ATMOSPHERE: Adding aliskiren to ACE inhibitor does not benefit patients with HF

CHICAGO — Aliskiren, a direct renin inhibitor, offered no benefit to patients with HF when added to ACE inhibitor treatment, researchers reported at the American College of Cardiology Scientific Session.

“There seems to be a ceiling to the benefit that can be obtained with renin-angiotensin system blockers,” said John J.V. McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, during a press conference. “Above a certain level of blockade, there were no additional benefits and [potential] harm.”

ATMOSPHERE was a multicenter, randomized, double-blind trial that enrolled 7,016 patients with HF. All patients (mean age, 63 years; 78% men) had already been treated with enalapril or another ACE inhibitor and a beta blocker.

Patients were switched from their existing ACE inhibitor and then entered the first part of a two-part run-in phase, in which they received 1 to 4 weeks of enalapril 5 mg twice daily in a single blind fashion and then 2 to 4 weeks of enalapril 10 mg/twice daily. Then patients were stratified by dose of enalapril that did not cause unacceptable adverse events. In the second part of the run-in phase, patients were given a daily dose of aliskiren (Tekturna, Novartis) 150 mg plus enalapril in a single blind fashion.

Patients who didn’t have serious adverse reaction to both drugs were then randomly assigned to either take enalapril alone at a dose of 300 mg/daily (n =2,336), aliskiren alone at a dose of 300 mg/day (n = 2,340) or both drugs (n = 2,340). The primary endpoint was a composite CV death and hospitalization for HF. Median follow-up was 36.6 months.

Study results were simultaneously published in The New England Journal of Medicine.

The rate of CV mortality or hospitalization for HF was 34.6% (n = 808) in the group treated with enalapril, and 32.9% (n = 770) in the combined therapy group (HR vs. enalapril alone = 0.93; 95% CI, 0.85-1.03). The rate of CV mortality or hospitalization was 33.8% in the group treated with aliskiren (HR vs. enalapril = 0.99; 95% CI, 0.90 to 1.10).

The prespecified test for noninferiority was not met and patients that were taking the combined therapy had a greater risk for symptoms of low BP than those who were on enalapril alone (13.8% vs. 11%; P = .005). Those assigned the combined therapy were also more at risk for elevated serum creatinine (4.1% vs. 2.7%; P = .009) and elevated potassium concentration (17.1 vs. 12.5%; P < .001) compared with those assigned enalapril alone. Adverse event rates for aliskiren alone were similar to those of enalapril alone.

McMurray said that these findings emphasize the importance of PARADIGM-HF, which showed the sacubitril/valsartan (Entresto, Novartis) was superior to full-dose enalapril.

A limitation to the study, according to McMurray, was that aliskiren was discontinued in all patients with diabetes and no new enrollment of patients with diabetes were allowed on the order of European drug regulators due to concern about other trial findings that suggested patients with diabetes might have worse outcomes when treated with aliskiren and an ACE inhibitor or ARB.

“However, contrary to ASTRONAUT trial, we saw a trend in favor of combination therapy with no worse outcomes in patients with diabetes,” McMurray said. – by Tracey Romero

Reference:

McMurray JJV, et al. Late-Breaking Clinical Trials V. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.

McMurray JJV, et al. N Engl J Med. 2016; doi:10.1056/NEJMoa1514859.

Disclosure: The ATMOSPHERE Trial was funded by Novartis, which also funded PARADIGM-HF. McMurray reports that Novartis paid the University of Glasgow for his work on both trials.