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Original Articles

Effects of the Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure

John J.V. McMurray, MD; Bertram Pitt, MD; Roberto Latini, MD; Aldo P. Maggioni, MD; Scott D. Solomon, MD; Deborah L. Keefe, MD; Jessica Ford, MSc; Anil Verma, MD; Jim Lewsey, PhD for the Aliskiren Observation of Heart Failure Treatment (ALOFT) Investigators

From the BHF Cardiovascular Research Centre (J.J.V.M.) and Department of Public Health and Health Policy (J.L.), University of Glasgow, Glasgow, Scotland, United Kingdom; University of Michigan School of Medicine (B.P.), Ann Arbor, Mich; Department of Cardiovascular Research (R.L.), Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; ANMCO Research Center (A.P.M.), Florence, Italy; Brigham & Women’s Hospital (S.D.S., A.V.), Boston, Mass; and Novartis Pharmaceuticals Corporation (D.L.K., J.F.), East Hanover, NJ.

Correspondence to Professor John J.V. McMurray, BHF Cardiovascular and Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, United Kingdom. E-mail j.mcmurray{at}bio.gla.ac.uk

Received September 18, 2007; accepted February 8, 2008.

Background— Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone (RAAS) cascade. This may overcome ACE inhibition but should be blocked by a direct renin inhibitor. We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure.

Methods and Results— Patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE inhibitor (or angiotensin receptor blocker) and β-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/d (n=156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients’ mean age was 68 years, mean ejection fraction was 31%, and mean±SD systolic blood pressure was 129±17.4 mm Hg. Sixty-two percent of the patients were in New York Heart Association functional class II, and 33% were taking an aldosterone antagonist. Plasma NT-proBNP rose by 762±6123 pg/mL with placebo and fell by 244±2025 pg/mL with aliskiren (P=0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo.

Conclusions— Addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and β-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated.

Key Words: heart failure • renin • angiotensin • pharmacology

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