Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular function in patients with symptomatic heart failure.
OBJECTIVE
Myocardial 5-HT(4) serotonin (5-HT) receptors are increased and activated in heart failure (HF). Blockade of 5-HT(4) receptors reduced left ventricular (LV) remodelling in HF rats. We evaluated the effect of piboserod, a potent, selective, 5-HT(4) serotonin receptor antagonist, on LV function in patients with HF.


RESULTS
This was a prospective, double-blind, parallel group trial in patients with NYHA class II-IV HF and LV ejection fraction (EF) < or =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 beta-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.


CONCLUSIONS
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.
Kjekshus
John K
JK
Department of Cardiology, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway. john.kjekshus@medisin.uio.no
Torp-Pedersen
Christian
C
Gullestad
Lars
L
Køber
Lars
L
Edvardsen
Thor
T
Olsen
Inge C
IC
Sjaastad
Ivar
I
Qvigstad
Eirik
E
Skomedal
Tor
T
Osnes
Jan-Bjørn
JB
Levy
Finn Olav
FO
D000368:Aged; D016001:Confidence Intervals; D018450:Disease Progression; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D006305:Health Status Indicators; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D020097:Natriuretic Peptide, Brain; D010078:Oxazines / Q000627:therapeutic use*; D010446:Peptide Fragments; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects*; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects*; D016138:Walking
D007211:Indoles; D010078:Oxazines; D010446:Peptide Fragments; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C479132:piboserod