Time for Guidelines to Recommend ARBs Over ACE Inhibitors?

A long-running dispute as to the supremacy of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in the treatment of cardiovascular disease should be put to bed once and for all, say the authors of a new review.

“Given the equal outcome efficacy but fewer adverse events with ARBs, risk-to-benefit analysis in aggregate indicates that at present there is little, if any, reason to use ACE inhibitors for the treatment of hypertension or its compelling indications,” write Franz Messerli, MD (Mount Sinai Medical Center, New York, NY), and colleagues in the April 3, 2018, issue of the Journal of the American College of Cardiology.

“Ever since the HOPE study, published in 2000, ACE inhibitors have become a sacred cow and nobody dared to say anything against them,” Messerli told TCTMD.

The exception has been Messerli himself, along with one of the co-authors on the current review, Sripal Bangalore, MD (NYU Langone Medical Center, New York, NY). Both have for years argued in favor of ARBs because they have fewer side effects than ACE inhibitors, which are an older class of drugs. Others have consistently stood by the older agents on the grounds that they do better at preventing mortality in patients with coronary artery disease, while ARBs have been linked to a higher risk of MI. The counterargument to that has been that ACE inhibitors were tested in trials now several decades old that predated other modern secondary prevention medications, most notably statins. ARBs, by contrast, went through testing on top of these more modern medicines.

In their review, Messerli and colleagues note that the first ACE inhibitor, captopril, came on the market in 1981, while the first ARB, losartan, debuted in 1995. Both agents are commonly used in patients with hypertension, heart failure, CAD, diabetes, and chronic kidney disease, but guidelines have tended to recommend ACE inhibitors as first-line therapy.

The upshot has been that payers, too, have preferentially covered ACE inhibitors, stating that ARBs were only suitable if a patient had failed ACE-inhibitor therapy. “If a physician used an ARB, he got a letter saying: use lisinopril first,” Messerli told TCTMD.

The JACC publication reviews the mechanisms of action for the two agents, as well as their effects on blood pressure, left ventricular hypertrophy, and proteinuria. Key outcomes studies and meta-analyses in patients without heart failure, including HOPE, CAMELOT, ALLHAT, and REACH, among others, do not support the superiority of ACE inhibitors over ARBs, the authors conclude. Indeed, in CAMELOT, which looked at patients with coronary artery disease, the ACE inhibitor studied was inferior to the ARB in the trial. Concerns that ARBs might increase the risk of MI have also been dispelled, Messerli et al write, “lead[ing] us to the conclusion that ARBs reduce CV events, including the risk of MI, as effectively as but more safely than ACE inhibitors.”

For other patient groups reviewed in the paper—including those with cerebrovascular disease, kidney disease, and diabetes—the bulk of the evidence shows ARBs to be equivalent or in some cases superior to ACE inhibitors, the authors write. Patients with heart failure have long been the group wherein ACE inhibitors are preferred over ARBs, but here, too, the evidence supports equivalence in terms of efficacy, Messerli and colleagues conclude.

Contacted by TCTMD, heart-failure specialist John McMurray, MD (University of Glasgow, Scotland), pointed out that ACE inhibitors were tested in clinical trials in heart failure before ARBs were available and were shown to reduce mortality. That made it difficult, subsequently, to do a placebo-controlled trial with an ARB in heart failure, he noted. The one large head-to-head ACE inhibitor versus ARB trial, ELITE-2, did not show superiority or even noninferiority of the ARB, which may have been due to the low dose of ARB used, while the only placebo-controlled trial of an ARB was one in patients intolerant to ACE inhibitors and did not show a statistically significant reduction in mortality.

“That was probably to do with its relatively small size and the benefits of the ARB tested were broadly similar to those of an ACE inhibitor,” McMurray said in an email. “However, because neither of these ARB trials gave as clear a demonstration of benefit as the prior ACE-inhibitor trials in heart failure, ACE inhibitors remain preferred over ARBs.”

All of this, to some extent, is water under the bridge in the era of neprilysin inhibitors, he added. “In heart failure, we now know that adding a neprilysin inhibitor to an ARB is better than an ACE inhibitor (or probably an ARB) alone,” McMurray concluded.

Same Upsides, Different Downsides

That leaves side effects. As Messerli and colleagues point out, the bulk of the evidence supports a higher rate of side effects with ACE inhibitors, the most common being cough. To TCTMD, Messerli stressed that angioedema in patients taking ACE inhibitors is rare, “but not something you can just neglect completely.”

For many years, the best argument in favor of ACE inhibitors was that they were cheaper in the same period that ARBs were perceived as too heavily marketed by their manufacturers. “There was a time when all ACE inhibitors were generic and practically no ARB was generic, so clearly cost was a distinct issue and that made it very difficult to use ARBs instead of ACE inhibitors,” Messerli told TCTMD, adding the newest ARB, azilsartan (Edarbi; Arbor Pharmaceuticals) is still on-patent in many countries. “But all the other ARBs are generic, and they cost pretty much the same as the ACE inhibitors,” he said.

Salim Yusuf, MD (McMaster University, Hamilton, Canada), who led a number of the major ACE inhibitor trials, has been an outspoken advocate for ACE inhibitors. In an email to TCTMD, Yusuf dismissed the angioedema issue, calling it “very rare.” He also disagreed with Messerli’s cost assessment, saying: “In most countries, ARBs are still quite a bit more expensive than ACE inhibitors, even when both are generic, and this is a very important consideration of which one to use. . . . For the majority of patients, ACE inhibition is to be preferred because it is more affordable, especially in low- and middle-income countries.”

Messerli, for his part, says he has heard these same arguments for years and believes the time has come for guidelines to change. Indeed, he said, many physicians are already opting for ARBs over ACE inhibitors, when cost or payers are not barriers.

“The newest [American Heart Association/American College of Cardiology] guidelines and the upcoming European guidelines actually put both ARBs and ACE with regard to efficacy in the same class, and they consistently state, ‘an ACE inhibitor or an ARB’ can be used—there is no longer any priority given to the ACE inhibitor,” he noted.

Because of the side-effect profile, Messerli said he would like to see guidelines go one step further: “The guidelines are changing, and I think they will change more and more. I would like to see an ARB as first-line and only if for some reason or another not tolerated, then the patient could be continued with an ACE inhibitor.”