For patients hospitalized with heart failure, aliskiren added no significant benefit to standard therapy in preventing cardiovascular death or heart failure readmission.
The drug did, however, have some problematic effects on patients with diabetes, including significant increases in the risk of cardiovascular death and heart failure readmission at 6 months and all-cause death at 1 year.
The negative interaction between diabetes and aliskiren – an inhibitor of the angiotensin-renin-aldosterone system (RAAS) – is unclear, according to Dr. Mihai Gheorghiade and colleagues.
"[The issue] may be related to the increased risk of hypotension, hyperkalemia, and worsening renal function with the study drug," wrote Dr. Gheorghiade of Northwestern University, St. Louis, Mo., and his colleagues. The conclusions were published in the March 10 issue of JAMA and simultaneously presented at the annual meeting of the American College of Cardiology in San Francisco (JAMA 2013;309:doi10.1001/jama.2013.1954).
The randomized, placebo-controlled ASTRONAUT trial compared 6-and 12-month outcomes of aliskiren plus standard therapy to standard therapy alone in patients hospitalized with heart failure.
The study randomized 1,639 patients; 1,615 were included in the final efficacy analysis. Patients in the investigational arm received 150 mg aliskiren daily in addition to standard treatment. Standard treatment was at the treating physician’s discretion, and could include, among others, diuretics, digoxin, ACE inhibitors, angiotensin receptor blockers, and beta-blockers. The study enrolled patients from 2009-2011; the median follow-up was 11 months
The patients were a mean of 65 years old. Their mean left ventricular ejection fraction was 28%, and mean estimated glomerular filtration rate was 67 mL/min/1.73 m3. Nearly half (41%) had diabetes.
At admission, the mean N-terminal pro–brain natriuretic peptide (NT-proBNP) level was 4,239 pg/mL. Other drugs taken at baseline included diuretics (96%), beta-blockers (82%), ACE inhibitors or ARBs (84%), and mineralocorticoid antagonists (57%).
The primary efficacy endpoint was a combination of cardiovascular death or heart failure readmission within 6 months. This occurred in 201 (25%) of the aliskiren group and 214 (26%) of the placebo group – a nonsignificant difference. Nor were there significant differences when CV death and readmission were examined separately.
The main secondary endpoint was the composite of cardiovascular death or heart failure readmission at 12 months; again, there was no significant between-group difference (35% vs. 37%), although the events were numerically less in the aliskiren group than the control group (283 vs. 301). Parsing down the number of first cardiovascular events after treatment, the investigators did find that myocardial infarction was significantly less common in the aliskiren group (2% vs. 5%; HR 0.93; P = 0.009).
A subgroup analysis found that the drug was especially problematic for patients with diabetes. Compared to patients without the disorder who had standard treatment, diabetic patients who took aliskiren were 16% more likely to experience cardiovascular death or heart failure readmission by 6 months, and 64% more likely to experience all-cause death by 12 months.
During the treatment period, death occurred in 24% of patients with diabetes who took aliskiren, compared with 17% who took placebo – also a significant difference.
"In contrast, the rates of death among patients without a history [of diabetes] were 15% and 20% in the aliskiren and placebo groups, respectively," the authors wrote.
A number of adverse events were significantly higher in the aliskiren group, including hyperkalemia (14% vs. 13%) and severe hyperkalemia (8% vs. 5%). Hyperkalemia-related events occurred in 21% of the aliskiren group and 17% of the control group. Hypotension was also more common in the aliskiren group (17% vs. 13%). Decreased eGFR was significantly more common among those taking the study drug (11% vs. 9%), as were events potentially related to renal dysfunction (17% vs. 12%).
"The results of the ASTRONAUT study do not support the routine administration of aliskiren in addition to standard therapy, to patients hospitalized for worsening chronic heart failure," the investigators concluded, adding that the subgroup analysis was "consistent with previous reports of poor outcomes with the use of aliskiren in patients with diabetes already taking RAAS inhibitors."
Further studies will be necessary to evaluate renin inhibiting drugs in patients with diabetes, they added.
Dr. Gheorghiade reported financial relationships with 32 pharmaceutical companies, including Novartis Pharma AG, the study sponsor.