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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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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Effect of piboserod, a 5-HT4 serotonin receptor antagonist, on left ventricular function in patients with symptomatic heart failure

John K. Kjekshus1,2,*, Christian Torp-Pedersen3, Lars Gullestad1,2, Lars Køber4, Thor Edvardsen1, Inge C. Olsen5, Ivar Sjaastad2,6,7, Eirik Qvigstad2,8, Tor Skomedal2,8, Jan-Bjørn Osnes2,8 and Finn Olav Levy2,8

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


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix
 References
 
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


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Appendix
 References
 
Pharmacological treatment of chronic heart failure (HF) counteracts neurohormonal compensatory mechanisms, which act unfavourably and reduce long-term survival. Important examples are treatment with β-adrenoceptor antagonists (β-blockers),1 angiotensin-converting enzyme (ACE) inhibitors2,3 or angiotensin receptor antagonists,4 and aldosterone receptor antagonists.5 Other neurohormonal mechanisms may possibly exist and these may provide the basis for novel pharmacological treatment of chronic HF.

Serotonin (5-hydroxytryptamine, 5-HT) mediates diverse effects in the central nervous system and in the periphery through 14 different receptors, grouped into the classes 5-HT1–7.6 In human atria, serotonin causes increased rate and force of contraction through 5-HT4 receptors.7 Recent results demonstrate that the human cardiac ventricle is responsive to serotonin through 5-HT4 receptors.8 The expression of 5-HT4 receptors is increased in the myocardium during HF both in experimental animals and in humans.8,9 Serotonin is released from activated platelets, which take up and store serotonin through a specific serotonin transporter, similar to the one on neurons, which is known to be the target of the antidepressant serotonin reuptake inhibitors. Plasma serotonin levels increase in human HF,10 and there is evidence for cardiac serotonin production,11 providing sources of serotonin to stimulate cardiac receptors. The 5-HT4-mediated positive inotropic response to serotonin resembles the inotropic response to β-adrenoceptor stimulation, which is mediated through cAMP and is deleterious in HF.8,9,12 The 5-HT4-mediated positive inotropic response appears concomitantly with declining β-adrenergic responsiveness in HF9 and may compensate for reduced β-adrenergic responsiveness.

Enhanced sympathetic activity and high neurohormone levels are important in HF progression.2 The adrenergic receptors mediate the adverse effects of excess catecholamines which result in myocardial ischaemia, apoptosis, remodelling, and arrhythmias. Treatment with β-blockers in HF reduces mortality and morbidity.13,14 Given the resemblance of 5-HT4-mediated and β-adrenergic inotropic responses, we hypothesized that treatment with a 5-HT4 serotonin receptor antagonist could provide similar and perhaps additional benefit in HF.15 Treatment of experimentally induced HF in rats has provided support for this hypothesis.16 The primary objective of the present study was to evaluate whether treatment with the 5-HT4 serotonin receptor antagonist piboserod could improve left ventricular ejection fraction (LVEF) compared with placebo. We also aimed to evaluate whether piboserod is safe when administered in addition to standard therapies in patients with stable HF.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Appendix
 References
 
Eligible patients were recruited from 18 outpatient clinics and private practices in Denmark, Norway, and the UK (Appendix). The study was conducted double blind according to the intention-to-treat principle and was approved by the relevant Institutional Review Boards (public Ethics Committees). All subjects gave informed consent before any study-specific procedure was undertaken.

Patients
Patients aged between 18 and 80 years could be included if they had a clinical diagnosis of HF (NYHA class II–IV), locally determined LVEF ≤0.35 [by acknowledged methods, i.e. either magnetic resonance imaging (MRI), echocardiography, LV angiography, or by a radionuclide cardiography], stable sinus rhythm, stable evidence-based pharmacological treatment with no current plan for changing CHF therapy, and a presumed ability and willingness to participate in the study. Exclusion criteria were unstable patients who had been hospitalized within the last 2 weeks, prolonged QTc interval (>450 ms), atrial fibrillation at the time of randomization, uncorrected haemodynamically significant primary obstructive valvular disease, haemodynamically significant obstructive cardiomyopathy, myocardial infarction or revascularization within the last 3 months, planned major surgery including cardiac revascularization, stroke with significant neurological deficit or within the last 3 months, acute myocarditis or constrictive pericarditis, symptomatic bradycardia or second- or third-degree AV-block, symptomatic hypotension or uncontrolled hypertension, clinically significant hepatic or renal disease, cardiac mechanical support, or congestive HF due to uncorrected thyroid disease. Any illness or disorder other than congestive HF that could preclude participation and/or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression would also exclude the patient.

Medication
The investigational treatment in this study was piboserod (previously known as SB207266), provided as tablets for oral intake or matching placebo in terms of appearance, smell, and taste. The study medication was manufactured by GlaxoSmithKline. Piboserod is a potent, selective, orally active, long-acting 5-HT4 serotonin receptor antagonist. Piboserod has been evaluated in irritable bowl syndrome and atrial fibrillation. Human studies have indicated 2–3% prolongation of the QT interval at doses exceeding 80 mg, but no proarrhythmic effect has been reported. All patients were treated according to the current guidelines for treatment of HF.

Procedures
Subjects who fulfilled the selection criteria were randomized to either piboserod or placebo treatment at a ratio of 1:1 according to a pre-determined randomization scheme in blocks of 4, generated by a computerized procedure. Patients were stratified according to whether they were prescribed β-blockers as underlying treatment or not. Baseline measurements, including MRI, were then performed. The treatment period was 26 weeks with an escalation period of 4 weeks (2 weeks on 20 mg dose, 2 weeks on 40 mg dose and then uptitration to 80 mg and a maintenance period of 20 weeks on the highest tolerated dose, before a tapering period of 2 weeks). Treatment was to be stopped if QTc increased and remained between 450 and 500 ms. After the first dose of piboserod (20 mg) or corresponding placebo and at each new dose level, the patients were monitored closely for adverse events and QTc prolongation on day 0, 1, 2, 4, and 5 after the dosing. A standard 12-lead electrocardiogram was used during all visits to monitor QTc. Patients were excluded if QTc exceeded 500 ms. If QTc did not return to <450 ms within 24 h of the last dose of study medication, the dose had to be reduced to the previous dose level or the patient had to be withdrawn from further study. A final follow-up visit, 2 weeks after the last study medication dose, was also scheduled.

The primary efficacy variable of the study was change in LVEF from baseline to end-of-treatment as measured by MRI using a Siemens or Philips 1.5 T scanner. Standard MRI recordings of the LV were obtained at each centre during or soon after the screening visit and at the end-of-therapy visit. In order to qualify for the study, every laboratory carrying out MRI uptakes had to send a sample image for pre-study quality control by the core MRI lab. All images were masked for identity and treatment and analysed for LVEF, systolic and diastolic volume at the Department of Cardiology, Rikshospitalet University Hospital, Oslo, by two independent cardiologists. The MRI studies were considered valid if at least six LV short-axis slices in each patient at inclusion and end-of-therapy were eligible for endocardial tracings.

Cardiopulmonary exercise capacity was determined by the 6 min walk test. The patient was asked to walk as fast as possible, and the distance covered in 6 min was recorded.

The Minnesota Living with Heart Failure (MLHF) questionnaire was used for measuring health-related quality of life (QoL). This was a 21-item self-administered QoL instrument to systematically and comprehensively assess the patients' perceptions of the effects of HF in their daily life. The questionnaire had been translated and validated in all languages relevant for this study, i.e. English, Danish, and Norwegian.

Laboratory tests
Standard blood tests were performed in a central laboratory. Plasma C-reactive protein (Roche Diagnostics, Basel, Switzerland), norepinephrine (Chromsystems, München, Germany), N-terminal pro-BNP (Biomedica, Vienna, Australia), and aldosterone (Siemens Healthcare Diagnostics, Los Angeles, CA, USA) were analysed using recognized methods.

Statistical methods
The sample size was chosen such that a difference of 4% in LVEF between the groups would be proven significant at the 5% level with a power of 90%. This difference was to be shown in the two strata, i.e. those patients with and those without concomitant β-blocker use. It was assumed that one-third of the eligible patients would not receive β-blockers, and this group would then determine the total sample size. With an estimated standard deviation of 4.0% in both groups, and assuming that a two-sided t-test was to be used, the sample size was determined to be 46 (23 in each group). Accounting for a 13% drop-out rate and that one-third of the patients would not be receiving a β-blocker, a total of 156 patients were to be randomized.

Data analyses were performed using SAS® software, version 9.1.3. Treatment differences between the two study groups were analysed using the t-test.

The authors had full access to the data and take responsibility for its integrity. All authors have read and agreed to the manuscript as written.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Appendix
 References
 
A total of 191 patients were screened and 137 patients were included in the study. Of these, 70 were randomized to placebo (64 reached the equivalent of the full dose) and 67 were randomized to piboserod (63 reached the full dose) (Figure 1). The demographic characteristics of the two treatment groups were comparable (Table 1).


Figure 1
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  		Figure 1 Trial profile.

 


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  		Table 1 Baseline characteristics and drug administration

 
Left ventricular volumes and ejection fraction
A total of 50 patients in the piboserod group and 56 in the placebo group had two valid MRI assessments (Table 2). After 24 weeks of treatment, end-diastolic volume index was reduced by 3.8 mL/m2 with piboserod and by 2.3 mL/m2 with placebo (P = 0.4). End-systolic volume index was reduced by 4.2 and 1.1 mL/m2, respectively (P = 0.068). Compared with placebo, piboserod significantly increased LVEF by 1.7% (CI 0.3, 3.2, P = 0.020). In a small subset of patients not on β-blocker therapy (n = 19), LVEF tended to increase by 2.7% (CI –1.1, 6.6, P = 0.15). There was a trend for a larger increase in LVEF among patients with the most depressed LV function (Figure 2). No centre-effect was observed.


Figure 2
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  		Figure 2 Baseline left ventricular ejection fraction (LVEF; %) and the change in left ventricular ejection fraction from baseline to the end of treatment with piboserod and placebo. Regression lines are illustrated for piboserod (continuous line) and placebo (dotted line).

 


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  		Table 2 Effect of piboserod vs. placebo on different efficacy variables

 
Neurohormonal markers
N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, norepinephrine, and aldosterone were clearly elevated in all patients consistent with moderate HF and were comparable among groups. These markers remained unchanged during the trial (Table 2). Improvement in EF was not associated with changes in norepinephrine, aldosterone, or NT-proBNP levels.

High-sensitivity C-reactive protein
No significant differences in the change in serum high-sensitivity C-reactive protein at the end of study compared with baseline were demonstrated between the groups (Table 2).

Six minute walk test
The 6 min walk test distance at baseline was 424 ± 136 m (mean ± SD) on piboserod and 440 ± 148 m (mean ± SD) (n.s.) on placebo, with no change within or between groups at the end of study (Table 2).

New York Heart Association functional class and quality of life score
Most patients were in NYHA class II and remained unchanged during the trial. There were no consistent changes. Six patients improved in both groups. Five became worse in the piboserod group compared with three in the placebo group (n.s.). The MLHF score was 29.7 before and 30.0 at the end of study in the piboserod group compared with 26.1 and 25.2 in the placebo group (n.s. between groups). The emotional, but not the physical, subscore increased (worsened) significantly in the piboserod group (Table 2).

Tolerance
Adverse events were slightly more often observed in the piboserod group than in the placebo group (Table 3). Eight patients discontinued treatment in the piboserod group compared with three in the placebo group (Table 3). The total number of serious adverse events reported was higher among piboserod-treated patients (n = 22) compared with placebo (n = 7) (Table 4). There were 14 hospitalizations in the piboserod group compared with 4 in the placebo group. Three patients died, all in the piboserod group, two due to terminal HF, and one because of septicaemia complicating unrecognized cancer.


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  		Table 3 Adverse events and discontinuations caused by adverse events (selected from key organ systems and frequency >5.0%)

 


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  		Table 4 Adjudicated serious adverse events

 
QT duration
No significant change in mean QTc from baseline to the end of study was identified. In patients randomized to piboserod, the mean QTc was 413 ms before and 420 ms at the end of study, and the respective values in patients randomized to placebo were 418 ms before and 420 ms at the end of study. However, the number of patients was too small to provide a meaningful conclusion regarding the effect of treatment on QTc dispersion.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Appendix
 References
 
This study demonstrates that patients with chronic HF have a small but significant improvement in LVEF when treated for 24 weeks with the 5-HT4 serotonin receptor antagonist piboserod. This improvement was obtained on top of evidence-based treatment for HF. There was a trend for further improvement in a small subset of patients not on chronic β-blocker therapy. But the improvement in EF was not reflected in favourable effects on concentrations of NT-proBNP, norepinephrine, aldosterone, quality of life, or exercise tolerance.

The results of this study are in line with animal experiments which have demonstrated an improvement in LV function when rats with post-infarction HF were treated with piboserod.16 No previous studies of a 5-HT4 serotonin receptor antagonist in HF patients have been reported. The most relevant comparison in humans is β-blocker use in HF, due to the similarities of the signalling pathways of the β-adrenoceptors and the 5-HT4 serotonin receptor. β-Blockade has not demonstrated convincing effects on exercise tolerance17 or on natriuretic peptides,18 but produces a clear improvement in EF.19 The improvement in EF seen in the current study is smaller than that observed in the β-blocker studies; however, this result is to be expected if the effect is additional to that obtained with a β-blocker. Although the numbers in our study are small, there was a tendency for a greater effect in patients who did not receive a β-blocker. Blockade of the renin–angiotensin–aldosterone system has revealed small but significant favourable effects on clinical class,20 EF,21 and exercise tolerance,22 and also some reduction in plasma natriuretic peptide plasma concentrations.18

Although statistically significant, the net improvement in EF was small, only 1.7%, corresponding to a relative improvement of 6.0% (1–12%) in the piboserod group compared with the placebo group. The effect was largely accounted for by a reduction in end-systolic volume in the piboserod group and the effect was obtained on top of concurrent use of β-blockers, ACE inhibitors, and aldosterone receptor blockers. Is it plausible that the improvement of LVEF with piboserod is commensurate with a beneficial clinical effect? The follow-up time was relatively short, but improvements in EF and clinical benefit have been demonstrated with β-blockers and ACE inhibitors within this time frame.

A moderate improvement in EF is not easily translated into a survival benefit. The combination of isosorbide dinitrate and hydralazine was inferior to enalapril for survival of patients with HF but improved EF more than enalapril.23 There is no simple surrogate for the survival benefit of neurohormonal blockade. There was no improvement of 6 min walk test or reduction of NT-proBNP which in other trials have been useful markers of benefit.

The results of the current study are less striking compared with the effects of renin–angiotensin–aldosterone blockade and β-blockers. Given that the signalling pathway is similar to that of β-receptors, it might be expected that piboserod could provide a clinical benefit in a similar direction as a β-blocker. But would piboserod then be beneficial when administered on top of a β-blocker? One study raises this possibility. In a comparison of metoprolol tartrate and carvedilol, only carvedilol demonstrated a survival benefit.24 A debate has followed about whether this was a dose and/or kinetic issue,25 but it appears likely that there are benefits to be found within the β-blocker concept.26 Following this reasoning, piboserod could provide clinical benefit as an alternative for patients intolerant to β-blocker treatment. Although the effect on LVEF is in favour of a protective effect of piboserod on the myocardium, the lack of a significant effect on other efficacy parameters and on heart rate should be considered when evaluating the potential usefulness of piboserod in the treatment of HF.

Although blockade of myocardial serotonin receptors in HF may improve systolic function, its relevance in clinical practice remains uncertain. In this context, it is of interest that serotonin reuptake inhibitors, which enhance the availability of serotonin on specific receptors in the brain and alleviate depressive symptoms, have been reported to improve prognosis of patients with myocardial infarction or HF. However, such an effect could also result from inhibition of serotonin uptake in platelets, which would render platelets less reactive due to lower serotonin content, and possibly result in reduced liability to thrombotic events. It might be suggested that piboserod could reduce the 5-HT4 receptor stimulation by serotonin in the brain. However, although one report documented anxiolytic-like effects of piboserod in rats,27 this effect is not easily reconciled with the reduced emotional subscore observed in our trial. As long as there are no available data relating 5-HT4 receptor stimulation or blockade to emotional status in humans, this remains speculative.

Piboserod was titrated slowly in the current study and there were no side effects associated with titration. The slow titration was chosen because of a possible effect on QTc and from previous experience with β-blockers where careful titration may be critical for detecting a beneficial effect.

The study was not designed for evaluating safety, but more adverse effects and hospitalizations were reported in the piboserod-treated patients compared with those treated with placebo. There were also more discontinuations in the piboserod group and more serious adverse events. All three deaths were in the piboserod group, although no causal relationship was documented. A clear limitation of the study was the small number of patients and slightly sicker patients at baseline in the piboserod group which might have contributed to more adverse events in this group. Nevertheless, these numbers are small and there was no detectable pattern to indicate a warning sign for piboserod.

In conclusion, we observed a significant, although modest, improvement in the primary endpoint, LVEF, supporting the concept that 5-HT4 receptor stimulation may have some injurious effect on the failing heart. Thus, our study adds new information about the role of serotonin in HF pathophysiology. The effect on LVEF was not, however, reflected in significant changes of other efficacy parameters. The total number of adverse events was higher on piboserod. Although the clinical relevance of piboserod in HF may therefore be limited, there may still be a potential for 5-HT4 antagonism in HF.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Appendix
 References
 
This study was sponsored by Bio-Medisinsk Innovasjon AS, Norway.

Conflict of interest: FOL is the inventor of a published patent application (WO03097065) covering the potential use of 5-HT4 antagonists for treatment of heart failure. The patent is owned by the Norwegian biotech company Serodus AS where several of the authors (IS, EQ, TS, FOL) are shareholders.


   Appendix
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix
References
 
Piboserod executive committee: J.K.K., C.T.-P., L.G., L.K., T.E., I.C.O., I.S., E.Q., T.S., J.-B.O., F.O.L., and C. Richards. Data Safety Monitoring Board: J. Camm, St George's Hospital Medical School, London, England (Chair); K. Thygesen, Århus University Hospital, Århus, Denmark. Piboserod Investigators: Norway, L.G., K. Dickstein, P.A. Sirnes, P.K. Rønnevik, R. Wiseth, and A. Westheim; Denmark, C.T.-P., L.K., J. Brønnum-Schou, G. Jensen, P Hildebrandt, K. Skagen, L. Videbæk, and K. Egestrup; England, J.G.F. Cleland, A. Memon, and M. Barlow. MRI Core laboratory: T.E., Oslo University Hospital, Rikshospitalet, Oslo, Norway.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Appendix
 References
 

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