Direct Renin Inhibitor Aliskiren Flops as Add-On Therapy in Systolic HF: ASTRONAUT

March 11, 2013

SAN FRANCISCO, California — Adding aliskiren (Tekturna, Novartis) on top of other heart-failure medications, starting less than a week after discharge from a hospitalization for low-LVEF heart failure, made no significant difference to CV death or hospitalization at six months, according to researchers of the randomized ASTRONAUT trial [1]. Nor was a clinical benefit seen out to one year.

Dr Mihai Gheorghiade

On the other hand, treatment with the direct renin inhibitor led to "significant and sustained" reductions in natriuretic peptide levels, an indirect sign of possible heart-failure improvement even if it didn't translate clinically, according to Dr Mihai Gheorghiade (Northwestern University, Chicago, IL) and colleagues. It's possible that a favorable effect on heart-failure progression was offset clinically by adverse effects associated with the drug, which included hyperkalemia, hypotension, and renal dysfunction, they speculate.

Their report was published online in the Journal of the American Medical Association at the time of Gheorghiade's scheduled presentation of ASTRONAUT here today at the American College of Cardiology 2013 Scientific Sessions.

Hopes have been that further inhibition of the renin-angiotensin-aldosterone system (RAAS) through a mechanism different from those of ACE inhibitors, angiotensin receptor blockers (ARBs), or aldosterone antagonists would have added clinical value in heart failure. Other research has suggested that aliskiren, already approved for hypertension, might fill that role as it blocks the RAAS "at its most proximal step" and might therefore suppress the compensatory renin increases seen with RAAS inhibition later in the pathway.

Notably, >50% of patients in ASTRONAUT were already on an aldosterone antagonist, 84% were on an ACE inhibitor or ARB, and >80% were on beta-blockers, the latter of which are indirect inhibitors of renin.

The trial was conducted at 316 centers in North and South America, Europe, and Asia and randomized 1639 stable patients with heart failure, an LVEF <40% (mean 28%), and elevated natriuretic peptides who had been discharged from a heart-failure hospitalization an average of five days before. About 40% had diabetes and 21% had renal insufficiency.

Patients received either aliskiren or placebo in addition to standard heart-failure medications. The active drug was given at 150 mg/day with escalation to 300 mg/day as tolerated, and patients were followed for a mean 11.3 months.

No significant differences were seen in the primary composite end point (CV death or heart-failure rehospitalization) or either of its components at six months, nor were results much different at one year.

Six-Month Outcomes in ASTRONAUT

6-mo outcomes HR (95% CI)
CV death or heart failure rehospitalization* 0.92 (0.76–1.12)
CV death 0.92 (0.68–1.26)
Heart-failure rehospitalization 0.90 (0.72–1.12)

*Primary end point

Significantly fewer patients in the aliskiren group discontinued randomized therapy due to any serious adverse event (p=0.03), and significantly more did so due to any nonserious adverse event (p<0.01).

Safety End Points in ASTRONAUT

End point Placebo (%) Aliskiren (%) p
Hyperkalemia 17.5 20.9 0.09
Renal impairment/failure 12.1 16.6 0.01
Hypotension 12.6 17.1 0.01

 

Reminiscent of aliskiren's performance in the ALTITUDE trial, which suggested possible harm from the drug in patient with diabetes, ASTRONAUT suggested that the drug may have increased the risk of death from any cause at 12 months in the 41% of patients with a history of diabetes. Nondiabetics who took the drug, on the other hand, showed a significant benefit for that end point as well as CV death/heart-failure rehospitalization. The researchers proposed that aliskiren might find a role in nondiabetics with heart failure based on future trials exploring that issue in particular.

Twelve-Month Outcomes in Diabetics and Nondiabetics in ASTRONAUT

End point Diabetics (HR, 95% CI) Nondiabetics (HR, 95% CI)
CV death or heart failure rehospitalization 1.16 (0.91–1.47) 0.80 (0.64–0.99)
Death by any cause 1.64 (1.15–2.33) 0.69 (0.50–0.94)

p<0.01 for treatment–diabetes interaction

The trial was sponsored by Novartis, for which Gheorghiade disclosed consulting along with Bayer HealthCare, Abbott, Astellas, AstraZeneca, Corthera, Cytokinetics, Debiopharm, Errekappa Terapeutici, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Otsuka, Pericor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, Solvay, and Takeda. Disclosures for the coauthors are listed in the paper.

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