Comparative Analysis Suggests ACE Inhibitors Equivalent to ARBs in Patients Without Heart Failure

Blockade of the renin-angiotensin-aldosterone-system with either an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor provides similar protection from cardiovascular events in patients with cardiovascular disease or risk factors, according to the results of a new meta-analysis.

Although ACE inhibitors are favored over ARBs in the US and European guidelines, the findings challenge the current thinking that ARBs are inferior to ACE inhibitors for reducing the risk of mortality or MI, say investigators.Comparative Analysis Suggests ACE Inhibitors Equivalent to ARBs in Patients Without Heart Failure

“We started with ACE inhibitor trials in the late 80s and 90s, and when compared to placebo, ACE inhibitors were shown to reduce not only mortality but also MI,” lead investigator Sripal Bangalore, MD, New York University School of Medicine, told TCTMD. “In other words, they were shown to have a profound effect. And positive trials tend to have a long-lasting, lingering effect on everybody, including physicians and the guidelines.”

ARBs emerged later, he noted, with randomized trials conducted between 2000 to 2010, but these clinical trials did not consistently show a mortality benefit compared with placebo. “This led many people to say, including the guideline writers, that ACE inhibitors are better and should be the frontline treatment,” said Bangalore.

In the meta-analysis, published January 2016 in the Mayo Clinic Proceedings, the researchers studied 106 randomized trials that enrolled 254,301 patients without heart failure. Compared with placebo, treatment with an ACE inhibitor significantly reduced mortality by 11% and cardiovascular mortality by 17%, with additional relative risk reductions for MI, stroke, heart failure, new-onset diabetes, and other endpoints. 

In contrast, the placebo-controlled trials with ARBs showed no such benefit. Overall, there was no effect on all-cause or cardiovascular mortality and no effect of treatment on MI risk. Stroke, heart failure, new-onset diabetes were significantly reduced with the ARB class, however.

Their study also examined clinical trials comparing ACE inhibitors and ARBs against active controls as well as against each other. In the active-control studies, the use of an ACE inhibitor significantly reduced the risk of MI by 12% but did not show a reduction in mortality, whereas ARBs versus an active-control arm showed no benefit in terms of mortality or MI. In the head-to-head studies, the outcomes between the 2 drug classes were equivalent. 

Generation Gap

To TCTMD, Bangalore noted the placebo-controlled studies with ACE inhibitors and ARBs were conducted in different eras. For example, in the studies of ACE inhibitors, 18 of the 32 trials were conducted after 2000 and only 9 studies were conducted after 2005. All 18 studies comparing an ARB against placebo were conducted after 2000, with 14 conducted after 2005.

To more fully understand this “generation gap,” the researchers examined the effect of the placebo event rate on clinical outcomes, noting that the lower the placebo event rate, the greater the likelihood the trial would not show a benefit on mortality or MI endpoints. The higher event rate in the control arm of the ACE inhibitor studies explained the difference in clinical outcomes between the drug classes, according to the group. A sensitivity analysis restricted to clinical trials performed after 2000 confirmed the assessment, showing no difference between the 2 drugs except that ARBs showed better tolerability than ACE inhibitors.

When the ACE inhibitor trials were conducted, lifestyle choices were very different, said Bangalore. “There were a lot more smokers, for example,” he said. “The guidelines were less stringent about blood-pressure control. There was no statin use, no aspirin. So when you start with a high-risk group of patients it’s easier to show a benefit. When ARBs came around, there were a lot less smokers and the guidelines had already changed.”

With the different era, and the shift toward tighter blood pressure and cholesterol control among other risk factors, it became more difficult to show a significant reduction in death or MI with the relatively newer agents, said Bangalore.

Drug Classes Used Interchangeably

Jan Griffin, MD, of Johns Hopkins Hospital (Baltimore, MD), told TCTMD that he believes ARBs can be used interchangeably with ACE inhibitors, although at his center they usually start an ACE inhibitor first. “We typically tend to go for an ACE inhibitor as our first choice; however, if patients have a sensitivity or adverse reaction to an ACE inhibitor, often an ARB can take its place,” said Griffin. “For example, patients can develop a dry cough associated with ACE inhibitor, in which case an ARB is an appropriate alternative. In addition, if a patient has previously tolerated either agent well, we will stick with what has been tried and tested.”

ACE inhibitors are also cheaply available as generic medications, and while some ARBs are off patent, not all agents are available generically. Whether a particular ARB is available as a generic factors into their clinical decision-making, said Griffin.

James Stein, MD, University of Wisconsin Medical School (Madison, WI), said they generally consider ARBs and ACE inhibitors interchangeable for hypertension. Both are “equally safe and effective, [with ARBs] slightly better tolerated, ” From a research standpoint, the present analysis “illustrates the perils of comparing active agents indirectly by looking at their effects relative to control groups that may be different,” Stein told TCTMD.

Bangalore S, Fakheri R, Toklu B, et al. Angiotensin-converting enzyme inhibitor or angiotensin receptor blockers in patients without heart failure: Insights from 254,301 patients from randomized trials. Mayo Clin Proc. 2016;91:51-60.

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  • Bangalore reports receiving honorarium from Abbott, Boehringer Ingelheim, Daiichi Sankyo, Merck, Gilead, and Pfizer.
  • Griffin and Stein report no conflicts of interest.

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