ARB/ACE-Inhibitor Combo a Risk in Clinical Practice

March 24, 2011

March 24, 2011 (Edmonton and Calgary, Alberta) — In clinical practice and as has been seen in clinical trials, combining an angiotensin-converting enzyme (ACE) inhibitor with an angiotensin-receptor blocker (ARB) more than doubles the risk of both renal failure and hyperkalemia compared with receiving only one of the agents, concluded researchers based on data from elderly patients in Alberta [1].

The findings, published online March 21 in CMAJ, belie the view by some that in actual practice, individualized dosing strategies can avoid the adverse effects from combined ACE-inhibitor/ARB therapy seen in clinical trials, according to the authors, led by Dr Finlay A McAlister (University of Alberta, Edmonton).

The "real-world" data they looked at came from >24 000 persons aged >66 years in Alberta who were new users of an ACE inhibitor, ARB, or both and in whom serum creatinine was measured both before and after starting on the drugs.

More striking than the risk increases, according to the group, was that a whopping 86% of patients who took both medications did not have clinical-trial–verified indications for taking them together. Those indications would include proteinuria or symptomatic LV systolic dysfunction despite therapy with either an ACE inhibitor or ARB.

In the analysis, dual-drug therapy was often stopped after only a few months, usually with the patient continuing on either the ACE inhibitor or ARB; the authors speculate that the reason was hypotension, as there were only minor changes in renal function and potassium levels.

"I'm not surprised that use of this combination of agents by these clinicians was often not guideline-based, as often the assumption is made that if two drugs alone are beneficial, then the combination of the two must be even more beneficial," McAlister said to heartwire in an email.

"The ONTARGET trial showed that in this case that wasn't true. [There was] more harm with the combination of the two agents. Our study confirms the risks of this combination in nontrial participants."

The current analysis borrowed a renal-outcomes end point from ONTARGET for use as its primary end point: "doubling of serum creatinine, development of end-stage renal disease requiring dialysis, or all-cause death" within six months of starting treatment with one or both of the drugs.

The primary end-point rates were 2.4 events/1000 patients per month among the 23 376 patients taking only one of the agents and 5.2 events/1000 patients per month for the 1424 on both types of drug. In multivariate analysis, the hazard ratio for the end point for dual-agent therapy vs monotherapy was 2.36 (95% CI 1.51–3.71).

The rates of hyperkalemia were 0.9 and 2.5/1000 patients per month, respectively; the hazard ratio for dual-drug vs monotherapy was 2.42 (95% CI 1.36–4.32).

The hazard ratios, according to McAlister et al, "closely mirror those reported in randomized controlled trials."

As previously covered by heartwire , ONTARGET randomized 25 620 patients with CHD or diabetes plus other CV risk factors who were >55 years of age and free of heart failure to receive the ACE inhibitor ramipril, the ARB telmisartan, or a combination of the two and followed them for a mean of 55 months [2].

The strategies were noninferior to each other in terms of the primary end point of CV death, MI, stroke, or heart-failure hospitalization, but combination therapy was associated with more renal dysfunction, hypotension, and gastrointestinal upset compared with ramipril alone.

"The ONTARGET investigators should be congratulated for doing the randomized trial to definitively establish whether a combination of two efficacious drugs would be more or less useful than either one alone," McAlister said. "There are too few of those types of randomized trials."

McAlister is supported by a "salary award from the Alberta Heritage Foundation for Medical Research." Disclosures for the coauthors are listed in the paper. ONTARGET was sponsored by Boehringer Ingelheim.

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