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ASTRONAUT: Aliskiren did not benefit hospitalized HF patients
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SAN FRANCISCO — In patients recently hospitalized with worsening chronic HF and reduced ejection fraction, aliskiren did not improve post-discharge mortality or hospitalizations when added to evidence-based therapy for HF, researchers reported.
Researchers for the double blind, randomized ASTRONAUT trial followed 1,639 patients hospitalized with HF. Patients were assigned aliskiren (Tekturna, Novartis) or placebo in addition to standard therapies 5 days after admission. Aliskiren was dosed starting at 150 mg and increased to 300 mg. Patients were initially followed every 2 weeks and then every 3 months for 1 year.
Mihai Gheorghiade
After 6 months, the likelihood of CV death or rehospitalization was similar in both groups, according to the data, which were published simultaneously in JAMA.
However, patients assigned aliskiren experienced a significant and sustained drop in blood levels of N-terminal proB-type natriuretic peptide through 1 year follow-up.
Hyperkalemia, renal dysfunction and hypotension were reported more frequently in the aliskiren group, according to Mihai Gheorghiade, MD, professor of medicine and surgery at Northwestern University Feinberg School of Medicine.
Subgroup analysis for secondary endpoints was consistent with previous reports of poor outcomes with the use of aliskiren in patients with diabetes already receiving RAAS inhibitors. Contrasting effects of aliskiren in patients with vs. without diabetes warrant further analysis, Gheorghiade said at a presentation.
“The results of the aliskiren study raise the hypothesis that treatment for this subgroup is not ‘one size fits all.’ We have to stop talking about our failure and identify the subgroups that will respond,” Gheorghiade said at a press conference. – by Deb Dellapena
For more information:
Gheorghiade M. Poster #13-LB-15880-ACC. Presented at: American College of Cardiology Scientific Sessions; March 9-11, 2013; San Francisco.
Gheorghiade M. JAMA. 2013;doi:10.1001/jama.2013.1954.
Disclosure: The ASTRONAUT study was sponsored by Novartis. Gheorghiade reports serving as a consultant for Novartis.
Perspective
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Biykem Bozkurt, MD, PhD, FACC
The lack of benefit in ASTRONAUT trial raises the question about the hypothesis of whether upstream renin inhibition in addition to background therapy with other RAAS (renin-angiotensin-aldosterone system) axis blocking agents could add further benefit in patients with HF. Potential effects may have also been counterbalanced by the adverse events profile such as hyperkalemia, hypotension and worsening renal function. Unfavorable outcomes in the subgroup of diabetic patients are consistent with former studies of renin inhibition in diabetic patients, who are especially vulnerable to development of renal dysfunction and hyperkalemia.
Going forward, newer treatment approaches, especially with RAAS antagonism in addition to optimal standard background therapy with ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists will need to weigh in the delicate balance of adverse events vs. potential benefit.
Perspective
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Franz H. Messerli, MD
ASTRONAUT is yet another pebble in the mosaic documenting inefficacy and lack of safety of dual renin-angiotensin system blockade with aliskiren. From other placebo-controlled, randomized trials we know it is futile to add aliskiren to standard therapy in diabetic hypertensive patients (ALTITUDE), in patients with acute MI (ASPIRE), and now also in patients with chronic HF. Subgroup analyses for 12-month end points of CV death or HF rehospitalization and all-cause death revealed a significant interaction by history of diabetes in that diabetic patients fared worse on aliskiren than non-diabetic patients. The ASTRONAUT investigators now ask for a HF study with aliskiren that excludes diabetic patients. Ironically, because aliskiren for years was marketed especially for the diabetic patient with the credo to be more beneficial than simple ACE inhibitors or angiotensin receptor blockers. Could it be that aliskiren is particularly detrimental in patients with diabetes? One may wonder at this juncture how many more trials are needed to convince regulatory agencies that dual RAS blockade in general and addition of aliskiren to either ACE inhibitor or angiotensin receptor blockers, specifically, are no longer acceptable in clinical practice. At best, aliskiren can be considered as another RAS blocker that has no specific benefits over ACE inhibitor/angiotensin receptor blockers, but, in contrast, exposes patients to a well-documented dose-dependent adverse effect (diarrhea).
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