Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE - ATMOSPHERE


The goal of the trial was to compare the safety and efficacy of aliskiren as add-on or monotherapy compared with enalapril in patients with symptomatic chronic heart failure (CHF).

Contribution to the Literature: The ATMOSPHERE trial suggests that aliskiren is not superior to enalapril either as monotherapy or as combination therapy in patients with CHF; criteria for noninferiority were also not met.

Study Design

Following an open-label run-in phase of 4-12 weeks, patients were randomized in a 1:1:1 fashion to either aliskiren 300 mg once daily (n = 2,340), enalapril 5 or 10 mg twice daily (n = 2,336), or enalapril 5 or 10 mg twice daily + aliskiren 300 mg once daily (n = 2,340).

  • Total number of enrollees: 7,012
  • Duration of follow-up: median 36.6 months
  • Mean patient age: 63 years
  • Percentage female: 22%
  • Percentage diabetics: 28%

Other salient features/characteristics:

  • Mean systolic blood pressure (SBP) 123 mm Hg
  • Beta-blockers: 92%

Inclusion criteria:

  • Age ≥18 years 
  • New York Heart Association class II-IV
  • Mean left ventricular ejection fraction ≤0.35
  • B-type natriuretic peptide (BNP) ≥150 pg/ml (NTpro-BNP ≥600 pg/ml) or if HF hospitalization within 12 months BNP ≥100 pg/ml (NTpro-BNP ≥400 pg/ml)
  • Background angiotensin-converting enzyme (ACE) inhibitor therapy equivalent to enalapril ≥10 mg/d
  • Beta-blocker unless contraindicated/not tolerated
  • SBP ≥95 mm Hg run-in/≥90 mm Hg at randomization
  • Estimated glomerular filtration rate (eGFR) ≥35 ml/min/1.73 m2 at randomization/no decrease >25% during run-in
  • Potassium <5.0 mmol/L run-in/<5.2 mmol/L at randomization

Exclusion criteria:

  • Symptomatic hypotension
  • SBP <95 mm Hg at screening (or <90 mm Hg at randomization)
  • eGFR <40 ml/min 1.73 m2 of body-surface area at screening (or <35 ml/min/1.73 m2 at randomization or a decline of >25% in the eGFR between screening and randomization)
  • Serum potassium concentration of 5.0 mmol or more per liter at screening (or ≥5.2 mmol/L at randomization)
  • History of inability to take ACE inhibitors

Principal Findings:

  • Primary outcome, cardiovascular death or CHF hospitalization for aliskiren + enalapril vs. enalapril: hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.85-1.03; p = 0.17 for superiority
  • For aliskiren vs. enalapril: HR 0.99; 95% CI 0.90-1.10; p  = 0.91 for superiority; p = 0.018 for noninferiority (not significant per prespecified threshold)

Secondary outcomes:

  • CHF hospitalization for aliskiren + enalapril vs. enalapril: p = 0.29; for aliskiren vs. enalapril: 0.91
  • Composite renal outcome for aliskiren + enalapril vs. aliskiren vs. enalapril: 1.7% vs. 1.1% vs. 0.8%, p = 0.18
  • Hypotension: 13.8% vs. 10.6% vs. 2.4%, p < 0.05 for both
  • Hyperkalemia: 5.0% vs. 3.0% vs. 3.6%, p = 0.02 and 0.29, respectively


The results of this trial indicate that aliskiren is not superior to enalapril either as monotherapy or as combination therapy in patients with CHF. It also did not meet criteria for noninferiority. There is a higher incidence of side effects with aliskiren, including hypotension and hyperkalemia.


McMurray JV, Krum H, Abraham WT, et al., on behalf of the ATMOSPHERE Committees Investigators. Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure. N Engl J Med 2016;374:1521-32.

Presented by Dr. John J.V. McMurray at the American College of Cardiology Scientific Session, Chicago, IL, April 4, 2016.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: ACC Annual Scientific Session, Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Enalapril, Glomerular Filtration Rate, Heart Failure, Hyperkalemia, Hypotension, Natriuretic Peptide, Brain, Stroke Volume

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