1. The angiotensin-converting-enzyme (ACE) inhibitor enalapril alone was just as effective at preventing death and hospitalization when compared to the renin inhibitor aliskiren alone or when it was used in combination therapy with enalapril.
2. There was a significantly higher risk of side effects in the combination group compared to the ACE group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Heart failure (HF) patients with reduced ejection fraction (EF) are prescribed ACE inhibitors, as they have been shown to lower risk of death and hospitalization. In light of this, other renin-angiotensin system altering treatments are being explored for their potential to reduce these risks even further. This study aimed to assess whether the renin inhibitor aliskiren alone or in combination with the ACE inhibitor enalapril would have lower mortality and hospitalization risks than enalapril alone.
There was no statistical difference in death or hospitalization outcomes for the renin or renin/ACE inhibitor groups compared to the ACE inhibitor group. Patients treated with combination therapy did experience adverse side effects of hypotension, renal dysfunction, and hyperkalemia more frequently than the other two groups. Blood pressure was significantly lower at 4 months of treatment for the combination therapy group compared to the ACE inhibitor group.
In-Depth [randomized controlled trial]: Chronic HF patients with New York Heart Association class 2-4 symptoms, an EF less than 35%, acceptable B-type natriuretic peptide concentrations, and being treated with a beta-blockers and ACE inhibitors were eligible for study enrollment. Patients were enrolled from 2009 to 2013 at 789 locations in 43 countries. Patients were randomly divided into treatment groups of ACE inhibitor (n=2336), renin inhibitor (n=2340), or combination therapy (n=2340). Patients were treated with prescribed doses of medications and followed for primary outcomes of death or hospitalization from heart attack. While the study was running, in 2013 two large studies indicated diabetic patients should not be treated with aliskiren, and the study and statistical analyses were adjusted accordingly to follow this recommendation (~40% of patients in each group were diabetic). Median follow-up time was 36.6 months. Primary outcomes were experienced in 32.9% of patients on combination therapy, 33.8% of patients on renin inhibitor, and 34.6% of patients on ACE inhibitor (HR=0.93; 95% [CI], 0.85 to 1.03). Diabetics on combination therapy versus ACE inhibitor did not experience statistically significant differences in primary outcomes (29.5% in the combination group vs. 33.1% in the enalapril group; HR=0.86; 95% [CI], 0.71-1.04; p=0.35 for interaction). Hypotensive symptoms were significantly higher in the combination-therapy group compared to the enalapril group (13.8% vs. 11.0%, p=0.005). Lastly, higher percentage of elevated creatinine (4.1% vs. 2.7%) and potassium levels were observed in the combination-therapy group compared to the enalapril only group (4.1% vs 2.7%, p<0.009 and 17.1% vs 12.5%, p<0.001, respectively).
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