adre-al medulla, and adult myocardium (predomi-antly on the interstitial fibroblasts). In cardiacissue, AT2 receptors are up-regulated in the pres-nce of atherosclerosis, ischemia, infarction, andeart failure,8 and may mediate myocardial re-odeling and fibrosis in addition to physiologi-

ally antagonizing AT1-receptor stimulation.9,10

n summary, therefore, short-term activation ofhe RAAS serves to preserve peripheral organ per-usion and prevent hemodynamic collapse. In theong term, however, it may impair ventricular sys-olic and diastolic performance by increasing theentricular workload and myocardial oxygen de-and, and create the foundation for deleterious

ardiac architectural changes (i.e., myocardial re-odeling and fibrosis), which in turn may providesubstrate for reentrant atrial and ventricular ar-

hythmias, ischemia, and heart failure.

ACE Inhibitor Pharmacology

rom an understanding of the physiology of theAAS, the pharmacodynamic response of ACE an-

agonism may be predicted: a short-term dose-ependent decrease in AG-II levels, preload andfterload reduction, lowering of both the systolicnd diastolic pressure with little or no change inhe cardiac output, reduction of proteinuric ne-hropathy, and inhibition of bradykinin degrada-ion. More exclusive effects of certain ACE inhib-tors such as ramipril and quinapril, perhaps

ediated through AT1 subtype receptor antago-ism, include plaque stabilization, enhancementf the effects of NO and prostaglandins, regressionf ventricular hypertrophy, regression of vascular
mooth muscle proliferation, decreased formation s
f superoxide anions, inhibition of NO degrada-ion, decreased coronary vasoconstriction, andntimacrophage function.11 Agents that demon-trate greater tissue affinity and improve endothe-ial dysfunction versus ACE inhibitors that do notave been termed tissue-specific ACE inhibitors.omplementary to understanding the basic phar-acology of ACE inhibitors is a knowledge of

ifferences in their pharmacokinetic profiles (Ta-le 1), which may be defined by biochemicaltructure and bioavailability, lipophilicity, tissuepecificity, hepatic prodrug transformation, renallimination, plasma half-life, ACE genotype, race,nd ACE inhibitor dose (Table 2). These variablesith the exception of dosing are discussed inreater detail elsewhere in this article. In general,he dose at which mortality benefits have beenbserved in major clinical trials (e.g., ATLAS12)hould be the target dose assuming patient toler-nce; several months of titration with serial mon-toring of the patient’s electrolytes, blood pres-ure, and renal function may be required.ikewise, higher doses may also be required tovercome gradual reactivation of tissue ACE orhe ACE escape phenomena.13,14 In the ATLAS trial,164 patients with New York Heart Associationlass II to IV heart failure with an ejection fractionf �30% were randomly assigned to either low- origh-dose lisinopril in addition to other standardeart failure medications and prospectively fol-

owed up over a period of 39 to 58 months tossess the impact of dosing on mortality. It wasound that high-dose lisinopril treatment was

ore effective than low-dose lisinopril in reduc-ng the combined endpoint of hospitalization24% fewer hospitalizations for heart failure; P �002) and mortality (high-dose group had a insig-ificant 8% lower risk of death [P � .128], but a

Table 1. Biochemical Classification of ACEInhibitors

ulfhydryl-containing ACE inhibitorsCaptopril, fentiapril, pivalopril, zofenopril, alacepril

icarboxyl-containing ACE inhibitorsLisinopril, benazepril, qinapril, moexipril, ramipril,

spirapril, perindopril, pentopril, cilazapril trandolaprilhosphorus-containing ACE inhibitorFosinopril

Abbreviation: ACE, angiotensin-converting enzyme.

ignificant 12% lower risk of death or hospitaliza-

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ion for any cause [P � .002]). This benefit waslso observed in various subgroups including pa-ients with diabetes, hypertension, renal dysfunc-ion, as well as the elderly.15,16 And although diz-iness and renal insufficiency were observed morerequently in the high-dose group, the 2 groupsere similar in the number of patients requiringiscontinuation of the study medication. Impor-antly, the use of high-dose instead of low-doseisinopril in chronic heart failure patients did notesult in a significantly lower all-cause mortality,ut was associated with a reduced risk of majorlinical events. These results may query whetherreater antagonism of ACE through a combina-ion therapy of ARBs with ACE inhibitors has anydditive or synergistic benefits with respect toorbidity and mortality reduction.The CHARM Added trial17 addressed this ques-

ion and was specifically designed to investigatehether treatment with the AG-II receptor antag-nist candesartan is associated with a reduction inhe primary endpoint of cardiovascular death orongestive heart failure (CHF) hospitalizations inatients with symptomatic heart failure (ejectionraction [EF] �.40) receiving ACE inhibitor ther-py. Combination therapy with ACE inhibitorsnd candesartan was associated with a signifi-antly lower endpoint of cardiovascular mortalitynd hospitalizations than the placebo arm (24.2%ersus 28.0%, P � .01). There was, however, areater incidence of hypotension and elevated se-um creatinine in the combination therapy arm. Its thus important to understand the pharmacologyf these agents and relevant trial data to achievehe best clinical result with minimal or no toxicityo the patient.

Clinical Applicationsof ACE Inhibitors

he following is a discussion of disease entities inhich ACE inhibitors have been proven to be ef-cacious. These include hypertension, symptom-tic or asymptomatic left ventricular systolic dys-unction, post–myocardial infarction, renalailure, and diabetic nephropathy.

ypertension

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ith more than a 50% reduction in the incidencef recurrent heart failure, 35% to 40% reduction introke, and 20% to 25% reduction in myocardialnfarction (MI).18 The RAAS is an important path-ay in the pathogenesis of hypertension and pro-ides excellent targets for drug therapy. In theeventh Report of the Joint National Committeen Prevention, Detection, Evaluation, and Treat-ent of High Blood Pressure, ACE inhibitors are

ecommended as the initial therapy in patientsith MI, diabetes, chronic renal failure, CHF, re-

urrent stroke, and presence of multiple cardio-ascular risk factors19 because of effectiveness andavorable side effect profiles. Unlike other antihy-ertensive medications, ACE inhibitors do notause hyperuricemia or adversely affect lipid andlucose metabolism, but instead improve insulinensitivity thereby maintaining euglycemia andreventing the development of type 2 diabetes inigh-risk patients with cardiovascular disease.20

From a cardiovascular perspective, ACE inhib-tors have been proven to cause a regression of leftentricular hypertrophy independent of its bloodressure–lowering effects. For patients intolerantf ACE inhibitors, ARBs may offer an effectivelternative; there are no significant differences be-ween them with respect to their ability to controllood pressure. Alternately, a calcium channellocker (CCB) may be used, as supported by theNVEST trial, which tested whether treatmentith a calcium antagonist-based blood pressure–

owering strategy is equivalent to treatment with aon–calcium antagonist–based strategy in hyper-ensive patients with coronary artery diseaseCAD) with regard to the composite of death, MI,r stroke. In this trial, 22,576 patients from 15ountries with a mean age of 66 years and 1 orore cardiovascular risk factor, including diabe-

es (27%), dyslipidemia (53%), prior smoking his-ory (46%), and mild obesity (80%), were ran-omized to either a CCB-based therapyverapamil � trandolapril � hydrochlorothia-ide) or a non-CCB–based therapy (atenolol �randolapril � hydrochlorothiazide). Patientsith a history of MI, unstable angina, or CHF were

xcluded. There was no difference in hyperten-ion control between the 2 treatment groups andquivalence of 2 therapeutic strategies was shownn terms of all-cause mortality, nonfatal stroke, oronfatal MI. Interestingly, there was a lower rate
f diabetes in the calcium treatment arm; whether t
his is the result of a renoprotective effect of con-urrent ACE inhibitors use with CCBs versusreater use of HCTZ in the non-CCB arm of thetudy is unclear.21 More recently, the results of theLLHAT study were published.22 This was alinded randomized trial comparing the effect ofhlorthalidone, amlodipine, doxazosin, and lisin-pril on the incidence of cardiovascular disease inypertensive patients. Although there were no dif-

erences in treatment outcomes with respect to therimary end points of fatal coronary heart diseaser nonfatal MI, chlorthalidone was superior inbsolute reduction of systolic blood pressure ver-us other agents. The results of this study are,owever, controversial because of the relatively

arge crossover rate and suggestions that the ACEnhibitor arm may have disadvantaged since therst add-on therapy was a �-blocker instead of aiuretic or CCB. Furthermore, the significance ofeaching secondary end points without attainingignificant differences in the primary end point isnclear. ACE inhibitors are thus a mainstay in thereatment of hypertension, either as monotherapyr in combination with other medications, al-hough there can be a variable response, especiallyn certain populations such as blacks and thoseith renal disease.

HF

rial data supporting the use of ACE inhibitors inhe treatment of CHF secondary to systolic dys-unction is well supported in numerous large,rospective, randomized trials (CONSENSUS,OLVD-prevention and treatment, SAVE, V-HEFT)Table 3). Participants in these large trials hadew York Heart Association (NYHA) class II–

V with an EF �0.40 and were treated withither enalapril, captopril, or a combination ofydralazine and nitrates (V-HeFT). In all of thetudies, a treatment advantage using ACE inhibi-ors versus other treatment regimens was consis-ently found with respect to an absolute reductionn death and hospitalization and arrhythmic deathn certain groups. These benefits were further-

ore independent of age, sex, and the baseline usef diuretics, aspirin, and �-blockers and thoughto involve reduction in preload and afterload, at-enuation of myocardial wall stress (which is aowerful stimuli for myocardial remodeling), na-
riuresis, reduction in ADH and aldosterone pro-

Table 3. Summary of Trials of ACE-inhibitors in Heart Failure

CONSENSUS-I23SOLVDTreatment24 V-HeFT25

SOLVDPrevention26 SAVE27 AIRE28 TRACE29

Patients (N) 253 2569 804 men 4228 2231 2006 1749Patient

characteristicsNYHA-IV CHF LVEF �0.35,

NYHA II-III(90%)

NYHA II-III EF �0.35 EF �0.40 post-MI MI, clinical CHF Post-Im survivorswith depressedLV systolicfunction

Medications used(mg/d)

Enalapril 2.5-40.0vs placebo

Enalapril 2.5-20.0 Enalapril 20.0 orcombination ofhydralazine 300plus isosorbide160

Enalapril 2.5-20.0 Captopril 12.5-150.0

Ramipril 2.5-5 mg/d

Trandolapril 1 mgonce daily

Follow up 188 d 41.4 mo 2 y 37.4 mo 42 mo 6-30 mo 36 monthsResults Crude mortality in

placebo groupwas 44% vs26% in treatedgroup with 40%reduction inmortality(P � .002)

Mortality inplacebo groupwas 39.7% vs35.0% in treatedgroup(P � .0036)

Mortality inenalapril groupwas 18%compared with25% inhydralazine-isosorbide group(P � 0.016)

Mortality inplacebo groupwas 15.8% vs14.8% in treatedgroup(P � .12)

Mortality was 25%in placebogroup vs 20% incaptopril group(P � .019)

Mortalityreduction, 27%

Significantreduction ofrelative risk ofdeath (p �0.001) andcardiovasculardeath (p �0.001) versusplacebo; risk ofrecurrent MIwas notsignificantlyreduced (p �0.29)

Remarks No difference insudden death

Little evidence ofarrhythmic deathreduction

Enalprilatarrhythmicdeaths in lesssymptomaticpatients

29% mortalityreduction,althoughstatisticallyinsignificant;20% reductionin combineddeath andhospitalization(P � .001)

Trandoloprildecreases deathfromcardiovascularcauses for MIsurvivors withdepressed LVEF

29TRACE: Am J Cardiol. 1994;73:44C-50C

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uction, downregulation of overall vascular sym-athetic tone, and an increase in bradykininoncentration. Whether these beneficial actions ofCE inhibitors extends to all cohorts with pre-

erved left ventricular function and stable CAD, aower-risk population for cardiovascular events,as at the time unclear and prompted additional

tudies (PEACE, TRACE, and HOPE). In theEACE study, the ability of add-on ACE inhibitorherapy in reducing major coronary events in pa-ients with known stable low-risk CAD and a leftentricular EF �40% who were already receivingontemporary management was assessed. Signifi-ant endpoints achieved in this study included aeduction in the incidence of cardiovasculareath, nonfatal MI, or a coronary revasculariza-ion procedure. Of note, the ACE inhibitor se-ected in this trial was trandolipril because it hadreviously been found in TRACE to reduce mor-ality in patients with post-MI left ventricular dys-unction. The two other independent landmarkrials were HOPE (ramipril) and EUROPA (perin-opril). In HOPE, patients randomized to theCE inhibitor ramipril achieved a significant 22%

eduction in the combined primary endpoint ofardiovascular death, MI, or stroke versus pla-ebo, prompting a debate whether to continueEACE or not. It was suggested that there were

mportant cohort differences between HOPE andEACE and that the study should continue. Forxample, PEACE trial participants were younger,ess hypertensive or diabetic, more likely to havendergone coronary revascularization, and on dif-

erent drug regimens prior to randomization.

Table 4. Summary of Trial

SAVE27 AIRE28 TRACE29

atients (N) 2231 2006 1749opulationcharacter

LVEF �40% CHF LVEF �4

reatment durationpost-MI

3-16 d 3-10 d 3-7 d

rug and dose (mg) Captopril12.5-50.0 tid

Ramipril2.5 bid

Trandola1-4 qd

ollow-up period 24-60 mo 6-30 mo �24 mootal mortality (%) Control: 24.6

Treated: 20.4Control: 23Treated: 17

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Abbreviations: bid, twice a day; CHF, congestive heart failure; Lid, three times a day.

hus, these studies have identified different co- t

orts with significantly different levels of risk foruture cardiovascular outcomes and may help indentifying patients who may benefit from ACEnhibitor monotherapy or in combination withRBs17 (CHARM Added Trial).In contrast to systolic heart failure, it is esti-ated that up to 47% of heart failure can occur

econdary to isolated diastolic dysfunction.30 Inhis patient population, �-blockers or CCBs arehe initial choice for drug therapy unless diastolicysfunction is secondary to left ventricular hyper-rophy associated with hypertension, in whichase ACE inhibitors and/or ARBs may be usedlone or in combination with other agents.

cute MI

CE inhibitor therapy is recommended for all pa-ients post acute MI, preferably given within 24ours if there is no contraindication.31 Several

arge prospective, randomized trials have demon-trated that ACE inhibitors improve survival foratients after MI and slow the progression toHF32 (Table 4). This benefit of ACE inhibition isreatest in patients with an anterior MI or severelyepressed left ventricular systolic function andanifests soon after therapy is initiated. In theRACE trial, designed to investigate if trandola-ril would decrease death from cardiovascularauses for MI survivors with depressed left ven-ricular systolic function, 1749 patients were ran-omized either to trandolapril or placebo. Over atudy period of 24 to 50 months, 304 patients34.7%) in the trandolapril group died compared

CE Inhibitors in Acute MI

SMILE CATS ISIS-4 GISSI-3

1556 298 58050 19000Acute MI,

postthrombolysis

Acute MI Hypotension

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Within first24 h

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he relative risk (RR) of death in the trandolaprilroup as compared with the placebo group was.78, and the relative risk of sudden death was.76; both results are statistically significant. Pro-ression to severe heart failure was less frequent inhe trandolapril group (RR, 0.71; 95% confidencenterval [CI], 0.56 to 0.89; P � .003), but the riskf recurrent MI was not reduced. The only studyot to show a significant survival benefit wasONSENSUS II, which assessed whether startingnalapril therapy early post-MI improves 6-monthurvival. In this trial, 6090 patients were random-zed to either placebo or intravenous enalapril.he life-table mortality rates in the 2 groups at 1nd 6 months were not significantly different6.3% and 10.2% in the placebo group versus 7.2%nd 11.0% in the enalapril group; P � .26).37 Thistudy was terminated early by Safety Committeeecause of the high probability that a beneficialffect may not be demonstrated and concern overdverse hypotensive side effects in the elderly.his trial, however, stimulated other studies tolarify the role of early administration of an oralCE inhibitor in acute MI (see Table 4).Overwhelmingly, these latter studies demon-

trated a benefit of early administration of ACEnhibitors (within 24 hours) in the setting of acute

I. Furthermore, a benefit from a combinationherapy of ACE inhibitor with other agents such as-blockers has also been demonstrated (GISSI-3nd ISIS-4).34 In these trials, 30% of the total mor-ality reduction was observed in patients treatedith ACE inhibitors within 24 hours of symptomnset, with the combination of ACE inhibitorsnd �-blockers demonstrating an additive benefitaverage age 79, asymptomatic left ventricularysfunction EF �40%, post-MI randomized to ei-her �-blocker, ACE inhibitor, or combined ACEnhibitor and �-blocker therapy with the combi-ation therapy reducing the development of neworonary events by 37% versus 25% by �-blockerlone and 17% by ACE inhibitor alone; and re-uced progression to CHF by 60% versus 41% by-blocker alone and 32% by ACE inhibitorlone).34

It can, therefore, be recommended that admin-stration of an oral ACE inhibitor within 24 hoursf an acute MI should be the standard of care ifhere is no contraindication. While data is lacking
ith respect to the duration of ACE inhibitor ther- m
py, it is generally recommended that it be contin-ed indefinitely post MI because of beneficial ef-

ect on remodeling and retardation of progressiveeft ventricular dilatation. In support of this hy-othesis are observations that in humans, ACE isarkedly increased at the edge of the infarct scar

nd that the incidence of left ventricular dilatationost-MI is increased in patients with the ACE-DDenotype (a genotype associated with increasedCE activity). Acute administration of ACE inhib-

tor therapy not only limits the degree of myocar-ial damage and the degradation of high phos-hate stores; it also restores endothelial-ependent arteriolar dilatory capacity andecreases plasminogen activator inhibitor-1PAI-1) concentrations.35 PAI-1 is the primary in-ibitor of the tissue fibrinolytic pathway and inhi-ition of PAI-1 contributes to the prevention ofeinfarction.36,37 This effect is more pronouncedor ACE inhibitors with strong tissue-penetratingffects, (e.g. quinapril �enalapril) and may not beclass effect of ACE inhibitors.38 Finally, in high-

isk patients with acute MI complicated by CHF,he AG-II receptor blocker valsartan has beenhown to be as effective as captopril (not superiorut noninferior) with the combination of bothalsartan and captopril having no additional ben-fit (VALIANT).39 In this double-blind study,703 patients post-MI were followed up for aean duration of 24.7 months with no significant

ifference in the mortality rate.

rrhythmia

t has been observed in TRACE that trandolaprilecreases the incidence of atrial fibrillation in pa-ients with reduced systolic function post-MI40

ersus placebo. Similar observations have alsoeen reported for enalapril decreasing the inci-ence of atrial fibrillation in the setting of leftentricular dysfunction (SOLVD).41 Additionally,aptopril in ISIS-4 was found to decrease the inci-ence of ventricular arrhythmias. Postulatedechanisms include a reduction of myocardialall tension, interference with ion currents, sym-atholytic activity, and reduction of electrical het-rogeneity within the myocardial substrate. Cur-ently, however, no recommendations can beade for the use of ACE inhibitors as antiarrhyth-
ic drugs.

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therosclerotic Vascular Diseases, Stroke, androgression of CAD

bservations that ACE inhibitors reduce the inci-ence of recurrent angina and MI in patients with

eft ventricular dysfunction (SAVE and SOLVD)as prompted studies of the effects of ACE inhib-

tors on vascular tissue beyond blood pressureeduction. The HOPE, BANFF, EUROPA, PEACE,nd PROGRESS trials are prototypical. In theOPE trial, 9541 patients aged 55 or older and atigh risk for cardiovascular events without leftentricular dysfunction or heart failure were ran-omized in a 2 � 2 factorial design to receive 1 ofregimens: ramipril 10 mg/d, placebo, or vitamin. The study was terminated early because resultsemonstrated benefits in the ramipril group: aighly significant 22% reduction in relative risk inrimary outcome, a composite of MI, stroke, andeath from cardiovascular causes, and also indi-idual causes. Notably, complications related toiabetes were also reduced (16%).42 In contrast,he BANFF trial was a comparative study of 4ntihypertensives assessing their ability to im-rove endothelial dysfunction in patients withnown CAD. A total of 80 patients randomized toof the 4 groups received either quinapril 20 mg,

nalapril 10 mg, losartan 50 mg, or amlodipine 5g daily for 8 weeks. Only quinapril, a highly

issue-specific ACE inhibitor was found to im-rove flow-mediated vasodilation as assessed byigh-resolution ultrasound.47 Results of thesetudies suggests that certain ACE inhibitors caneverse endothelial dysfunction in patients withype II diabetes or hypertension, and in patientsith high-risk CAD but with a normal blood pres-

ure. Proposed mechanisms of action include neu-ralization of superoxide radical formation andnhibition of PAI-1 expression in atheroscleroticrterial segments. Moreover, this beneficial actions more pronounced with ACE inhibitors display-ng higher tissue specificity such as ramipril anduinapril.44

Such mortality benefits have also been demon-trated in low-risk CAD patients (EUROPA trial).n this study, 12,218 low-risk patients with stableAD were treated with either perindopril (8 mg)r placebo in addition to other standard anti-isch-mic therapy with an average duration of fol-ow-up of 4.2 years. It was found that among pa-
ients with stable CAD, perindopril was associated i
ith a 20% reduction in the combined primaryndpoint of cardiovascular death, MI, or cardiacrrest was versus placebo.45 Thus, although ACEnhibitors had been previously shown to be effec-ive in other subgroups such as left ventricularysfunction, heart failure, and high-risk CAD,his trial was the largest to show a benefit in low-isk CAD. Similar results have been found inEACE and the APRES trial (discussed below).he purpose of the PEACE trial was to assesshether the addition of trandolapril to standard

herapy will reduce the incidence of cardiovascu-ar mortality, nonfatal MI, or the occurrence of aoronary artery bypass graft surgery or percutane-us transluminal coronary angiography in pa-ients with CAD and preserved left ventricularunction. In APRES,46 patients with chronic stablengina, left ventricular ejection fraction 30% to0%, and no clinical heart failure who had eitherypass surgery or angioplasty were treated withamipril. At 33 months, ramipril significantly re-uced the composite endpoint of cardiac death,cute MI, or clinical heart failure (10% versus 23%or placebo; risk reduction 58%; 95% CI 7 to 80)ndependent of the left ventricular ejection frac-ion and the method of revascularization (bypassurgery or angioplasty). A 30% decrease in MI,troke, and cardiovascular death was observed in297 patients with a history of stroke or MI orther risk factors taking ramipril over an averageollow-up period of 4.5 years. This benefit wasbserved irrespective of age, entry blood pressure,resence of other cardiovascular risk factors, andoncurrent use of other standard medical treat-ent.47

Interestingly, ACE inhibitor therapy has alsoeen found to significantly reduce carotid intimalhickness compared to placebo and vitamin EPROGRESS and other studies).48,49 The formerrial was a double blinded, placebo-controlled,andomized trial in which the primary endpointas fatal or nonfatal stroke, the secondary end-oints were fatal or disabling stroke, total majorascular events (a combination of fatal or nonfatalI, fatal or nonfatal stroke), death, hospital ad-issions, cognitive impairment, and dementia.atients randomized to the treatment group re-eived either 4 mg/d of perindopril or perindoprilmg/d plus indapamide 2.0 to 2.5mg/d; patientsere followed for 4.1 years. Other nonstudy med-

cations included antihypertensive medications

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50%), antiplatelet therapy (77%), and lipid-low-ring agents (15%). The participants in this trialere 6105 patients from 172 centers in 10 coun-

ries with history of stroke or transient ischemicttack within the past 5 years. In the group treatedith ACE inhibitors, a risk reduction of 28% (95%I 17% to 38%; P � .0001) was observed. This

isk reduction began to appear after 1 year of ther-py with a decrease in ischemic stroke by 24%95% CI 10 to 35; P � .005), cerebral hemorrhagey 50% (95% CI 26 to 67; P � .005), and nonfatalr disabling stroke by 33% (95% CI 15% to 46%).he use of ACE inhibitors in atherosclerotic vas-ular diseases, stroke, and progression of CAD isherefore well-justified.

enal Failure

he use of ACE inhibitors and ARBs in patientsith renal impairment and diabetic nephropathy

s supported by several studies that demonstrateheir renoprotective effects by reducing albumin-ria, delaying the progression to end-stage renalisease49,50 and improving mortality.51 This ben-fit is independent of the blood pressure reductionnd has a more robust effect in type I versus type IIiabetic patients with a combination of ACE in-ibitor and ARB being superior to that of the sin-le agent.52 The renoprotective mechanism of ac-ion of ACE inhibitors and ARBs may involve aeduction of the intraglomerular pressure, a localnti-fibrinogenic effect of ACE inhibitor, and in-ibition of various local cytokines such as trans-

orming growth factor-�.53

The clinical use of ACE inhibitors in renal fail-re can be a significant source of concern for phy-icians because of concerns of exacerbating renalailure and pre-renal acute tubular necrosis. As aeneral guideline, an increase in the pretreatmenterum creatinine up to 30% may normally occurue to ACE inhibitor–mediated dilatation of thefferent glomerular arterioles and is not a valideason to discontinue therapy. However, an in-rease in the serum creatinine to a level greaterhan 30% may indicate renal intolerance or a sec-nd cause for renal deterioration and shouldrompt withholding therapy until renal function

mproves. One useful algorithm for the use of ACEnhibitors and ARBs with renal insufficiency sug-ests the following: for an increase in the blood
rea nitrogen and or plasma creatinine by less h
han 50%, maintain the dose of the ACE inhibitor;or an increase 50% to 100% decrease the dose by0%; for an increase in serum creatinine greaterhan 100%, stop the medicine. Typically, most ofhe increase in creatinine will stabilize in 2 to 3eeks and will not progress. Another source of

oncern may be ACE inhibitor–mediated hyper-alemia. This, however, is typically mild (0.4 to.6 mmol/L) and self-limited.58 Concurrent riskactors, however, for significant hyperkalemia in-lude potassium intake especially in food, substi-uted salts, and dry fruit; concomitant aldosteronentagonism or ARB use; and a baseline creatinineevel greater than 144 �mol/L.

Side Effects and Contraindications

he use of ACE inhibitors in clinically indicatedonditions at recommended doses has been estab-ished as safe and effective. As with all drugs, rec-gnition and management of drug side effects andoxicity is critical. Provided in Table 5 is a reviewf the major ACE inhibitor side effects listed byrgan system.ACE inhibitors are generally safe and well-tol-

rated in patients with advanced compensatedeart failure with poor left ventricular systolic

unction. It is important to ensure that the patients not volume depleted; an abrupt decline in AG-IIevels can precipitate hypotension and can be ofarticular importance in the elderly or in thoseith heart failure who are at a higher risk for

Table 5. Side Effects of ACE Inhibitors

ObstetricFetal abnormalities

CVSHypotension

RespiratoryCough (10-44%)

GastrointestinalHepatic toxicityTaste disturbances

RenalHyperkalemiaDeterioration of renal functionProteinuria

DermatologicRash (1%)Angioneurotic edema (0.1-0.2%)

HematologicNeutropenia (�0.005%)

ypotension and in which the dose of ACE inhib-

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tor can be typically reduced by half. Additionalosing concerns are as follows: ACE inhibitorherapy may need to be actively downtitrated oremporarily withheld in unstable patients such ashose with decompensated heart failure, hypoten-ion, and azotemia, pending renal and hemody-amic recovery. All patients undergoing activerug titration should have clinical follow-upithin 7 to 10 days to assess the full antihyperten-

ive effect of the drug as well as renal tolerancend electrolyte changes. If the target blood pres-ure has not been achieved on follow-up, the dosean be gradually titrated to target doses used in theforementioned major clinical trials.

Other side effects of ACE inhibitors includeough and angioneurotic edema. The develop-ent of a nonproductive cough is thought to beediated by inhibition of bradykinin or substancecatabolism55 and can occur in up to 44% of

atients; this is more common in patients of Asianthnicity. While excluding other causes of cough,RBs offer an alternative. Angioneurotic edema isn uncommon side effect that may occur with anncidence of 0.1% to 0.2% and is more prevalent inhe black population. Although angioneuroticdema typically occurs within the first 2 weeks ofnitiating ACE inhibitor therapy, it may take placeears later and is an absolute contraindication forCE inhibitor use thereafter.Important drug–drug interactions to recognize

nclude, but are not limited to the following: (1)ntacids, which can reduce the bioavailability ofCE inhibitors; (2) digoxin and lithium, serum

evels may be increased by ACE inhibitors; (3)ombination use of ACE inhibitors, ARB, potas-ium-sparing diuretics or potassium supplementsncreasing the risk for hyperkalemia; (4) nonste-oidal anti-inflammatory agents, which may atten-ate the antihypertensive effect of ACE inhibitorsy inhibiting prostaglandin formation; and (5) as-irin, which at higher doses may attenuate theenefit of ACE inhibitors (a dose of 81 mg/d cane used when concurrently using an ACE inhibi-or; low-dose aspirin appears to offer the sameardiovascular protection as higher doses withess interference with ACE inhibition).56

Important contraindications to ACE inhibitorherapy include pregnancy, angioneurotic edema,hock, hypotension, bilateral renal artery stenosis,nd prior significant worsening of renal function
ith ACE inhibitors (see Table 5).
ACE Inhibitors and ARBs

he major use of ARBs in addition to or in substi-ution of ACE inhibitors may be appreciatedhrough an understanding of the ACE escape con-ept, which is a decrease in the efficacy of ACEnhibitors secondary to an increase in circulatingG-II levels from chronic ACE inhibition. Tovercome this excess AG-II concentration, ARBs,hich competitively block AG-II receptor bind-

ng, may be used. And although AG-II receptorpregulation may occur, experimental data sug-est that there is insufficient AG-II to overwhelmhe ARB drug concentration at the receptor site tochieve full receptor occupancy. This suggestshat ACE inhibitors and ARBs may have an addi-ive effect, which is supported experimentally innimal heart failure models produced by rapidtrial pacing. For example, a combination ofenazeprilat and valsartan versus benazeprilatlone has been shown to improve myocyte �-ad-energic response, retard post-MI deleterious re-odeling, reduce circulating catecholamine lev-

ls, and improve myocyte shortening velocity andlobal ventricular function.56-58 A list of FDA-ap-roved ARBs is provided (Table 6). Specific dis-ases in which ARBs may be used include theollowing:

Hypertension: ARBs have been found to beequally effective as ACE inhibitors and do notcause a cough.60 Their effect on left ventricularregression, however, a powerful independentpredictor of mortality, is unclear.Heart failure: Although ACE inhibitors havebeen shown to improve survival, there are cur-rently insufficient data to support using ARBsas a first-line therapy in place of ACE inhibitorsin the treatment of heart failure.65 They may,however, be considered in patients who areACE inhibitor intolerant.Diabetic nephropathy: ACE inhibitors reduce al-buminuria and prevent progression of diabeticnephropathy in patients with type 1 diabetesmellitus, whereas ARBs are proven to be reno-protective in patients with type 2 diabetes mel-litus.66

Chronic renal failure patients not due to diabetes:There still exists controversy if ARBs have the
same renoprotective effects as ACE inhibitors.

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Conclusions

he RAAS is an important neurohormonal path-ay that can be targeted by ACE inhibition in the

uccessful management of cardiovascular dis-ases. Thus, whenever possible, ACE inhibitorshould be used in the treatment of patients withcute MI, asymptomatic or symptomatic left ven-ricular dysfunction, diabetic nephropathy, renalailure, and hypertension. Furthermore, this ther-py should generally be implemented taking intoonsideration a patient’s hemodynamic profile,ace, renal function, comorbidity, concurrentedications, patient compliance, tolerance, and

ost. Although there are insufficient data to rec-mmend the duration of therapy for patients witheft ventricular dysfunction after MI, it is the sug-ested that ACE inhibitors be continued indefi-itely given their beneficial effects on cardiac re-odeling, which may occur over a period of many

ears. For ACE inhibitor intolerant patients, ARBshould be considered in certain situations and asescribed. The current challenge for investigators

s to determine which effects of ACE inhibitors areclass effect and which are attributable to the drug

tself such as tissue specificity. For example, canhe findings of quinapril and ramipril be extrapo-ated to other ACE inhibitors? The answer to thisuestion is not currently known. We thereforeuggest that the ACE inhibitor prescribed shoulde the one that was used in a specific trial tochieve the positive clinical outcome attained inhat study.

Selected Clinical Pearls

1. Captopril requires tid dosing, enalapril bid,

Table 6. Angioten

enericame Trade Name

andesartan Atacand, AstraZeneca, Molndal, Swedenprosartan Tevetan, Solvay Pharmaceuticals, Mariet

Georgia, USArbesartan Avapro, Sanofi-Synthelabo, Paris, France

osartan Cozaar, Merck, Westpoint, PAlmesartan Benicor, Sankyo Pharma, Parsippany, N

USAalsartan Diovan, Novartis, East Hanover, NJ, USA

all the others qd, based on their pharmaco-

kinetic profiles, making captopril usefulwhen an initial challenge is needed and mak-ing enalapril a less reasonable choice thanwhen it was first introduced.

2. Trandolapril, quinapril, benazapril, and ra-mapril (in that order) have greater lipophi-licity (and thereby presumed tissue ACE in-hibition) than the other ACE inhibitors.Inhibition of tissue ACE likely has clinicalrelevance regarding the following:a. Inhibition of the formation of angiotensin

II in cardiac and vascular muscle cells;inhibition of macrophage migration intoplaque.

b. Enhancement of the effects of prostaglan-din and NO in the endothelium.

c. Regression of ventricular hypertrophyand of vascular smooth muscle hypertro-phy; ventricular remodeling.

d. Reduction of plaque instability and coro-nary vasoconstriction.

e. Possibly in the magnitude of the reduc-tion of proteinuria.

To note in this regard: Quinapril was moreeffective at increasing endothelium-depen-dent, brachial artery flow-mediated vasodi-lation than enalapril or losartan in hyperten-sive patients with coronary disease whendosed to similar blood pressure reductionlevels47; and b) trandolapril reduced rein-farction (and sudden death) in its post-MItrial67 unlike the post-MI data with otherACE inhibitors, which is consistent with ef-fects on plaque stabilization and endothelialfunction. Because lisinopril is likely differ-ent in these respects than trandolapril, rama-

eceptor Blockers

Dose(mg/d)

Bioavailability(%)

t1/2 toPeak (h) Clearance

4-32 15 3-4 Urine 26%400-800 13 1-2 Feces 90%

Urine 7%75-300 60-80 1.5-2.0 Feces 80%

Urine 20%25-100 25-30 1 Urine 4%20-40 26 1-2 Feces 56-65%

Urine 35-50%80-320 25 2-4 Feces 83%

Urine 13%

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pril, and quinapril, one can speculate that

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the results of ALLHAT might have been dif-ferent if one of these high tissue penetratingACE inhibitors had been used in lieu oflisinopril.

3. Trandolapril has both hepatic and renalelimination; thus, it does not require doseadjustments in hepatic or renal dysfunction.

4. Trandolapril and lisinopril have the longesthalf-lives and are recognized in the Joint Na-tional Committee VI and VII reports as beingtrue once-a-day agents.

5. Trandolapril is the ACE inhibitor that hasbeen chosen for the PEACE trial, sponsoredby the National Institutes of Health, to studyeffects in CAD patients who have not yet hadan MI or left ventricular dysfunction.

6. Trandolapril (in the TRACE study) and ra-mapril (in the HOPE study) have beenshown to substantially reduce the develop-ment of diabetes.

7. Trandolapril reduced the incidence of atrialfibrillation in TRACE. As this observationhas not been made in other ACE inhibitortrials, it is not clear if this is a drug-specificor a tissue ACE inhibition specific effect, orwhether it just has not been adequately stud-ied with other ACE inhibitors.33,34,35,36

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The clinical use of angiotensin-converting enzyme inhibitors

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