European Journal of Heart Failure Advance Access originally published online on June 30, 2009
European Journal of Heart Failure 2009 11(8):771-778; doi:10.1093/eurjhf/hfp087
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Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular function in patients with symptomatic heart failure
1 Department of Cardiology, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0027 Oslo, Norway
2 Center for Heart Failure Research, University of Oslo, Oslo, Norway
3 Department of Cardiology, Gentofte Hospital, Copenhagen, Denmark
4 The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
5 Smerud Medical Research International, Oslo, Norway
6 Institute for Experimental Medical Research, University of Oslo, Oslo, Norway
7 Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway
8 Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway
* Corresponding author. Tel: +47 97595455, Fax: +47 23073676, Email: john.kjekshus{at}medisin.uio.no
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Abstract |
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Aims: Myocardial 5-HT4 serotonin (5-HT) receptors are increased and activated in heart failure (HF). Blockade of 5-HT4 receptors reduced left ventricular (LV) remodelling in HF rats. We evaluated the effect of piboserod, a potent, selective, 5-HT4 serotonin receptor antagonist, on LV function in patients with HF.
Methods and results: This was a prospective, double-blind, parallel group trial in patients with NYHA class II–IV HF and LV ejection fraction (EF) 
0.35. Patients receiving standard HF treatment were randomized to placebo (n = 70) or piboserod 80 mg (n = 67) for 24 weeks including 4 weeks up titration. The primary endpoint was LVEF measured by cardiac magnetic resonance imaging (MRI). Secondary endpoints were LV volumes, N-terminal pro-brain natriuretic peptide, norepinephrine, quality of life, and 6 min walk test. Piboserod significantly increased LVEF by 1.7% vs. placebo (CI 0.3, 3.2, P = 0.020), primarily through reduced end-systolic volume from 165 to 158 mL (P = 0.060). There was a trend for greater increase in LVEF (2.7%, CI –1.1, 6.6, P = 0.15) in a small subset of patients not on chronic β-blocker therapy. There was no significant effect on neurohormones, quality of life, or exercise tolerance. Patients on piboserod reported more adverse events, but numbers were too small to identify specific safety issues.
Conclusion: Although patients with chronic HF had a small but significant improvement in LVEF when treated with piboserod for 24 weeks, the result was not reflected in significant changes in other efficacy parameters, and its clinical relevance remains uncertain.
Clinical trials.gov, NCT 00421746
Key Words: Heart failure • Serotonin antagonist • Piboserod • NT-proBNP • Left ventricular function • 6 min walk test
Received April 21, 2009; Revised May 13, 2009; Accepted May 14, 2009