A subgroup analysis in HF patients with diabetes from the ATMOSPHERE trial has failed to show benefit and signals the end of the road for aliskiren in heart failure. The findings were presented in a late breaking trial session at ’Heart Failure 2016 and the 3^rd World Congress on Acute Heart Failure’ today.

Aliskiren is a renin-angiotensin-aldosterone system inhibitor that is used in patients with hypertension. The Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failure (ATMOSPHERE) included 7016 patients with heart failure and reduced left ventricular ejection fraction (HFrEF), of whom 2340 were randomly assigned to enalapril plus aliskiren, 2340 to aliskiren, and 2316 to enalapril. Of these, 1944 (27.7%) had diabetes and 5072 (72.3%) were non-diabetics.
The main study results were published in April and showed that aliskiren was not superior or non-inferior to standard treatment with an ACE inhibitor. The addition of aliskiren to an evidence-based dose of enalapril led to more adverse events without an increase in benefit (HR primary endpoint  of CV death or hospitalization for HF: 0.93). Aliskiren monotherapy did not show non-inferiority as compared with enalapril (HR primary endpoint: 0.99).

Following the results of two separate trials (ALTITUDE and ASTRONAUT), the EMA requested the withdrawal of all patients with diabetes from ATMOSPHERE. The Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) had been stopped after patients with diabetes and a high risk of cardiovascular events were found to have an excess risk of cardiovascular and renal events with aliskiren. The Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) had found a tendency towards harm in patients with diabetes.

The current study is a prespecified subgroup analysis of ATMOSPHERE according to baseline diabetes status. Due to the premature withdrawal of patients with diabetes from the study drug, median follow-up was shorter in those with diabetes than those without (24.1 months versus 46.0 months; p<0.0001).

The investigators found that the effect of aliskiren on the primary endpoint of CV death or hospitalisation for HF did not significantly differ by baseline diabetes status. In those with diabetes, the primary endpoint occurred in 196 (29.5%) patients in the combination group, compared to 216 (33.1%) in the enalapril group (HR: 0.86; 95%CI: 0.71–1.04; p=0.13), and in 172 (27.4%) patients in the aliskiren group (HR: 0.83; 95% CI 0.68–1.01; p=0.053 compared with enalapril). All-cause mortality showed no difference between the three treatment arms.

“This was a subgroup analysis with the inherent limitations of this type of study. It failed to show superiority or non-inferiority of aliskiren over the ACE inhibitor enalapril in heart failure patients with diabetes,” said principal investigator Professor Lars Kober, a consultant cardiologist at Rigshospitalet – Copenhagen University Hospital in Copenhagen, Denmark.

Regarding the safety of aliskiren in patients with diabetes, compared with enalapril it was associated with a lower risk of symptomatic hypotension (6.7% versus 10.0%; p=0.04). Other adverse events were evenly distributed.

Professor Kober said: “Aliskiren monotherapy looked promising in heart failure patients with diabetes, with an 18% almost significant reduction in cardiovascular death or heart failure hospitalisation compared to enalapril. There was a lower rate of symptomatic hypotension and no increase in other adverse events. This suggests that aliskiren could be an alternative for patients who cannot tolerate an ACE inhibitor.”

Combination therapy with aliskiren and enalapril was associated with more adverse events compared with enalapril alone. As the two drugs together did not produce a better outcome, the trial does not support the combination of an ACE inhibitor and aliskiren.
Press release ESC May 23, 2016 and Late Breaking Clinical Trials Session III