What is the clinical evidence from this study?

Study design: RCT. Population: Chronic Heart Failure with reduced ejection fraction (HFrEF) with and without diabetes (n=7016). Intervention: Aliskiren alone or enalapril plus aliskiren vs. Enalapril. Primary outcome: Cardiovascular death or hospitalization for heart failure (HR 0.82, 95% CI 0.67-1.00, p=0.053).

What does this research mean for the field?

In patients with HFrEF and diabetes, aliskiren monotherapy showed a trend toward reducing cardiovascular death or heart failure hospitalization compared to enalapril (HR 0.82; 95% CI 0.67-1.00; P=0.053) with no signal of harm, whereas combination therapy increased adverse events without improving outcomes. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

September 25, 2017Open Access

Aliskiren Alone or in Combination with Enalapril vs. Enalapril Among Patients with Chronic Heart Failure with and without Diabetes: A Subgroup Analysis from the ATMOSPHERE Trial

Key Result

In patients with HFrEF and diabetes, aliskiren monotherapy showed a trend toward reducing cardiovascular death or heart failure hospitalization compared to enalapril (HR 0.82; 95% CI 0.67-1.00; P=0.053).

Study Design

Type

RCT (n=7,016)

Randomization

Randomized

Structured PICO

Does aliskiren alone or in combination with enalapril improve cardiovascular outcomes compared to enalapril alone in HFrEF patients with and without diabetes?

Population

7,016 patients with heart failure and a reduced ejection fraction (HFrEF), including a subgroup of 1,944 (27.7%) patients with diabetes.

Intervention

Aliskiren alone or aliskiren in combination with enalapril

Comparator

Enalapril alone

Outcome

Composite of cardiovascular death or hospitalization for heart failurecomposite

In HFrEF patients with diabetes, aliskiren monotherapy showed no signal of harm and a trend toward benefit compared to enalapril, while combination therapy increased adverse events without improving outcomes.

Main Result

Effect estimate: HR 0.82 (95% CI 0.67-1.00)

Absolute Event Rate: 27.4% vs 33.1%

p-value: p=0.053

Limitations

Study treatment was stopped prematurely in patients with diabetes because of concerns about the safety of aliskiren.

Abstract

AIMS: Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes. METHODS AND RESULTS: ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053, and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril 42 (6.7%) vs. 65 (10.0%); P = 0.04, whereas other adverse events were generally balanced between the three groups. CONCLUSION: In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.