NEW YORK (Reuters Health) – The combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) is often prescribed for elderly patients who do not have trial-established indications for its use, a Canadian population-based study shows.
Randomized controlled trial data have shown that patients with proteinuria or symptomatic left ventricular systolic dysfunction despite treatment with an ACE inhibitor or ARB alone benefit from the combination of the two.
In their study, Dr. Finlay McAlister and colleagues found that less than one-seventh of the elderly residents of Alberta who were prescribed the two drug combo over about four and half years had either of these indications.
Dr. McAlister, of University of Alberta, said he was not surprised by this, telling Reuters Health: “Often the assumption is made that if two drugs alone are beneficial, then the combination of the two must be even more beneficial. The ON-TARGET trial showed that in this case that wasn’t true (more harm with the combination of the two agents).” (See Reuters Health Report Aug. 14, 2008).
Similarly, Dr. McAlister’s group found greater than two-fold increased risks of renal dysfunction and hyperkalemia with dual ACE/ARB therapy in their cohort.
They published their findings March 21 in CMAJ (Canadian Medical Association Journal).
The “take home message,” Dr. McAlister said, “is that, as clinicians, we should be cautious about extrapolating too far away from the randomized trial evidence.”
To study the safety of combination ACE/ARB therapy in clinical practice, the researchers analyzed data on 32,312 elderly individuals who started an ACE inhibitor and/or an ARB between May 1, 2002 and December 31, 2006. Their mean age was 76 years.
A total of 1,750 of these patients (5.4%) received both drugs and 1,512 (86.4%) of these patients did not have trial-proven indications such as heart failure or proteinuria.
In a Cox proportional hazards model, dual therapy (compared with monotherapy) was associated with a greater than two-fold excess risk (HR, 2.36) of the primary outcome: a doubling of serum creatinine, development of end-stage renal failure or death from any cause. Patients in their 80s and beyond were at greatest risk.
For renal dysfunction, event rates per 1,000 patients per month were 5.2 with combination therapy versus 2.4 for monotherapy. For hyperkalemia, events rates were 2.5 vs 0.9.
The investigators note that “although the absolute risks appear to be relatively low in our cohort of elderly patients, a 0.52% monthly risk of adverse renal outcomes is not insubstantial for a drug combination that would need to be taken for years to show any nephroprotective or cardioprotective effects.”
The investigators also observed that most of the patients on combination therapy stopped at least one of the drugs within three months, on average. They speculate that this may have been due to low blood pressure, although they can’t say for sure because blood pressure measurements were not part of the dataset.
CMAJ 2011.
