Hopes for the hypertension drug aliskiren to be beneficial for heart failure patients with diabetes ended with the announcement that it did not reduce the rate of patient death during a clinical trial. The results were reported in a presentation at the Heart Failure 2016 conference.
The subgroup analysis in heart failure patients with diabetes from the ATMOSPHERE trial means the end of the road for aliskiren in heart failure. Aliskiren, marketed as Tekturna in the US and Rasilez in the UK, 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.
Principal investigator Professor Lars Kober, a consultant cardiologist at Rigshospitalet-Copenhagen University Hospital in Copenhagen, Denmark, said:
“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.
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.”
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.
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.
Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel.
John J.V. McMurray, M.D., et al. Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure N Engl J Med 2016; 374:1521-1532April 21, 2016DOI: 10.1056/NEJMoa1514859
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