ARB/ACE-Inhibitor Combo Not Recommended in CHF

September 10, 2009

September 10, 2009 (Barcelona, Spain) — The combination of angiotensin-receptor blockers (ARBs) and ACE inhibitors should not be used to treat congestive heart failure (CHF), because the benefits do not outweigh the risks, according to the results of a new meta-analysis. Dr Andrea Kuenzli (University Hospital, Basel, Switzerland) reported the findings at the European Society of Cardiology 2009 Congress last week.

Kuenzli and colleagues found that the combination of ARB and ACE inhibitor reduced hospitalizations for heart failure but did not affect mortality or hospitalizations overall and was associated with adverse events. "Combination therapy is expensive and has the risk of serious side effects, such as hyperkalemia and worsening renal failure," senior author Dr Alain Nordmann (University Hospital) told heartwire . "[This] combination therapy should not be used unless you encounter a problem with treating a patient or the patient is not doing well on therapy with beta blockers and/or ACE inhibitors," he said.

Nordmann said it may be that specific heart-failure patients might benefit from this combination--for example, those with good renal function or younger patients--and that he and his colleagues had hoped to try to identify such candidates by performing an individual patient-data meta-analysis. "But unfortunately, the principal investigators of the trials that were industry sponsored--such as CHARM--were not willing to share their data, so we had to rely on aggregate data to conduct this meta-analysis."

Before anyone goes on to conduct another randomized controlled trial in this patient population, he says it "would be really helpful to do an individual patient-data meta-analysis, so that the patients who would benefit most from combination therapy could be identified."

Some Limitations to the Meta-Analysis

The researchers identified eight randomized controlled trials comparing combined therapy with ACE inhibitors and ARBs vs ACE-inhibitor therapy alone in patients with heart failure, with a minimal follow-up of six months. These included RESOLVD, ValHeFT, CHARM-Added, and VALIANT, with a total of 18 061 patients.

End points included overall mortality, hospitalizations for heart failure, hospitalizations for any reason, fatal and nonfatal MI, side effects--such as worsening renal function, hyperkalemia, and symptomatic hypotension--and discontinuation of study medication.

But the meta-analysis was limited in that there were only four trials that aimed at reaching the recommended full dose of the ARB and/or the recommended full dose of the ACE inhibitor and in which more than 50% of patients were taking a beta blocker, Nordmann explained.

In addition, "we could report only relative risk (RR) and were not able to report nonvalidity to treat or absolute RR, which would have helped us to weigh the number of side effects compared with the benefits of fewer patients being rehospitalized for heart failure," he said. An individual patient-data meta-analysis would have enabled the data to be presented in absolute terms, and additional subgroup analysis or time-to-event analysis could have helped identify those most likely to benefit, he noted.

Meta-analysis: Combined therapy with ACE inhibitors and ARBs vs ACE-inhibitor therapy alone in patients with heart failure

End point RR 95% CI p for heterogeneity
Mortality 0.97 0.92–1.03 0.49
Fatal MI 0.97 0.76–1.22


Nonfatal MI



Hospitalizations--CHF 0.81 0.72–0.91 0.04
Hospitalizations overall 0.92 0.82–1.05 0.03
Hyperkalemia 1.95 0.85–4.48 0.01
Renal dysfunction 1.91 1.40–2.60 0.11
Hypotension 1.57 1.43–1.71 1.0
Medication discontinued 1.21 1.07–1.37 0.14

The overall results show that the combined therapy of ARBs and ACE inhibitors does not reduce mortality in patients with heart failure, although it may reduce hospitalizations for heart failure, Nordmann said. But it led to more side effects and did not change overall hospitalization rates.

Avoid Combination Therapy in Most Patients

The clinical implications of these findings, for the time being, are that combined therapy should be considered only in patients with persistent heart-failure symptoms already taking ACE inhibitors and beta blockers, he noted, and that there should be close monitoring of blood pressure and serum creatinine levels in any patient taking this combination.

"The hope was always that a combination of an ACE inhibitor and an ARB would be better than monotherapy alone [in CHF] because from a pathophysiological point of view, it made sense, since the renin-angiotensin system [RAS] is not completely blocked by monotherapy," he explained.

Nordmann believes that another trial must be conducted to definitely answer the question of whether this combination of ARB and ACE inhibitor is beneficial or not and that in such a trial it is imperative that the CHF patients enrolled are already on optimal therapy with a beta blocker and/or ACE inhibitor. However, before this happens, "we should look at the data already out there and reanalyze these randomized controlled trials that have been published on an individual patient-data basis," he concluded.