Time to Ditch ACE Inhibitors for CVD?

April 05, 2018

There is "little, if any, clinical reason" to use angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension or other cardiovascular indications because angiotensin receptor blockers (ARBs) are just as effective with fewer side effects, a new review concludes.

The review, published in the Journal of the American College of Cardiology on April 3, was led by Franz Messerli, MD, University Hospital, Bern, Switzerland.  

Messerli and colleagues reviewed data from 119 randomized clinical trials of ACE inhibitors and ARBs in more than half a million patients and found no difference in efficacy between the two drug classes with regard to the surrogate endpoint of blood pressure and the outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease.  

But ACE inhibitors have a higher incidence of adverse reactions — namely cough and very low risks of angioedema and fatalities — that are more prevalent in dark-skinned people, they write.

Despite this, most guidelines for the management of patients with cardiovascular disease recommend ACE inhibitors as first-choice therapy, whereas ARBs are merely considered an alternative for ACE inhibitor–intolerant patients, Messerli and colleagues point out.

"Because efficacy is similar but adverse events are fewer with ARBs, comprehensive risk-to-benefit analysis indicates that clinicians no longer have any valid reason to prescribe ACE inhibitors for the treatment of hypertension and its compelling indications. The present data are prone to swiftly archive ACE inhibitors into the list of drugs of historical interest only," Messerli said in a statement.

Sacred Cow

To theheart.org | Medscape Cardiology, he added: "Ever since the superb HOPE trial in 2000, ACE inhibitors have become a sacred cow. The original trials in coronary heart disease (CHD) were done with ACE inhibitors, and these trials were larger and the placebo event rates were higher than the later trials with ARBs, so it was easier to show convincing benefits. It has now become part of our culture to use ACE inhibitors in CHD."

But actually, ARBs are just as effective and have fewer side effects, he added. "Some may think the ACE inhibitor cough is just a nuisance, but it can cause patients to keep coming back to the doctor or stop taking the drug altogether," he noted. "And the side effect of angioedema, although rare, can be fatal, and if ACE inhibitors are proposed as part of the polypill then millions will be exposed and fatalities will occur. I hope our paper will make doctors think more fully about this."

Experts contacted by theheart.org | Medscape Cardiology had mixed reactions to the review.

"Dr Messerli and colleagues have conducted a very thorough review of the clinical trials and they are right that, by and large, there is no evidence that ACE inhibitors are more effective at reducing blood pressure or cardiovascular outcomes, and ARBs have fewer side effects," said hypertension expert Michael Weber, MD, SUNY Downstate College of Medicine, New York City. "Both are now available generically and are therefore relatively inexpensive, although ACE inhibitors are still slightly cheaper, which will make a difference in some communities."

"But if even only 5% of patients develop a cough and keep coming back because of it, the very small financial savings disappear straight away," Weber added. "This is particularly relevant in Asia where cough with ACE inhibitors occurs more frequently, and in Africa, as angioedema is more common in blacks."

George Bakris, MD, from the University of Chicago Medicine in Illinois, added: "Messerli and colleagues make some very good points. ACE inhibitors are older and have decade more data than ARBs. They are effective for slowing nephropathy and reducing events in heart failure, but so are ARBs. ACE inhibitors have a 20% cough incidence, closer to 50% in the Asian populations, ARBs don't. ARBs have placebo-like effects and should be started at the maximal dose. The argument by some is there is no good evidence for major cardiovascular event reductions with ARBs; however, the TRANSCEND trial did show a benefit on CV event reduction for telmisartan. In short, I do prefer ARBs to ACE inhibitors for most people, but primarily because ARBs have a greater blood pressure–lowering effect than ACE inhibitors — at least this was the case for azilsartan. So should we abandon ACE inhibitors? No, but they are not 'the end all be all.' "

Heart failure expert John McMurray, MD, University of Glasgow, United Kingdom, noted that ACE inhibitors were tested in clinical trials in heart failure before ARBs were available and were shown to reduce mortality. "Consequently, it was difficult, subsequently, to do a placebo-controlled trial with an ARB in heart failure."

He said that generally, ARB trials have not given as clear a demonstration of benefit as the prior ACE inhibitor trials, "so ACE inhibitors remain preferred in heart failure." But, he added, "Of course, 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."

Minor Issue

Lead investigator of the landmark HOPE trial, Salim Yusuf, MD, McMaster University, Hamilton, Ontario, Canada, commented that "Whether an ACE inhibitor or an ARB should be used is a minor issue as long as one or the other is used in people who need it."

He agreed with Messerli that efficacy is likely similar between the two classes of drugs, but there is less cough with ARBs and ACE inhibitors can cause the "very rare (one per thousand case)" angioedema.

But Yusuf pointed out that the major difference between ARBs and ACE is cost. "This may matter less in the 20% of people living in rich countries but does matter a lot in the 80% of people in low- and middle-income countries.

"I would leave the choice of ACE inhibitor or ARB to the clinician and the patient to use whatever they are comfortable with and what they can afford in their local setting," he said.

Yusuf also pointed out that the major issue is controlling blood pressure rather than worrying too much about specific agents used.

"Around 80% of patients with hypertension in the world do not have their blood pressure controlled using the <140/<90 threshold, and it is likely more than this if we use even lower thresholds. This is the big unmet clinical and public health need.

"I suggest that we spend more time and effort discussing how we can improve blood pressure control at low cost (combination of low doses of two or three different classes of drugs). That has the potential to avoid many hundreds of thousands of cardiovascular events than the side show of ACE inhibitor versus ARB."

Messerli has served as a consultant or advisor for Daiichi-Sankyo, P fi zer, Abbott Vascular, Servier, Medtronic, WebMD, Menarini, Ipca, Hikma, American College of Cardiology, Relypsa, and Sandoz.

J Am Coll Cardiol. Published online April 3, 2018. Abstract

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