Aliskiren/Enalapril Combination Therapy Led to More Adverse Events in Chronic Heart Failure

The addition of aliskiren to enalapril led to more adverse events in patients with chronic heart failure without an increase in benefit.

The addition of aliskiren to enalapril led to more adverse events in patients with chronic heart failure (HF) without an increase in benefit, according to results from the ATMOSPHERE (the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure) trial.

Lead investigator John J.V. McMurray, MD, of the British Heart Foundation Cardiovascular Research Centre, presented the study findings at the 2016 Annual American College of Cardiology Scientific Sessions & Expo in Chicago.

Investigators set out to explore 3 hypotheses: to determine whether or not combination therapy of aliskiren added to enalapril would be superior to enalapril alone, to determine if aliskiren monotherapy would be superior to enalapril, and to determine whether the latter would at least be noninferior.

ATMOSPHERE was conducted in 43 countries at more than 800 sites with a total of 8835 patients initially screened. Of these patients, 1771 did not fulfill the inclusion criteria and additional 48 were enrolled erroneously. For the intention-to-treat analysis, 2340 patients were assigned to combination therapy, 2340 to aliskiren alone, and 2336 to enalapril alone.

Eligible patients had chronic HF with New York Heart Association (NYHA) class II to class IV symptoms and an ejection fraction of ≤35% at baseline. They also had plasma B-type natriuetic peptide (BNP) concentrations of 150 pg/mL, or N-terminal proBNP (NT-proBNP) concentrations of ≥600 pg/mL.

Patients were also required to have been receiving “stable doses” of an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker (equivalent of ≥10 mg/day of enalapril).

The primary outcome was a composite of cardiovascular death or a first hospitalization for heart failure. Secondary outcomes included change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score from baseline to 12 months, as well as change in the NT-proBNP concentration from baseline to 4 months.

During the course of the trial, the Clinical Trial Facilitation Group of the Heads of Medicines Agencies in Europe mandated that all patients with diabetes (either at baseline or that had developed during the trial) discontinue the treatment and be switched to conventional therapy. This mandate was the result of premature termination of 2 other clinical trials, ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease End points) and ASTRONAUT (Aliskiren Trial on Acute Heart Failure Outcomes), due to safety issues and futility.

Researchers therefore revised the statistical analysis to reflect this change in the trial. As they explained in a simultaneously publication in the New England Journal of Medicine, “In patients with diabetes, follow-up for trial outcomes was censored on the date of the enactment of the protocol amendment (or on the date of other country-specific requests mandating the stopping of the trial treatment. Comparison of combination therapy with enalapril in patients without diabetes because an additional superiority hypothesis.  The change in the NT-proBNP concentration was removed as a secondary outcome.”

The primary outcome occurred in 770 patients in the combination therapy group (11.7 events per 100 person-years), 791 patients in the aliskiren group (12.1 events per 100 person-years), and 808 patients in the enalapril group (12.4 events per 100 person-years).

The combination therapy group compared with the enalapril group had a hazard ratio [HR] of 0.93 (95% confidence interval [CI]: 0.85-1.03; P=.17). Similarly, the HR in the aliskiren group compared with the enalapril group was 0.99 (95% CI: 0.90-1.10; P=.91 for superiority). “Although the noninferiority margin of 1.104 was met with the use of the 95% CI, the one-sided P value of 0.0184 did not fulfill the prespecified requirement of a P value of 0.0123 or less,” the researchers wrote.

In addition, there were no statistically significant differences in KCCQ score or other prespecified secondary outcomes.

“All adverse events [prespecified hypertension, renal impairment, and hyperkalemia] were more common in combination therapy than in monotherapy,” Dr McMurray stated in his presentation. “This finding differs from prior ARB [angiotensin-receptor blockers] add-on trials and may reflect a difference in study design—in that the previous trials did not require an evidence-based dose of ACE inhibitor.”


  1. McMurray JJV, for the ATMOSPHERE Committees Investigators. LBCT V. Direct rennin-inhibition with aliskiren alone and in combination with enalapril, compared with enalapril, in heart failure (the ATMOSPHERE trial). Presented at the 65th Annual American College of Cardiology Scientific Sessions & Expo. April 2-4, 2016; Chicago, IL.
  2. McMurray JJV, Krum H, Abraham WT, et al; for the ATMOSPHERE Committees Investigators. Aliskiren, enalapril, or aliskiren and enalapril in heart failure. N Engl J Med. doi: 10.1056/NEJMoa1514859.