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European Journal of Heart Failure 2008 10(1):89-95; doi:10.1016/j.ejheart.2007.10.012
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© 2008 European Society of Cardiology

A randomised trial of a pre-synaptic stimulator of DA2-dopaminergic and {alpha}2-adrenergic receptors on morbidity and mortality in patients with heart failure

Christian Torp-Pedersena,*, Lars Køberb, Jan E. Carlsenc, Dilek Akkand, Niels E. Bruund, Dimitri Dacoroniase, Kenneth Dicksteinf, Torben Haghfeltg, Hans Öhlinh and John JV McMurrayi

a Dept. Cardiology, Bispebjerg University Hospital, Bispebjerg Bakke 2400 Copenhagen NV, Denmark
b Department of Cardiology, The National Hospital Copenhagen, Denmark
c Cyncron A/S Copenhagen, Denmark
d Department of Cardiology, Gentofte University Hospital Copenhagen, Denmark
e Corporate Medical Department, Chiesi Farmaceutici S.p.A. Parma Italy
f Cardiology Division, University of Bergen, Stavanger University Hospital Norway
g Department of Cardiology, Odense University Hospital Odense, Denmark
h Department of Cardiology, University Hospital Lund, Sweden
i Department of Cardiology, Western Infirmary Glasgow, Scotland, UK

* Corresponding author. Tel.: +45 35316161; fax: +45 39760107. E-mail address: ctp{at}heart.dk (C. Torp-Pedersen).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Background: By pre-synaptic stimulation of DA2-dopaminergic and {alpha}2-adrenergic receptors, nolomirole inhibits norepinephrine secretion from sympathetic nerve endings. We performed a clinical study with nolomirole in patients with heart failure (HF).

Methods: The study was designed as a multicentre, double blind, parallel group trial of 5 mg b.i.d. of nolomirole (n=501) versus placebo (n=499) in patients with severe left ventricular systolic dysfunction, recently in New York Heart Association (NYHA) class III/IV. The primary endpoint was time to all cause death or hospitalisation for HF, whichever came first. The study was event driven and required 420 primary events. The study was completed as scheduled.

Results: Mean age of patients was 70 years, and 73% were male. Heart rate and blood pressure were not different in the two treatment groups. There were no changes in blood pressure. There were 233 primary events in the nolomirole group versus 208 in the placebo group (p=0.1). There were 142/145 deaths and 369/374 all cause hospitalisations in the nolomirole/placebo groups. There were no differences in walking distance, quality of life or NYHA class.

Conclusion: A dose of 5 mg b.i.d. of nolomirole was not beneficial (or harmful) in patients with heart failure.

Key Words: Nolomirole • Heart failure • Survival • Controlled clinical trial

Received August 26, 2007; Accepted October 18, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Despite progress in management, morbidity and mortality in patients with heart failure remains high. Because of the marked improvement in outcomes obtained with beta-blockers, the possibility of gaining further benefit from alternate or additional inhibition of the sympathetic nervous system has been tested, with mixed results. The COMET study demonstrated, that in patients treated with an ACE-inhibitor, the intensity of beta-blockade, the range of adrenoceptors blocked, or both, had a marked influence on outcome [1]. In another study, the centrally acting sympathetic inhibitor [2] moxonidine increased mortality and morbidity. Moxonidine caused a pronounced fall in plasma neorepinephrine, suggesting that very intense adrenergic inhibition may not be desirable. Thus, further efforts are needed to clarify to what extent the adrenergic system may/can be blocked, in order to achieve further beneficial effects. Nolomirole is a pre-synaptic stimulator of DA2-dopaminergic and {alpha}2-adrenergic receptors in peripheral sympathetic nerve endings [3]. These receptors act as a negative feedback mechanism, inhibiting norepinephrine secretion. [4] In early phase clinical studies lasting 1-3 months, nolomirole reduced peripheral systemic resistance and 24 hour blood pressure and increased cardiac output. [5,6] In a study of 29 patients with heart failure, followed for 10 days, a reduction in plasma norepinephrine was demonstrated. [7] In this study there was no effect on heart rate, blood pressure or natriuretic peptides.

Since nolomirole appeared to be a mild inhibitor of the sympathetic nervous system, we studied its clinical effects in patients with heart failure in the EchoCardiography and Heart Outcome Study (ECHOS).


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A
 References
 
2.1. Patients
Participating centres were required to screen all consecutive patients older than 18 years, admitted with a clinical diagnosis of heart failure. To be eligible for inclusion in the study, patients were required to have a history of dyspnoea or fatigue at rest or on slight exercise, corresponding to New York Heart Association (NYHA) class III-IV, within the last month and had to be in NYHA class II-IV at the time of randomisation. Patients were also required to be treated with a diuretic. As part of the screening procedure, an echocardiogram was recorded on videotape and sent for evaluation in a core laboratory. A left ventricular wall motion index score was calculated [8], as described previously. Inclusion criteria to the study were the screening criteria specified above, in addition patients had to be enrolled within 7 days of hospitalisation and have a wall motion index ≤1.2-corresponding to a left ventricular ejection fraction ≤35%. [9] Exclusion criteria were acute pulmonary oedema within 12 h, uncorrected haemodynamically significant obstructive valvular disease, clinically significant obstructive cardiomyopathy, a myocardial infarction within 1 month, cardiac revascularization within 1 month, planned major surgery, stroke within 1 month, acute myocarditis or constrictive pericarditis, symptomatic bradycardia or advanced atrio-ventricular block unless treated with a pacemaker, sitting systolic blood pressure <90 mm Hg, sustained systolic blood pressure>160 mm Hg or diastolic blood pressure>100 mm Hg, clinically significant hepatic or renal disease (serum creatinine >300 µmol/l or 3.4 mg/dl), any illness or disorder other than heart failure which could preclude participation or severely limit survival, pregnancy or childbearing potential but not using an approved method of contraception, cardiogenic shock and ongoing treatment with an intravenous pressor agent, patients on a respirator, likelihood of poor compliance, current participation in a trial with an investigational drug or an investigational device (excluding stents), previous participation in this trial, unwillingness or inability to provide informed consent.

2.2. Organisation and design of the study
This was a prospective, double blind, randomised, placebo-controlled, parallel group, multicentre trial evaluating the effect of nolomirole 5 mg twice daily, over a treatment period of at least 12 months in patients with heart failure and left ventricular systolic dysfunction.

The study was approved by authorities in participating countries as well as by relevant ethics committees and it was conducted in accordance with the Declaration of Helsinki III and Guidelines for Good Clinical Practice in the European Union. The study was led by a Steering Committee. The Steering Committee formulated the design of the trial, reviewed the protocol, oversaw the conduct of the trial and wrote this manuscript. Members of the Steering Committe who were employees of the sponsor or contract research organisation were non-voting. An Events Committee reviewed available event data on a blinded basis and according to predefined criteria. A Data and Safety Monitoring Board overviewed the results in an unblinded fashion at predetermined intervals. Investigators and members of committees are listed in the Appendix. The trial was financed by Chiesi Pharmaceutial company who also owns the database. The Steering Committee had full access to the data.

Eligible patients were randomly assigned to double-blind treatment with either 5 mg of nolomirole or matching placebo. Allocation was done by computerised random numbers and stratified according to centre.

Patients were seen after 1 month and 3 months and then at 3 monthly intervals until the end of the study. Follow-up echocardiograms were transferred to the core laboratory at 6 months and 12 months for determination of left ventricular volumes (Simpsons biplane method) and wall motion index. Six minute walking test was performed at randomisation and after 1, 6 and 12 months. NYHA class was scored at all visits. Physician and patient global assessment scales were completed after 1, 6 and 12 months and at completion of the study. The global assessment consisted of a 7 point scale, where 1 was markedly improved, 4 unchanged and 7 markedly worse. A Minnesota Living with Heart Failure score was also obtained after 1, 6 and 12 months.

In a single centre sub-study, 24 hour blood pressure measurements were performed with a Takeda TM-2421 (A&D, Tokyo, Japan) device. Measurements were scheduled during the first day of the study, during the second day and after 1 month.

2.3. End points
Clinical endpoints were evaluated by an Events Committee who were blinded to all other results. The primary end point was time to death from any cause or hospitalisation due to worsening of heart failure. A hospitalisation due to heart failure required that there were relevant symptoms of heart failure (in particular dyspnoea), relevant signs or heart failure and the need for intensified treatment of heart failure.

The secondary endpoint was time to death or hospitalisation from any cause. Tertiary endpoints were death, hospitalisation from any cause, change in left ventricular function, change in NYHA class, change in plasma neurohormones, change in heart failure symptom score, change in physician and patient global assessment score and change in Minnesota Living with Heart Failure score.

2.4. Statistical analysis
The trial was designed to randomise 1000 patients with a minimum of 1 year follow-up. In addition, the study was event driven and 420 primary events were required to reach a 90% power to detect a 20% difference in the primary endpoint with a type 1 error of 5%.

Comparisons of time to events were performed with the log rank test and supplementary analyses were performed with Cox proportional hazard models. All comparisons were 2-sided with a significance level of 5%.

Continuous variables are presented as means±standard deviation and compared with a t-test, categorical variables were compared with Fischer's exact test. No data were replaced when data were missing or the patient had died.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A
 References
 
A total of 3954 consecutive patients with heart failure were screened for entry in the 43 participating hospitals in Denmark, Norway and Sweden. As planned, 1000 patients were randomised — 25% of those screened. The trial profile is shown in Fig. 1 and demographic characteristics in Table 1. The first patient was enrolled on 23 April 2001 and the last patient was completed on 23 January 2004


Figure 01
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  		Fig. 1 Trial profile showing the number of patients in the study.

 


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  		Table 1 Baseline characteristics

 
The study was conducted as scheduled. The final result was 441 primary endpoints with 72/161 deaths/hospitalisations for heart failure in the nolomirole groups and 86/122 in the placebo group. A Kaplan Meier curve for the primary endpoint is shown in Fig. 2, there was no significant difference between the treatments, p=0.19


Figure 02
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  		Fig. 2 Primary endpoint. Kaplan Meier curves of time to death or admission for worsening of heart failure, showing no significant difference between nolomirole (N) and placebo (P).

 
The secondary endpoint was time to death or hospitalisation from any cause. For this endpoint there were 18/369 deaths/hospitalisations in the nolomirole group and 20/374 in the placebo group, Fig. 3. The Kaplan Meier curves shown in Fig. 3 were nearly superimposed, p=0.92. There were 142/145 total deaths (p=0.86) in the nolomirole/placebo groups (Fig. 4) and 369/374 hospitalisations (p=0.97).


Figure 03
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  		Fig. 3 Secondary endpoint. Kaplan Meier curves of time to death or any hospitalisation, showing no significant difference between nolomirole (N) and placebo (P).

 


Figure 04
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  		Fig. 4 Kaplan Meier curves of time of death, showing no significant difference between nolomirole (N) and placebo (P).

 
In a sub-study, left ventricular volumes were measured at baseline in 225/241 (nolomirole/placebo) patients, after 6 months in 92/99 patients and after 12 months in 84/87 patients. At baseline, left ventricular volumes were nearly identical in the 2 treatment groups (diastolic volumes 218/219 ml p=0.9, systolic volumes 168/167 ml, p=0.9). After 6 months diastolic volumes were 215/199 ml, p=0.19, and systolic volumes were 156/139 ml, p=0.11). After 12 months diastolic volumes were 216/194 ml, p=0.07, and systolic volumes were 152/132 ml, p=0.07). There were no differences between ejection fractions in the 2 treatment groups (data not shown).

NYHA class was reported at each visit and at no time was there any relation between NYHA class and treatment allocation (all p values>0.3). As a supportive analysis, an overall analysis of the relationship between NYHA class at all visits and treatment allocation was performed (logistic regression) and again no statistically significant association was demonstrated.

A small sub-study of neurohormones was performed. At baseline, plasma norepinephrine concentration was 4.1±2.8 nmol/l (mean±standard deviation (SD), n=32) in the nolomirole group and 3.6±2.2 nmol/l (n=24) in the placebo group. At baseline, mean (±SD) plasma B type natriuretic peptide concentration was 118±95 pmol/l in the nolomirole group (n=27) and 187±324 pmol/l (n=34) in the placebo group. There were no significant changes over time or between study groups (data not shown).

Baseline mean (±SD) heart rate was 81±17/79±15 bpm in the nolomirole/placebo groups. At the final visit, the values were 72±16/72±13 bpm. Similarly blood pressure values at baseline and at the final visit were 120±19/73±12-126±24/74±14 mm Hg in the nolomirole group and 121±19/73±13-127±22/75±11 mm Hg in the placebo groups. None of these values differed significantly between the groups, and this was also the case for the values obtained at intermediate visits.

The ambulatory blood pressure sub-study included 12/9 patients on nolomirole/placebo on day 1 of the study after administration of drug, 13/9 on day 2 and 11/8 after one month. Mean 24 hour systolic blood pressures on the three occasions were 120±16/113±25 (ns), 113±25/115±26 (ns) and 117±22/120±25 (ns) mm Hg. Mean 24 hour diastolic blood pressures were 76±14/74±18 (ns), 76±22/74±18 (ns) and 79±26/77±16 (ns) mm Hg. Finally, 24 hour mean heart rates were 66±12/77±9 (p=0.03), 58±17/76±13 (p=0.01) and 52±19/65±10 (p=0.07) bpm.

At baseline, the mean (±SD) walking distances in the nolomirole/placebo groups were 325±124/329±115 m (n=499/501), respectively. There were no significant differences between the two study groups during the trial and no significant change over time.

Finally, there were no significant changes in the global assessments by patients or physicians or change in Minnesota Living with Heart failure score (data not shown).

Analysis of the primary and secondary endpoints was carried out in the following subgroups as identified at inclusion into the study: sex, median age, NYHA class, presence of atrial fibrillation, treatment with ACE-inhibitor, beta-blocker, spironolactone, or digoxin/cardiac glycoside, history of diabetes and history of ischaemic heart disease. There were no differences observed between the treatments in any of these subgroups. (data not shown).

The majority of patients continued in the trial unless they died (Table 2). A total of 7587 adverse events (including serious) occurred in 966 patients during the trial. In the nolomirole treated group, 482 patients experienced 3913 adverse events and in the placebo group 484 patients experienced 3674 events. The vast majority of events were mild or moderate. There was no particular pattern of adverse reactions with respect to treatment modality, and no significant difference between nolomirole- or placebo-treated patients. The most frequent adverse or serious adverse events in the nolomirole/placebo groups were (n): dizziness 88/102, exacerbated dyspnoea 86/60, pneumonia 91/88, aggravated heart failure 73/53, increased creatinine 78/61 and increased potassium 60/57.


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  		Table 2 Discontinuation

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A
 References
 
This study demonstrated that nolomirole 5 mg twice daily was neither beneficial nor harmful in patients with heart failure. The study also demonstrated that patients admitted to hospital with heart failure - even those randomised in trials - continue to have a high mortality, if enrolled consecutively.

This study was neutral with respect to every pre-selected endpoint and other biological measures, including blood pressure and heart rate. Only in the small single centre study of ambulatory blood pressure was nolomirole associated with a significant reduction of pulse during the first days of the trial. There was only a trend in this small study after 1 month. Consequently, nolomirole may have had no therapeutic effect because the dose and formulation of drug used exerted little or none of the anticipated pharmacological effect. Nolomirole has a plasma half life of approximately 3 h, but the phase II programme (unpublished) indicated longer binding to the drug receptors and a 24 hour effect on blood pressure. Since these actions could not be replicated in this study, it is possible that the short half life of the formulation used in the current study is the reason for the apparent lack of biological effect of the drug.

Even if the drug did have some pharmacological action, we cannot tell whether the present study was neutral because this action was weak or because the pharmacological action of the drug was ineffective in heart failure, regardless of intensity i.e. whether the drug was inactive or ineffective.

These findings illustrate the difficulty in selecting a dose of drug for phase 3 outcome studies in heart failure, particularly drugs that inhibit sympathetic outflow. We were concerned in designing this study to avoid intense inhibition of the sympathetic nervous system in view of the experience with moxonidine, especially as our patients were recruited while acutely unwell and because many would be treated with a beta-blocker. Further attempts at sympathetic inhibition should focus on achieving more effective, but moderate, reductions in plasma norepinephrine.

The present study confirmed another important lesson for future trial design. The one year mortality was approximately 20%. Over a series of studies [10-13] the principle of consecutive screening of patients hospitalised with heart failure or myocardial infarction - and using centralised echocardiography to select patients with left ventricular systolic dysfunction - has resulted in much higher event rates than in most comparative trials. Indeed, the event rates have been close to those observed in epidemiological series. This is important in view of the decreasing event rates found in most trials and the consequent increase in size and duration needed to test for therapeutic action. The present study illustrates how careful selection of patients can still identify a high risk population.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
References
 
The following committees and investigators were involved in ECHOS

Steering Committee: Christian Torp-Pedersen, Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark; John McMurray, Department of Medicine & Therapeutics, University of Glasgow, Glasgow, Scotland; Lars Køber, Department of Cardiology, The National Hospital, Copenhagen, Denmark; Ole Gøtzsche, Med. Cardiology Department, Århus Amtssygehus, Århus, Denmark; Torben Haghfelt, Department of Cardiology, Odense University Hospital, Odense, Denmark; Hans Ohlin, Hjärteintensiven, Lund University Hospital, Lund, Swenden; Kenneth Dickstein, Cardiology Division, Central Hospital Stavanger, Stavanger, Norway; Dimitri Dacoronias, Corporate Medical Department, Chiesi Farmaceutici S.p.A. Parma Italy; Monici Preti, Corporate Medical Department, Chiesi Farmaceutici S.p.A. Parma Italy; Jan Carlsen, Medicon A/S, Copenhagen, Denmark; Anita Vedel Christiansen, Medicon A/S, Copenhagen, Denmark; Charlotte Qwist, Medicon A/S, Copenhagen, Denmark; Anette Dahl, Medicon A/S, Copenhagen, Denmark;

DSMB: John Hampton, Queens Medical Clinic, Nottingham University Hospital, Nottingham, UK; Gorm Jensen, Mediac centre, Hvidovre Hospital, Hvidovre, Denmark; David Jones, Department of Epidemiology and Public Health, University of Leicester, Leicester, UK;

Event Committee: Kenneth Egstrup, Medical Department, Sygehus Fyn Svendborg, Svendborg, Denmark

Niels Gadsbøll, Medical Center, Cardiol. Clinic, H:S Bispebjerg Hospital, Copenhagen, Denmark; Ole Lederballe Pedersen, Medical Department, Viborg Hospital, Viborg, Denmark; Ole Hansen, Clinic of Cardiology, Malmø University Hospital, Malmø, Sweden; Lars Gullestad, Department of Medicine, Bærum Hospital, Bærum, Norway;

Investigators: Henrik Nielsen, Med. Center/Kardiologisk Klinik, Amager Hospital, København S, Denmark; J. Fischer Hansen, Med. Center, Kardiologisk Klinik Y, Bygn. 40, Bispebjerg Hospital, København NV, Denmark; Tonny Nielsen, Stue 416, afd 242, Esbjerg Centralsygehus, Esbjerg, Denmark; John Markenvard, Medicinsk Afd., Fredericia Sygehus, Fredericia, Denmark; Per Hildebrandt, Kardiologisk klinik, Frederiksberg Hospital, Frederiksberg, Denmark; Holger Sejersen, Medicinsk afdeling, Frederikshavn Sygehus, Frederikshavn, Denmark; Chr. Torp-Pedersen, Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark; Jens Rokkedal, Kardiologisk Afd. C41, Glostrup (KAS), Glostrup, Denmark; Hans Rickers, Medicinsk afd. M3, Grenå Sygehus, Grenå, Denmark; Erik Agner, Kardiovaskulært forskningscenter, med. afd. Plan 3. Afsnit 31, Helsingør Sygehus, Helsingør, Denmark; Knud Skagen, Kardiologisk forskningsamb. 104, stue 1, Herlev Amtssygehus, Herlev, Denmark; Line Olesen, Medicinsk afd., Herning Sygehus, Herning, Denmark; Jens Petersen, Intern Medicinsk afd., Hjørring Sygehus, Hjørring, Denmark; Else Vigholt, Medicinsk afd., Horsens Sygehus, Horsens, Denmark; Søren Lind Rasmussen, Med. Center/Kardiologisk Klinik/Afsnit 110, Hvidovre Hospital, Hvidovre, Denmark; Henrik Madsen, Medicinsk afd., Kalundborg Sygehus, Kalundborg, Denmark; Morten Scheibel, Medicinsk amb., plan 4, Viborg Sygehus, Viborg, Denmark; Mogens Asklund, Kardiologisk ambulatorium, Kolding Sygehus, Kolding, Denmark; Kim K. Klarlund, Hjertemed. Afd., Køge-Roskilde Amts Sygehus, Køge, Denmark; Anni Nymann Davidson, Medicinsk afdeling, Nykøbing Mors Sygehus, Nykøbing Mors, Denmark; Roman Sykulski, Kardiologisk Afd. 11, Næstved Centralsygehus, Næstved, Denmark; Torben Haghfelt, B Ambulatoriet 1. Sal, Odense Universitetshospital, Odense C, Denmark; Liv Gøtzsche, Medicinsk afd., Randers Centralsygehus, Randers, Denmark; Lars Køber, Afd. 2. 14. 1, Rigshospitalet, København Ø, Denmark; Ingolf Nielsen, Medicinsk Afd. B72, Roskilde Amtssygehus, Roskilde, Denmark; Frode Rømer, Medicinsk afd., Silkeborg Centralsygehus, Silkeborg, Denmark; Svend Erik Stentebjerg, Medicinsk afd., Skive Sygehus, Skive, Denmark; Carl Gustav Dahlstrøm, Medicinsk Afd. B2, Slagelse Sygehus, Slagelse, Denmark; Kenneth Egstrup, Medicinsk afd., Svendborg Sygehus, Svendborg, Denmark; Birger Engby, Medicinsk afd., Vejle Sygehus, Vejle, Denmark; Jens Berning, Kardiologisk afdeling, Aalborg Sygehus Syd, Aalborg, Denmark; Ole Gøtzsche, Med. kardiologisk afd.A, Århus Amtssygehus, Århus C, Denmark; Jens Refsgård, Hjertemedicinsk Forskningsenhed, Viborg Sygehus, Viborg, Denmark; Allan McNair, Medicinsk Afdeling, Frederikssund Sygehus, Frederikssund, Denmark; Jeppe Launbjerg, Medicinsk afd. B0841, Hillerød Sygehus, Hillerød, Denmark; Preben Wiggers, Kard. Lab., Haderslev Sygehus, Haderslev, Denmark; Morten Brøns, Medicinsk afdeling, Tønder Sygehus, Tønder, Denmark; Hans Öhlin, Hjärtintensiven, Lunds Universitetssjukhus, Lund, Sweden; Lena Jonasson, Medicinkliniken, Höglandssjukhuset Eksjö/Nässjö, Eksjö, Sweden; Stellan Bandh, Hjärtmottagningen, Centrallasarettet Västerås, Västerås, Sweden; Ulf Hurtig, Medicinkliniken, Mora Lasarett, Mora, Sweden; Kenneth Dickstein, Forskningsstiftelsen Hjertelaget, Central Sykehuset Rogaland, Stavanger, Norway; Tone Nerdrum, Hjertepoliklinikken, Aker Universitets Sykehus, Oslo, Norway.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 

  1. Poole-Wilson P.A., Swedberg K., Cleland J.G., et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet (2003) 362(9377):7–13.[CrossRef][Web of Science][Medline]
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