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McMurray JJ, et al. "Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure". The New England Journal of Medicine. 2016. :.

Clinical Question

In patients with chronic heart failure receiving standard therapy, is the use of aliskiren safe and effective at improving heart failure-related morbidity and mortality?


In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Aliskiren alone did not meet the criteria for non-inferiority as compared to enalapril.

Major Points

Enalapril is an Angiotensin-converting-enzyme (ACE) inhibitor, used to treat congestive heart failure in adults. ACE inhibitors have been proven to reduce mortality and hospitalization in patients with chronic heart failure. Renin inhibitors block the activity of renin and cause vasodilation. Renin inhibitors are currently FDA approved for the treatment of hypertension. The safety and efficacy of the use of both a renin inhibitor alone, aliskiren, and a combination therapy of enalapril and aliskiren in this population are unknown.

The Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) study randomly assigned 2340 chronic heart failure patients with a reduced ejection fraction to the combination therapy of enalapril plus aliskiren, 2340 to aliskiren alone and 2336 to enalapril alone for the intention-to-treat principle. At a median follow-up of 36.6 months, the addition of aliskiren to enalapril let to an increase in adverse events without an increase in benefit for the primary composite outcome (hazard ratio in combination group compared to the enalapril group was 0.93, 95% [CI], 0.85 to 1.03; P= 0.17). The use of aliskiren alone did not meet criteria for noninferiority compared to the use of enalapril alone (hazard ratio in aliskiren group compared to enalapril was 0.99, 95% [CI], 0.90 to 1.10; P= 0.91 for superiority). Hypotension, renal dysfunction and hyperkalemia occurred more frequently in the combination therapy group than with enalapril. Rates of these events were similar in the aliskiren group and the enalapril, except for Hypotension, which was more common in enalapril alone than aliskiren alone. Compared with the value at randomization, the mean systolic blood pressure at 4 months was significantly lower with combination therapy than with enalapril alone (difference v. enalapril, -1.84 mmHg; 95% CI, -2.70 to -.098; P<0.001). The composite renal outcome (composite of death from renal cause, end-stage renal disease, or doubling of serum creatinine level) occurred significantly more often in combination therapy than in enalapril alone. At 4, 8 and 12 months, the decrease from baseline in the NT-proBNP concentration was greater in combination therapy than enalapril. The increase in hyperkalemia with combination therapy was greater among patients treated with an aldosterone antagonist (P <.0001) at baseline than among those who were not (P= 0.0146). Of note, this trial discontinued aliskiren treatment in patients with type 2 diabetes due to futility and safety concerns and findings in the aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) showing worse outcomes in diabetes patients treated with aliskiren compared to those treated with placebo.

Combination therapy of enalapril and aliskiren did not result in a lower risk of death from cardiovascular causes or hospitalization due to heart failure compared to enalapril alone. This finding contrasts those of earlier studies, which concluded the addition of an ARB to an ACE inhibitor was of some benefit. This difference is likely that this study was the first to require an evidence-based dose of an ACE inhibitor. The hazard ratio and difference for the primary composite outcome, death from cardiovascular causes or first hospitalization for worsening heart failure was not significant.


2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/ AHA Guideline for the Management of Heart Failure

  • The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors or ARBs in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, is recommended for patients with chronic HF or EF to reduce morbidity and mortality.
  • The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HF or EF to reduce morbidity and mortality.
  • The use of ARBs to reduce morbidity and mortality is recommended in patients with prior with prior or current symptoms of chronic HF or EF who are intolerant to ACE inhibitors because of cough or angioedema.
  • The use of aliskiren specifically is not directly address in these guidelines.

Study Design

  • Prospective, randomized, double-blind trial
  • N=7016
    • Enalapril plus Aliskiren (n= 2340)
    • Aliskiren (n=2340)
    • Enalapril (n=2336)
  • Setting: 43 countries
  • Enrollment: 2009-2013
  • (Median follow-up: 36.6 months
  • Analysis: Intention-to-treat
  • Primary outcome: Composite death from cardiovascular causes or a first hospitalization for heart failure

Inclusion criteria

Patients eligible for inclusion in this study had to fulfill all of the following criteria:

  • Patients ≥ 18 years of age, male or female.
  • Patients with a diagnosis of chronic heart failure
    • LVEF ≤ 35% at visit 1
    • Elevated BNP or NT-proBNP at visit 1: BNP ≥ 150 pg/ml
    • OR NT-proBNP ≥ 600 pg/ml
  • Patients must be treated with an ACE inhibitor at a stable dose for at least 4 weeks prior to visit 1
  • Patients must be treated with a beta blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to visit 1
  • Written informed consent to participate in the study and ability to comply with all requirements

Exclusion criteria

Patients with any of the following were excluded from participation in the study:

  • History of hypersensitivity to any of the study drugs including history or allergy to ACEi’s as well as known or suspected contraindications to the study drugs or previous history of intolerance to high doses of ACEi’s during up-titration process.
  • Patients treated concomitantly with both ARB and aldosterone antagonist in addition to study drug at visit 1.
  • Current acute decompensated HF
  • Symptomatic hypotension and/or less than 95 mmHg SBP at visit 1 and/or less than 90 mmHg SBP at visit 4.
  • Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months prior to visit 1.
  • Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after visit 1.
  • Right heart failure due to severe pulmonary disease.
  • Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to visit 1.
  • Patients with a history of heart transplant or who are on a transplant list or with LVAD
  • Documented ventricular arrhythmia with syncopal episodes within past 3 months, prior to visit 1, that is untreated.
  • Documented history of ventricular tachycardia or ventricular fibrillation without ICD producing significant hemodynamic consequences or considered life-threatening within the 3 months prior to visit 1.
  • Treatment with Vaughn Williams Type Ic antiarrhythmic agents.
  • Symptomatic bradycardia, or second or third degree heart block without a pacemaker. 14.Implantation of a CRT (cardiac resynchronization therapy) device within the prior 3 months from visit 1 or intent to implant a CRT device.
  • Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
  • Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs
  • Serum potassium ≥ 5.0 mmol/L at visit 1 or ≥ 5.2 mmol/L at visit 4
  • History or presence of any other diseases (i.e. including malignancies) with a life expectancy of < 5 years.
  • Current double-blind treatment in HF trials.
  • Participation in an investigational drug study at the time of enrollment or within the past 30 days or 5 half lives of enrollment whichever is longer.
  • Any surgical or medical condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety.
  • History of noncompliance to medical regimens and patients who are considered potentially unreliable.
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG)
  • Women of childbearing potential
    • defined as all women physiologically capable of becoming pregnant
      • women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
      • women whose partners have been sterilized by vasectomy or other means
  • Chronic long-term requirement for NSAIDs (high dose) or COX 2 inhibitors, with the exception of aspirin at doses used for CV prophylaxis (≤ 325 mg o.d.).
  • Current treatment with cyclosporine and/or itraconazole at visit 1.
  • Treatment with any of the following drugs within the past 4 weeks prior to visit 1:
    • Direct renin inhibitor including aliskiren
    • Intravenous vasodilators and/or intravenous inotropic drugs
  • Patients with diabetes mellitus according to investigator discretion (e.g. medical history, therapy for diabetes mellitus, local laboratory test i.e. HbA1c, fasting blood glucose, oral glucose tolerance test).

Baseline Characteristics

From the aliskiren group.

  • Age: 63.3 years
  • Female: 22.7%
  • Race: White 64.9%, Asian 25.3%, Black 1.6%
  • Cause of heart failure
    • Ischemic cardiomyopathy 55.3%
    • Nonischemic cardiomyopathy 44.7%
  • NYHA functional class
    • II: 64.0%
    • III: 34.3%
    • IV: 1.6%
  • Physiological Measure
    • Heart Rate: 72 beats/min
    • Systolic BP: 124 mm Hg
    • BMI: 27.4
  • Laboratory Measure
    • NT-proBNP: 1167 pg/mL
    • Estimated GFR: 74 mL/min
  • Medical History
    • Hypertension 62.4%
    • Diabetes 26.8%
    • Atrial fibrillation 33.7%
    • Hospitalization for HF 59.1%
    • MI 39.7%
    • Stroke 7.1%
  • Medications at randomization
    • Digitalis 32.0%
    • Diuretic 79.1%
    • Beta-adrenergic blocker 91.2%
    • Mineralocorticoid antagonist 36.9%
  • Device for treating HF at screening visit
    • Defibrillating device 15.5%
    • Cardiac-resynchronization therapy 5.1%

There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%,), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%) and an elevated potassium level (17.1% vs. 12.5%)

  • These were the only values that showed significant differences among groups.


The trial included a two-part run-in phase:

  • After switching from their existing ACE inhibitor, eligible patients entered the first part of the run-in phase, during which they received 1 to 4 weeks of enalapril at a dose of 5 mg twice daily, in a single-blind fashion, followed (if the level of adverse events was not unacceptable) by 2 to 4 weeks of enalapril at a dose of 10 mg twice daily; patients who had been taking a dose of ACE inhibitor that was equivalent to 20 mg of enalapril daily before the trial could start at the second step directly. At the end of this period, patients were stratified according to the dose of enalapril that could be taken without unacceptable adverse events: 5 mg twice daily (low-dose stratum) or 10 mg twice daily (high-dose stratum).
  • Patients then entered the second part of the run-in phase, during which they received aliskiren at a dose of 150 mg once daily, in a single-blind fashion, in addition to enalapril. Patients who could take both treatments were randomly assigned, in a 1:1:1 ratio, to double-blind, double-dummy treatment in one of three groups with the use of a voice-based computerized randomization system involving concealed trial-group assignments. Patients were assigned to the combination of enalapril at a dose of 5 or 10 mg twice daily and aliskiren at a dose of 150 mg once daily, aliskiren at a dose of 150 mg once daily, or enalapril at a dose of 5 or 10 mg twice daily. Two weeks after randomization, the dose of aliskiren was increased to 300 mg once daily in the combination-therapy group and the aliskiren group, with sham adjustment in the enalapril group. Patients were evaluated every 2 to 8 weeks during the first 4 months and every 4 months thereafter. The dose could be decreased in patients who could not take the target doses.


Comparisons are aliskiren vs. enalapril vs. combination therapy at 36.6 months.


Death from cardiovascular causes or hospitalization for heart failure

Combination-Therapy Group

770 patients (32.9%) (11.7 events per 100 patients)

Aliskiren Group

791 patients (33.8%)

(12.1 events per 100 person-years)

(hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10)

Enalapril Group

808 patients (34.6%)

(12.4 events per 100 person-years)

(hazard ratio Combination-Therapy vs. Enalapril, 0.93; 95% confidence interval [CI], 0.85 to 1.03)


Death from cardiovascular causes, hospitalizations for heart failure, nonfatal myocardial infarction, nonfatal stroke, or resuscitated cardiac arrest

Combination-Therapy Group

841 patients (35.9%)

(Hazard Ratio Combination-Therapy vs. Enalapril, 0.94; 95% confidence interval [CI], 0.86 to 1.04)

Aliskiren Group

874 (37.4%)

(Hazard Ratio Aliskiren vs. Enalapril, 1.01; 95% confidence interval [CI], 0.92 to 1.11)

Enalapril Group

877 patients (37.5%)

(Hazard Ratio Aliskiren vs. Enalapril, 1.01; 95% confidence interval [CI], 0.92 to 1.11)

Change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score.

Combination Therapy vs. Enalapril (Hazard ratio; -0.03; 95% confidence interval [CI], -1.56 to 1.50)


The effect of combination therapy as compared with enalapril was consistent for the primary outcome across the prespecified sub-groups, as was the effect of aliskiren as compared with enalapril.

Adverse Events

Combination-therapy group vs. enalapril group

  • Higher risk of hypotensive symptoms (13.8% vs. 11.0%, P=0.005, NNH=36)
  • Higher risks of elevated serum creatinine level (4.1% vs. 2.7%, P=0.009, NNH=72)
  • Higher risks of elevated potassium level (17.1% vs. 12.5%, P<0.001,NNH=22)
  • Composite renal outcome (1.7% vs. 0.8, p=0.007, NNH=112)


  • Possible errors due to diabetes patients having to switch therapies half-way through.

(Mandate that persons with diabetes at baseline and those in whom diabetes developed during the present trial discontinue the treatment and be switched to conventional therapy and that no further patients with diabetes be enrolled.)


  • Funded by Novartis Pharmaceutical Company, manufacturer of aliskiren (brand name: Tekturna)


1. Drug Approval Package: Tektuma (Aliskiren) Tablets [Internet]. U.S. Food & Drug Administration. 2007 [cited 28 April 2017]. Available from:

2. Lommi J. Chronic Heart Failure [Internet]. Essential Evidence Plus. 2016 [cited 28 April 2017]. Available from:

3. Yancy C, Jessup M, Bozkurt B, Butler J, Casey D, Colvin M et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure [Internet]. 2017 [cited 28 April 2017]. Available from: