European Journal of Heart Failure Advance Access published online on November 5, 2009
European Journal of Heart Failure, doi:10.1093/eurjhf/hfp154
Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT)
1 Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, SE-416 85 Göteborg, Sweden
2 Department of Cardiology, University Pierre et Marie Curie Paris VI, La Pitié-Salpétrière Hospital, Paris, France
3 Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany
4 Division of Cardiovascular Medicine and the Howard Gilman Institute for Heart Valve Disease, State University of New York Downstate Medical Center, Brooklyn and New York, NY, USA
5 Robertson Centre for Biostatistics, University of Glasgow, Scotland, UK
6 GVM Hospitals of Care and Research, Cotignola, Italy
* Corresponding author. Tel: +46 31 3434078, Fax: +46 31 258933, Email: karl.swedberg{at}gu.se
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Abstract |
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Aims: Elevated heart rate is a significant marker for mortality and morbidity in cardiovascular disease including heart failure. Despite background treatment with a beta-blocker, many patients with heart failure and low ejection fraction maintain a heart rate above 70 b.p.m. Ivabradine reduces heart rate directly through inhibition of the If ionic current.
Methods: SHIFT is a randomized, double-blind study designed to compare ivabradine with placebo on outcomes in patients with symptomatic chronic heart failure (NYHA class II–IV), left-ventricular ejection fraction 
35%, and a prior hospitalization for worsening heart failure within the previous 12 months. Randomized treatment is given on top of guidelines-based therapy for chronic heart failure, including a beta-blocker at optimized dose. Resting heart rate at baseline must be 
70 b.p.m. The primary endpoint is the composite of the time to first event of cardiovascular death or hospitalization for worsening heart failure. Secondary endpoints include all-cause, cardiovascular and heart failure mortality, and hospitalization. The randomized treatment period lasts approximately 12–48 months. The study will include approximately 6500 patients and will continue until 1600 primary endpoints have occurred. The first patient was randomized in October 2006, and the study is expected to end in 2010.
Conclusion: The SHIFT study will assess if a heart rate reduction by direct sinus node inhibition can reduce cardiovascular outcomes in patients with chronic heart failure and left-ventricular systolic dysfunction.
Key Words: Chronic heart failure • Heart rate • Ivabradine • Randomized trial • Treatment
Received September 1, 2009; Revised September 23, 2009; Accepted October 5, 2009