ACE Inhibitors Better ARBs in New Meta-Analysis in Hypertensives

April 23, 2012

April 23, 2012 (Updated April 26, 2012) (Rotterdam, the Netherlands) — A new meta-analysis has shown that use of ACE inhibitors is associated with a 10% reduction in all-cause mortality over four years in hypertensive patients, compared with contemporary therapy that included blood-pressure lowering with drugs other than ACE inhibitors or angiotensin-receptor blockers (ARBs) [1]. In contrast, ARBs had a neutral effect on deaths, note Dr Laura C van Vark (Erasmus Medical Center, Rotterdam, the Netherlands) and colleagues in their report, published online April 17, 2012 in the European Heart Journal.

Even a small reduction in mortality in absolute terms would translate into lots of lives saved, at little cost, because most ACE inhibitors are now available generically.

This is the first study that scientifically evaluates the value of renin-angiotensin-aldosterone-system (RAAS) inhibitors on mortality in their main indication of hypertension, say van Vark and colleagues. All previous findings of reductions in both cardiovascular morbidity and mortality with ACE inhibitors and ARBs have been in trials that primarily enrolled patients with indications such as heart failure and coronary artery disease, she and her colleagues note.

Coauthor Dr K Martijn Akkerhuis (Erasmus Medical Center) told heartwire : "These new findings provide an additional argument to treat patients with hypertension with ACE inhibitors. This provides an extra mortality benefit, albeit small in absolute terms (3.8 per 1000 patient-years), but remember this was in addition to contemporary background therapy with aspirin, statins, and other agents.

"Also, because millions suffer from hypertension, even a small reduction in mortality in absolute terms would translate into lots of lives saved, at little cost, because most ACE inhibitors are now available generically. This finding will enhance the widespread use of these agents as a first-line treatment option," he stresses.

Controversial Finding Should Be Interpreted With Caution

The researchers acknowledge that the differential effect between ACE inhibitors and ARBs "should be considered a post hoc observation and interpreted with caution." But Akkerhuis notes that a meta-analysis of 37 trials published last year also showed a neutral effect of ARBs on mortality in a broad population of patients. Dr Franz H Messerli (St Luke Roosevelt Hospital, New York, NY), who was senior author on this ARB meta-analysis but is not involved in the new research, told heartwire there are a couple of possible explanations.

Previous work has shown ACE inhibitors to be relatively more cardioprotective, whereas ARBs are more cerebroprotective, Messerli says. "Although stroke remains the most devastating complication of hypertension, many more people die of heart disease than of cerebrovascular disease. Thus, cardioprotection is prone to have a greater impact on mortality than cerebroprotection," he notes. And, on average, ARB trials were done more recently than ACE-inhibitor trials. "The event rate has been declining over the past few years due to concomitant statin treatment, etc, and obviously it is much harder to show benefits with low than with high event rates," he observes.

Dr Adrian Brady (University of Glasgow, Scotland), a European Society of Cardiology spokesperson on hypertension, says meta-analyses are "bouillabaisses. It depends what you put into them. van Vark [et al's] findings are based on a selected set of trials, but they leave out some crucial ones, principally ONTARGET, which would negate their findings." Also, they "chose mortality as the only end point to analyze, which is unusual for a study of people who are basically healthy and middle-aged. And four-year mortality doesn't really tell you lifetime mortality."

Several other meta-analyses have shown equivalence between ACE inhibitors and ARBs in terms of outcomes such as MI and stroke, he asserts, adding that, in his opinion, "avoiding a nonfatal stroke is the most important end point, and on this all [antihypertensive] drugs are broadly similar."

Lowering BP is the most important thing. Which drug you use is a long, long way secondary.

ACE inhibitors and ARBs "are both valuable classes of drugs," Brady stresses, and although there will always be individuals for whom one drug class is slightly better than another, "lowering BP is the most important thing. Which drug you use is a long, long way secondary."

Akkerhuis acknowledges: "What we found is kind of controversial. There are believers and there are nonbelievers. It would not surprise me if we get a lot of letters to the editor [on this]," he says, adding that there "should be more research on this topic."

Treatment Effect Results Entirely From ACE Inhibitors

van Vark et al analyzed 20 cardiovascular morbidity-mortality trials performed between 2000 and 2011; at least two-thirds of the patients in each trial had to have been diagnosed with hypertension--so that the expected benefits would come mainly from a decrease in BP--and randomized to treatment with a RAAS inhibitor or control (placebo, active control, or usual care).

They note that INVEST, ACCOMPLISH, and ONTARGET were excluded from the analysis because RAAS inhibitors were used simultaneously in both trial arms in these studies.

The evidence, apart from our study--the evidence in the whole spectrum of patients--is solid and substantial, and so much larger for ACE inhibitors than for ARBs.

Their cohort included 158 998 patients, 71 401 of whom took RAAS inhibitors and 87 597 control treatment. The incidence of all-cause death was 20.9 and 23.3 per 1000 patient-years in those randomized to RAAS inhibition and controls, respectively.

Overall, RAAS inhibition was associated with a 5% reduction in all-cause mortality (HR 0.95; p=0.032) and a 7% reduction in cardiovascular mortality (HR 0.93; p=0.018) over a mean follow-up of 4.3 years.

Although the primary aim was to evaluate RAAS inhibitors as a whole, ACE inhibitors and ARBs have partly different modes of action, so the researchers decided to also look at the two drug classes separately. Drilling down into the data in this way, they discovered that the observed treatment effect "resulted entirely from the class of ACE inhibitors," which were associated with a significant 10% reduction in all-cause mortality (HR 0.90; p=0.004), whereas no mortality benefit could be demonstrated with ARB treatment (HR 0.99; p=0.683).

This mortality reduction was found when compared with placebo as well as in comparison with a broad range of other contemporary risk-reduction strategies, including statins, antiplatelet therapy, beta blockers, and diuretics, van Vark et al note. "The findings are firm," they state.

Don't Change Treatment Recommendations at the Moment

This difference in treatment effect between ACE inhibitors and ARBs on all-cause mortality was statistically significant (p for heterogeneity=0.036). But the difference in effect on cardiovascular mortality between ACE inhibitors and ARBs was not, the researchers note, adding also that two previous studies designed to compare these two drug classes in a hypertensive population--ONTARGET and DETAIL--did not show a differential treatment effect.

"Thus, at present, the results of this analysis do not warrant changing clinical-practice treatment guidelines that recommend that an ARB may be used in ACE-inhibitor–intolerant patients," they state.

But Akkerhuis stresses that ACE inhibitors should be used as first-line treatment, unless there is a contraindication or the patient belongs to a group that is known not to respond well to ACE inhibitors (eg, African Americans).

"The evidence, apart from our study--the evidence in the whole spectrum of patients--is solid and substantial and so much larger for ACE inhibitors than for ARBs," he notes.

Brady observes, however, that while "it's always good to shake the tree of hypertension," ACE inhibitors themselves are not without drawbacks. There are a number of deaths per million users from angioedema with this drug class, and patient tolerability is an issue, with coughs on ACE inhibitors deterring many from taking their medication, he notes.

He adds that ARBs such as losartan and candesartan are now off patent in many markets, so cost comparisons between the two drug classes are also becoming less important.

van Vark and Akkerhuis have no conflicts of interest; disclosures for the coauthors are listed in the paper.

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