Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure

Hannah Webb, Mercer University College of Pharmacy

 

It is stated that among patients with chronic heart failure, angiotensin-converting- enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is considered to be unknown. [1]

 

The Joint National Convention 8 (JNC8) recommends an ACE inhibitor or an angiotensin II receptor blockers (ARB) plus a beta blocker, a diuretic, and spironolactone for patients with heart failure. [2]

Title: Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure [3]
Design Randomized, double blind trial; N= 7,064
Objective To compare the ACE inhibitor enalapril with the renin inhibitor aliskiren by testing the superiority of one to the other or in combination in patients with heart failure and a reduced ejection failure
Study Groups Aliskiren (n= 2,340); enalapril (n= 2,336); combination therapy (n= 2,340)
Methods 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 2 to 4 weeks of enalapril at a dose of 10 mg twice daily. 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 or 10 mg twice daily. 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.
Duration 4.5 years
Primary Outcome Measure Composite of death from cardiovascular causes or a first hospitalization for worsening heart failure
Baseline Characteristics   Combination Therapy Aliskiren Enalapril
Average Age (years) 63.2 63.3 63.3
Sex (female %) 21.1 22.7 21.4
Hypertension 61.8% 62.4% 61.0%
Diabetes 28.4% 26.8% 27.9%
Atrial fibrillation 34.2% 33.7% 34.3%
Hospitalization for heart failure 60.2% 59.0% 59.8%
Myocardial infarction 41.7% 39.7% 40.4%
Stroke 7.2% 70.5% 6.7%
 
Results   Combin-ation Therapy Aliskiren Enalapril Combinatio-n Therapy vs. Enalapril

p value

Aliskiren vs. Enalapril p value
Death from cardiovascular causes 21.9% 562 547 0.23 0.34
First hospitalization for worsening heart failure 18.37% 442 452 0.29 0.91
Adverse Events Common Adverse Events:
  Combination Aliskiren Enalapril
Symptomatic hypotension 7.4% 148 139
Renal dysfunction 1.7% 20 30
Hyperkalemia 8.1% 116 144
Cough 8.2% 152 164
Serious Adverse Events:
  Combination Aliskiren Enalapril
Cardiac failure 6.60% 7.37% 6.35%
Atrial fibrillation 11.12% 13.29% 10.96%
Pneumonia 8.48% 9.20% 7.97%
Sudden death 4.18% 3.79% 3.67%
Percentage that Discontinued due to Adverse Events: combination (44.2%), aliskiren (40.5%), enalapril (41.9%)
Study Author Conclusions It was found that the addition of the renin inhibitor aliskiren to enalapril did not result in a lower risk of death from cardiovascular causes or hospitalization due to heart failure, as compared with enalapril alone, but did cause more side effects including hypotension, renal dysfunction, and hyperkalemia. Noninferiority was not shown for aliskiren as compared with enalapril.

 

The study showed that there is a therapeutic ceiling for blockade of the renin-angiotensin system beyond which there is little to no additional efficacy and only more adverse effects. Clinically, this study shows that in patients with heart failure and reduced ejection fraction, there is no benefit from the addition of a renin inhibitor to a therapeutic dose of enalapril.

 

References

  1. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-35.
  2. 2014 Evience-Based Guideline for the Management of High Blood Pressure in Adults. JNC8 Hypertension Guideline Algorithm. February 5, 2014. Vol. 311, No. 5.
  3. McMurray, John, Henry Krum, William Abraham, Kenneth Dickstein, Lars Kober, Akshay Desai, Scott Solomon, Nicola Greenlaw, Atif Ali, Yanntong Chiang, Qing Shao, Georgia Tarnesby, and Barry Massie. Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure. The New England Journal of Medicine. Published April 4, 2016.
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