ACE Inhibitors vs.

ARBs for
Myocardial Infarction
Am Fam Physician. 2007 Jun 15;75(12):1854-1856.
Background: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor
blockers (ARBs) are used for similar indications. ACE inhibitors have demonstrated reductions in
cardiovascular morbidity and mortality, and are used to prevent nephropathy and treat
hypertension. One advantage of ARBs is that they do not produce cough, an adverse effect of
ACE inhibitors that occurs in less than 10 percent of all patients and in less than 5 percent of
patients when compared with controls. Winkelmayer and colleagues performed a head-to-head
comparison of ACE inhibitors and ARBs in terms of effectiveness and mortality outcomes after
myocardial infarction.
The Study: The authors used claims data from four drug entitlement programs to find patients
discharged from the hospital after myocardial infarction. Patients who were released from the
hospital within 30 days and survived at least 90 days were included in the study. Sex, age, race,
comorbid conditions, and health care usage indicators were abstracted from the claims data.
Data about filled prescriptions also were obtained.
Results: Of the 43,416 postmyocardial infarction patients participating in one of the drug
entitlement programs, 14,612 were eligible and had filled a prescription for an ACE inhibitor or an
ARB within 90 days after admission, and 422 filled a prescription for both medications.
Over the 10-year study, an increasing proportion of new patients received only an ARB, with 17.6
percent receiving a new prescription in 2004, up from 2.7 percent at the beginning of the study.
Of the group using ACE inhibitors, ARBs, or both, 16.1 percent died within one year of
experiencing a myocardial infarction. The difference between ACE inhibitor and ARB users who
died was not significant: one-year mortality was no different after univariate analysis (hazard ratio
[HR], 0.92; 95% confidence interval [CI], 0.80 to 1.05) or multivariate analysis (HR, 1.04; 95% CI,
0.88 to 1.22).
Conclusion: The authors found that ARB use after myocardial infarction increased over the
course of the study but with no additional health benefit. All-cause mortality was similar
regardless of whether the patients were taking an ACE inhibitor or an ARB. This is similar to the
findings in two randomized trials, which also showed no difference between drug classes, and, of
note, no benefit from taking an ACE inhibitor and an ARB simultaneously. Because the percentage of persons on ARBs greatly exceeded the expected percentage of patients with a cough
from an ACE inhibitor, this was likely not the reason for the increased use of ARBs. Eighteen
percent of postmyocardial infarction patients on ARBs had never used ACE inhibitors. Together
with those who switched from or used combinations including ACE inhibitors, the percentage of
patients taking ARBs represents overuse of this class of drugs. ACE inhibitors should be the firstline drugs after myocardial infarction, and the much more expensive, but no more effective, ARBs
should be reserved for patients with cough or angioedema related to ACE inhibitors.
CAROLINE WELLBERY, MD

SOURCE
Winkelmayer WC, et al. Angiotensin inhibition after myocardial infarction: does drug class
matter? J Gen Intern Med. December 2006;21:12427.

ACE Inhibitors Versus ARBs: Clinical Evidence

Roberto Ferrari; Eric Boersma
Disclosures
Expert Rev Cardiovasc Ther. 2013;11(6):705-717.
The results the authors obtained and reported above indicate that ACE inhibitors
and ARBs have different effects on mortality reduction in hypertension, although
they both act on the RAAS and may appear similar at first glance; ACE inhibitors
and ARBs share many of the same clinical benefits, such as BP reduction, stroke
reduction and improvement of heart failure symptoms[26]and both are used to treat
cardiovascular risk factors in different types of cardiovascular disease. [27] All this
raises the question, if ACE inhibitors and ARBs have so many clinical benefits in
common, why are there differences in the way they reduce mortality in
hypertension?
If one looks beyond hypertension, this is not the first report of differences in
mortality reduction between ACE inhibitors and ARBs. In a meta-analysis of MI in
11 randomized controlled ARB trials versus active treatment or placebo in 55,050
patients,[28] nine trials had excess rates of MI, which reached significance in two
trials (one trial vs placebo and one trial vs active treatment [amlodipine]). ARBs
significantly increased the risk of MI by 8% (95% CI: 116; p = 0.03) and had no
effect on all-cause mortality (odds ratio = 1.01; 95% CI: 0.961.06; p = 0.80). A
parallel analysis of 150,943 patients in 42 ACE inhibitor trials showed that ACE
inhibitors significantly reduced all-cause mortality, cardiovascular death and MI by
9% (95% CI: 0.860.95), 12% (95% CI: 0.820.95) and 14% (95% CI: 0.820.90)
versus placebo and all active comparators, including ARBs (all p < 0.001). [28]
This lack of mortality reduction with ARBs was further underlined by Bangalore et
al. in 2011 in a systematic review of 37 ARB studies in 147,020 patients with
hypertension, heart failure, stroke, acute MI, coronary artery disease or newonset diabetes mellitus.[29] The review found that ARBs were not associated with
any reduction in the RR of all-cause mortality (RR = 1.00; 95% CI: 0.971.02; p =
0.75) or cardiovascular mortality (RR = 0.99; 95% CI: 0.941.04; p = 0.73)
compared with controls.[29]However, the majority of these data were retrospective
and thus not randomized.

Two randomized controlled trials prospectively investigated whether there is a

difference in outcome between ACE inhibitors and ARBs ONTARGET (in
patients with high cardiovascular risk)[30] and DETAIL (in patients with diabetic
nephropathy).[31] The results of these trials suggested there was no difference in
outcome, but reductions in BP with the ARB and ACE inhibitor were different: the
ARB telmisartan reduced BP more than ramipril in ONTARGET and more than
enalapril in DETAIL. It is worth noting that in both trials a long-acting ARB was
compared with a short-acting ACE inhibitor given once daily in the morning.
The relationship between BP decrease and reduction in cardiovascular risk is not
straightforward; as is the case in the ONTARGET and DETAIL trials, large
decreases in BP do not always lead to large decreases in the risk of
cardiovascular outcomes and mortality.[14,21,22] The mean systolic BP reductions
achieved with ARBs in three randomized controlled trials 3.2 mmHg in the
SCOPE study, 4 mmHg in the TRANSCEND study and 3.8 mmHg in theh
PRoFESS study did not translate into better reduction of cardiovascular
outcomes and mortality risk versus placebo. Several ARB meta-analyses have
also shown that BP reduction with ARBs, regardless of comparator, does not
reduce the risk of MI.[3234] By contrast, there is evidence that BP-dependent
beneficial effects in the prevention of stroke and heart failure are similar for ACE
inhibitors and ARBs.[35]
The reverse may also be true: small decreases in BP may lead to important
decreases in cardiovascular risk. In a meta-analysis of 26 randomized controlled
trials featuring 146,838 hypertensive patients, [35]ACE inhibitors caused small
decreases in BP but induced an additional 9% BP-independent reduction in the
RR of coronary heart disease (95% CI; 314%) in addition to the reduction in RR
of coronary heart disease from BP reduction. This meta-analysis of the Blood
Pressure Lowering Treatment Trialists' Collaboration also showed that ARBs had
the opposite effect; they increased the BP-independent RR of coronary heart
disease by 8% (95% CI: -1739), and the difference between ACE inhibitors and
ARBs was significant (p = 0.002).[35]
In view of these data, differences in BP-independent effects between ACE
inhibitors and ARBs,[35] such as diminution of oxidative stress and endothelial
dysfunction, improvement in glucose metabolism, and inhibition and stabilization
of atherosclerotic plaque, might account for some of the differences seen in
mortality reduction between these two types of RAAS inhibitor.[36] Other
differences between ACE inhibitors and ARBs exist, notably the way in which

they act on the RAAS, and these may also explain the differences in mortality
reduction.