Florence, Italy - 23 May 2016: A subgroup analysis in heart failure 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 for the first time today in a late breaking trial session at Heart Failure 2016 and the 3rd World Congress on Acute Heart Failure.1
"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 angiotensin-converting enzyme (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.
He continued: "The result may have been positive had the European Medicines Agency (EMA) not asked us to withdraw patients with diabetes from the trial. We will never know, as the angiotensin receptor neprilysin inhibitor LCZ696 has since emerged and bypassed the need for aliskiren."
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, 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.2
Following the results of two separate trials, 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 cardiovascular death or hospitalisation for heart failure 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 (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.71-1.04; p=0.13), and in 172 (27.4%) patients in the aliskiren group (HR 0.82; 95% CI 0.67-1.00; p=0.053 compared with enalapril).
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.
Professor Kober said: "We did a rigorous trial which should have shown that aliskiren is as good as an ACE inhibitor. The drug was never given the chance to demonstrate how good it is because of regulatory interference. That will never be tested now. This could have been a major problem for patients if the neprilysin inhibitor had not emerged."