CMAJ: Combining ACE inhibitors + ARBs in elderly increases death, kidney failure

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Combining angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in elderly patients increased kidney failure and death when compared with monotherapy, according to a study published in the March 21 issue of the Canadian Medical Association Journal.

"Renin-angiotensin system combination therapy with concurrent use of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers confers additional benefits over the use of either agent alone for certain patients who have diabetic nephropathy or advanced systolic dysfunction of the left ventricle," the authors wrote. However, previous trials have shown an increased risk of renal dysfunction in patients  administered combination therapy.

Finlay A. McAlister, MD, of the University of Alberta in Canada, and colleagues evaluated the safety of a combination ACE and ARB therapy in 32,312 seniors aged 65 and older in the Alberta, Canada, region. The researchers compared patients receiving the combination therapy and patients who received only monotherapy between May 1, 2002, and Dec. 31, 2006.

Patients' mean age was 76.1 years, median creatinine levels were 92 umol/L and 1,750 patients received combination therapy. However, one-seventh of the patients who were administered the combination therapy did not have trial-established indications such as heart failure or proteinuria.

The researchers reported a higher risk of adverse events—high creatinine levels, end-stage renal disease and death—in patients administered combination therapy. 

In fact, renal dysfunction was more common among patients administered combination therapy as compared to those administered monotherapy, 5.2 events per 1,000 patients per month vs. 2.4 events per 1,000 patients per month. Rates of hyperkalemia were also higher in patients given the combination therapy compared with those given monotherapy, 2.5 events per 1,000 patients per month vs. 0.9 events per 1,000 patients per month.

Twelve percent of patients only took the combination therapy for a short time period--a median time period of three months. The authors suggested that hypotension may have been a limiting factor for this elderly population and the reason why therapy was ceased.

The researchers reported that of the 350 patients in whom the primary outcome was seen during follow-up, 120 showed a doubling in serum creatinine, 20 had end-stage renal disease and 234 died.

"Our most striking findings were that combination therapy was commonly prescribed for patients who did not have the trial-proven indications and that it was frequently stopped after only a few months, even when hyperkalemia or renal dysfunction did not occur," concluded the researchers.

McAlister and colleagues said that trial limitations could have stemmed from the fact that they may have underestimated the frequency with which the treatment was stopped and the risk of adverse events.