Aliskiren Observations of Heart Failure Treatment - ALOFT - Presented at ESC 2007

Sep 02, 2007
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Trial Sponsor:
Novartis
Date Presented:
01/01/2007
Date Published:
01/01/2011
Date Updated:
09/02/2007
Original Posted Date:
09/02/2007
References

Description:

The goal of the trial was to evaluate the safety and tolerability of the oral renin inhibitor aliskiren compared with placebo among patients with stable heart failure.

Study Design

Patients Screened: 776
Patients Enrolled: 302
Mean Follow Up: 3 months
Mean Patient Age: Mean age, 67 years
Female: 22

Patient Populations:

New York Heart Association class II-IV heart failure with current or prior hypertension and a plasma BNP level >100 pg/ml

Exclusions:

Heart failure due to obstructive valve disease; treatment with both an ACE inhibitor and an ARB; systolic blood pressure <90 mm Hg; creatinine >2.0 mg/dl; myocardial infarction, stroke, transient ischemic attack, or coronary revascularization in the prior 6 months; or cardiac resynchronization therapy

Drug/Procedures Used:

Following a 2-week run-in phase of treatment with placebo, patients were randomized in a double-blind manner to aliskiren (150 mg; n = 156) or placebo (n = 146) for 12-week therapy. All patients were also treated with standard heart failure therapy in addition to the randomized therapy. Biomarker and echocardiographic data were collected at study entry and 12 weeks.

Principal Findings:

At study entry, mean left ventricular ejection fraction (LVEF) was 31%, and 79% of patients had an EF ≤40%. Average duration of heart failure was 4.1 years in the aliskiren group and 4.9 years in the placebo group. Concomitant therapy included beta-blockers in 94% of patients, angiotensin-converting enzyme (ACE) inhibitors in 83% of patients, and angiotensin receptor blockers (ARBs) in 15%. Study drug was discontinued in 9.0% of the aliskiren group and 7.5% of the placebo group.

As expected, larger reductions from baseline to 12 weeks were seen with aliskiren in plasma renin activity levels (-5.71 ng/ml/h vs. -0.97 ng/ml/h, p < 0.001). The reduction in B-type natriuretic peptide (BNP) was greater in the aliskiren group than in the placebo group (-61 pg/ml vs. -12.2 pg/ml, p = 0.016), as was change in NT-proBNP (-243.6 pg/ml vs. +761.7 pg/ml, p = 0.01). There was no difference in plasma aldosterone (-48.6 pmol/L vs. -30.9 pmol/L), but the reduction in urinary aldosterone was greater with aliskiren (-9.2 mmol/d vs. -7.0 mmol/d, p = 0.015).

Among the echocardiographic parameters, there was no difference in change in EF (1.7% in the aliskiren group vs. 1.6% in the placebo group, p = 0.96). MR/LA area ratio was reduced in the aliskiren group (-4.1 vs. +1.3, p = 0.0006), as was E/E' (-0.84 vs. 0.12, p = 0.047).

Among the safety events, renal dysfunction occurred in 1.9% of the aliskiren group compared with 1.4% of the placebo group, symptomatic hypotension in 3.2% versus 1.4%, and hyperkalemia in 6.4% versus 4.8%, respectively, all numerically but not significantly higher with aliskiren. The frequency of any of these events was 10.9% in the aliskiren group and 7.5% in the placebo group (p = NS).

Interpretation:

Among patients with stable heart failure, treatment with the oral renin inhibitor aliskiren was tolerable and was associated with a greater reduction in BNP than placebo at 3-month follow-up.

The present trial provides evidence of an effect of aliskiren on BNP levels, a marker of the degree of heart failure. These findings were evident even on background therapy with beta-blockers and ACE inhibitors, blockers of the renin angiotensin system. However, a larger trial would be needed to determine if this reduction in biochemical markers translates into a reduction in clinical events.

Additionally, the safety profile in this population needs further evaluation. It is not known if a larger outcomes trial will be conducted using aliskiren as add-on therapy to ACE inhibitors/ARBs, or if aliskiren will be studied in comparison to these agents as a potential alternative to ACE inhibitors and ARBs. Aliskiren has previously been shown to produce greater reductions in both systolic blood pressure and diastolic blood pressure compared with other antihypertensive agents in patients with elevated blood pressure, but has not been extensively studied in the setting of heart failure.

References:

Jackson CE, MacDonald MR, Petrie MC, et al. Associations of albuminuria in patients with chronic heart failure: findings in the ALiskiren Observation of heart Failure Treatment study. Eur J Heart Fail. 2011 Jul;13(7):746-54.

Keywords: Angiotensin Receptor Antagonists, Hypotension, Renin-Angiotensin System, Blood Pressure, Hyperkalemia, Fumarates, Heart Failure, Peptide Fragments, Stroke Volume, Hypertension, Natriuretic Peptide, Brain


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