European Journal of Heart Failure

European Journal of Heart Failure 2002 4(3):321-329; doi:10.1016/S1388-9842(02)00025-9

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© 2002 European Society of Cardiology

Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET

Philip A. Poole-Wilson^*, John G.F. Cleland, Andrea Di Lenarda, Peter Hanrath, Michel Komajda, Marco Metra, Willem J. Remme, Karl Swedberg and Christian Torp-Pedersen

Cardiac Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College Dovehouse Street, London, SW3 6LY, UK

^* Corresponding author. Tel.: +44-0-20-7351-8179; fax: +44-0-20-7351-8113. E-mail address: p.poole-wilson{at}ic.ac.uk

	Abstract

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
In large clinical trials both carvedilol and metoprolol have been shown to reduce mortality and morbidity in patients with chronic heart failure. Carvedilol is an adrenoceptor antagonist, which inhibits beta₁-, beta₂-, and alpha₁-adrenergic receptors. Carvedilol has additional metabolic and antioxidant properties. Metoprolol is a selective antagonist of beta₁-adrenergic receptors. The carvedilol or metoprolol European trial (COMET) is the first study to investigate whether beta-blocking agents with differing pharmacological profiles exert different effects on morbidity and mortality in patients with chronic heart failure. 3029 patients from 15 different European countries were enrolled into COMET and will be followed until 1020 fatal events have been observed, unless the data and safety monitoring committee (DSMC) recommends early termination. The target dose for carvedilol is 25 mg bid and for metoprolol tartrate 50 mg bid. This manuscript outlines the rationale, design and possible outcomes of COMET.

Key Words: Carvedilol • Metoprolol • Chronic heart failure • Mortality • Clinical trial • Beta-blockade

Received November 26, 2001; Accepted January 14, 2002

	1. Introduction

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
Chronic heart failure is common, causes distressing symptoms and carries a poor prognosis [1,2]. The most frequent aetiology is coronary heart disease [3]. The mean age of onset in the population is 74 years and in younger age groups the condition is more common in males than females. Improved survival from acute coronary syndromes and demographic changes (increased proportion of elderly in the population) will inevitably result in heart failure becoming more common. The costs to health systems of the management including diagnosis, drug treatment and hospitalisation amount to as much as 2% of the total health budget in developed countries [4]. Large clinical trials have demonstrated that the judicious use of angiotensin converting enzyme (ACE) inhibitors together with diuretics alleviates symptoms, lessens hospital admissions and reduces mortality [5–7]. Despite these advances in drug treatment, mortality remains high and symptoms often persist.

The addition of beta-blocking agents in stable patients with chronic heart failure has also been shown to impact favourably on mortality. This class of drug was initially advocated in 1975 [8] but did not gain wide acceptance until the results of recent large randomised trials became available [9–13]. The underlying rationale for the use of beta-blocking drugs in chronic heart failure is that these drugs inhibit the harmful effects of chronic activation of the sympathetic system. Plasma norepinephrine is elevated in heart failure, predicts prognosis, directly relates to the severity of left ventricular function and is lowered by treatment with diuretics [14–17]. The specific mechanism of benefit of beta-blockade is unknown. Reduction of heart rate, increased diastolic coronary flow (anti-ischaemic effect), reduction of blood pressure, prevention of arrhythmias and inhibition of direct metabolic actions on the myocardium of the failing heart may all be of importance. Four large trials of beta-blockade added to treatment with diuretics and ACE inhibitors have shown an advantage in terms of hospitalisation and mortality (Table 1). One study with bucindolol showed no advantage but a favourable trend [13]. The benefit in terms of symptoms has been less easy to demonstrate [18,19].

View this table: [in this window] [in a new window]   Table 1 Large trials of beta-blocking drugs given for the treatment of heart failure

 
These studies do not allow a comparison of the merits of any particular beta-blocking drug or the conclusion that these drugs are equally efficacious. Substantial differences exist in the pharmacological effects of these agents. Metoprolol has a high specificity for the beta-1 receptor. Carvedilol blocks both beta-1 and beta-2 receptors. Carvedilol also blocks alpha-1 adrenergic receptors, resulting in a reduction in systemic vascular resistance [20]. Carvedilol increases insulin sensitivity whereas metoprolol does the opposite [21]. The antioxidant effect of carvedilol may have beneficial effects on endothelial dysfunction and apoptosis, mechanisms that could be important in the progression of chronic heart failure [22]. In a comparison of 150 chronic heart failure patients over 13–15 months, carvedilol showed a significantly greater increase in left ventricular ejection fraction compared to metoprolol and decreased pulmonary wedge pressure to a greater extent than metoprolol [23]. This different effect of the two drugs on ejection fraction has also been suggested by a recent meta-analysis of 2184 patients [24].

The objective of the carvedilol or metoprolol European trial (COMET) is to compare directly the effects of carvedilol and metoprolol on mortality and morbidity in patients with moderate and severe chronic heart failure.

	2. Study design and patient population

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
COMET is a multi-centre, double-blind, and randomised parallel group trial in patients with moderate to severe chronic heart failure. The study is being performed in 341 centres in 15 countries (Austria, Belgium, Denmark, Finland, France, Germany, Hungary, Italy, Norway, Portugal, Spain, Sweden, Switzerland, The Netherlands and the United Kingdom).

Patients fulfilling the inclusion and exclusion criteria were randomised 1:1 to one of the two treatment arms (Fig. 1). The first patient was enrolled in November 1996. The study is event-driven and will be terminated when 1020 deaths have occurred. The planned number of patients for enrolment was 3000. The end of the trial is anticipated in November 2002.

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Study design of the COMET trial.

 
COMET has enrolled 3029 patients.

2.1. Inclusion criteria
Adult male or female patients with moderate or severe chronic heart failure (NYHA II–IV) are required to meet the criteria below:

• Patients should be on stable treatment with diuretics at a daily dose of furosemide 40 mg or equivalent (bumetanide 1 mg; torasemide 10 mg; hydrochlorothiazide 100 mg; bendroflumethiazide 10 mg) for at least 2 weeks prior to randomisation.
  
• Patients should be on an ACE-inhibitor for at least 4 weeks, unless there is a contraindication. Digitalis and/or vasodilators can be used at the discretion of the physician.
  
• Left ventricular ejection fraction must be 0.35 using echocardiography, radionuclide ventriculography or contrast ventriculography. If ejection fraction was not determined then left ventricular end diastolic diameter >6.0 cm and a fractional shortening <20% as measured by echocardiography could also qualify patients.
  
• At least one hospitalisation for a cardiovascular reason should have taken place during the last 2 years.
  
• Written informed consent must be obtained.
  

2.2. Major exclusion criteria
2.2.1. Relating to cardiovascular disease

• Recent change of heart failure therapy defined as the introduction of a new class of drug for heart failure treatment within 2 weeks prior to randomisation.
  
• Treatment with oral β- or -adrenergic blockers within the previous 2 weeks prior to randomisation.
  
• Requirement for intravenous inotropic therapy.
  
• Current treatment with calcium channel blockers of the diltiazem or verapamil class.
  
• Current treatment with amiodarone >200 mg per day.
  
• Unstable angina within the last 2 months.
  
• Myocardial infarction within 2 months prior to the study.
  
• Cardiac surgery or angioplasty within 2 months prior to the study.
  
• Uncontrolled hypertension (systolic BP >170 mmHg or diastolic BP >105 mmHg).
  
• Haemodynamically significant valvular disease.
  
• Symptomatic and sustained ventricular arrhythmias within the last 2 months not adequately treated with antiarrhythmic drugs or implantation of a defibrillator.
  
• Class I anti-arrhythmic drugs.
  

2.2.2. Contraindications to beta-blocker therapy

• Heart rate <60 bpm, sitting.
  
• Peripheral arterial disease, symptomatic at rest.
  
• Sick sinus syndrome, bifascicular block, second or third degree AV block, unless treated with a pacemaker.
  
• Sitting systolic blood pressure <85 mmHg.
  
• History of asthma or other chronic obstructive pulmonary disease.
  
• Unstable insulin-dependent diabetes mellitus.
  

2.2.3. General exclusion criteria

• Hepatic disease (serum transferase >3 times normal).
  
• Stroke within the last 2 months.
  
• Endocrine disorders such as phaeochromocytoma, active hyperthyroidism and untreated hypothyroidism.
  
• Cancer or other serious systemic disease with reduced life expectancy.
  
• Pregnant women and females with childbearing potential unless adequate contraception.
  

Known drug or alcohol abuse or poor compliance with treatment.

Administration of any study drug within the preceding 30 days.

	3. Endpoints

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
The primary endpoint is all-cause mortality. During the conduct of the trial, two studies have been reported [11,12] indicating that both drugs used in this study were efficacious when tested against placebo. In May 2000, while the study was in progress, and without knowledge of any interim results or treatment assignments, the Steering Committee decided to add a co-primary endpoint recognising the importance of hospitalisation in this patient population. The primary endpoints, thus, were changed to be identical to those used in the MERIT-HF trial [11].

3.1. Primary endpoints

• All-cause mortality.
  
• All-cause mortality or all-cause hospitalisation.
  

3.2. Secondary endpoints

• Combined endpoint (all-cause mortality or cardiovascular hospitalisation).
  
• Combined endpoint (cardiovascular death, non-fatal acute myocardial infarction, heart transplantation or worsening of heart failure).
  
• Cardiovascular death.
  
• NYHA class.
  
• Worsening of heart failure.
  
• Hospital admissions and duration of hospitalisations for heart failure and other reasons.
  
• Discontinuation of study therapy.
  

3.3. Safety and classification of death

• Serious adverse events.
  
• Adverse events.
  
• Laboratory tests.
  

An Endpoint Committee consisting of three experienced cardiologists will review all fatal events. This committee will classify deaths as cardiovascular or non-cardiovascular, and within the cardiovascular deaths further classify them as sudden cardiac death, worsening of heart failure, stroke or other cause of cardiovascular death.

Adverse events and laboratory parameters will be reported periodically to the clinical trial data centre. All serious adverse events are to be notified within 24 h of occurrence.

3.4. Safety supervision of the study
The Steering Committee (SC) and the Sponsor appointed an independent data safety monitoring committee (DSMC) to monitor all safety aspects of the study. The primary responsibility of the DSMC is to ensure the safety of patients.

	4. Study procedures, patient screening and recruitment (Table 2)

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
4.1. Baseline assessment
Written informed consent, demographic data, medical history, and a patient baseline assessment was obtained from eligible patients. Once eligibility had been assessed at baseline, patients entered a titration phase followed by a maintenance phase. Patients were to be randomised to receive either carvedilol (3.125 mg bid) or metoprolol (5 mg bid). There was no open-label beta-blocker therapy run-in phase in COMET.

View this table: [in this window] [in a new window]   Table 2 Timing of assessments of patients in the COMET trial

 
4.2. Dosages of study drugs
The Steering Committee selected 25 mg bid for carvedilol and 50 mg bid for metoprolol tartrate to be used as target doses in COMET. These doses were chosen as the existing evidence suggested that such doses would achieve a comparable degree of beta blockade in both groups.

4.3. Up-titration
The dose of each beta-blocker was to be increased to the target dose at 2 week intervals. Dose titration followed the schedule 6.25 mg bid, 12.5 bid and 25 mg bid for carvedilol and 12.5 mg bid, 25 mg bid and 50 mg bid for metoprolol. At each visit during the titration phase clinical status (NYHA class and physical examination) and tolerability of the study medication was documented. The patients were kept under observation at the clinic for 2 h after the first dose at each new level.

In case of hypotension, the previous dose was continued for a further 2 weeks. If necessary, the ACE-inhibitor dose was temporarily reduced. If the study medication was well tolerated, uptitration to maximum target doses was encouraged.

4.4. Maintenance
As soon as a patient reached the maximum dose, or remained on the same dose for more than 4 weeks, the maintenance phase began. A clinical assessment (NYHA class and physical examination) will be performed at each 4 monthly maintenance visits and at the end of the study. A blood sample will be taken for haematology and biochemistry at the maintenance visits in the first year, annually thereafter and at the end of the study. A resting 12 lead ECG will be performed annually and at the end of the study.

All randomised patients will be followed to the end of the study, defined as at least 3.5 years from completion of recruitment, but not before 1020 fatal events have been recorded.

4.5. Laboratory parameters
For assessment of brain natriuretic peptide (NT-proBNP), blood samples were taken at baseline and in selected centres will be taken during the course of the trial in order to look for a correlation between this marker peptide and the progression of the disease in the individual patient.

	5. Statistical design and analysis

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
5.1. Primary variables, statistical hypothesis and sample size
The study was planned with an event-driven design to investigate whether there is a difference between carvedilol and metoprolol with regard to all-cause mortality in patients with chronic heart failure (statistical null hypothesis: no difference between carvedilol and metoprolol for the time-to-event distribution of all cause mortality). Originally the trial was designed to detect a 20% reduction in mortality with 90% power assuming an overall two-sided type I error of 0.05. Using these assumptions this required 2800 patients to be randomised within 1.5 years and for 750 deaths to have occurred (unless the DSMC recommended early termination after one of the regular interim analyses). Highly conservative stopping rules were used resulting in virtually no impact on the -level for the final analysis (Peto method).

The introduction of the co-primary endpoint and the implication of the dilution effect on the possible difference in mortality caused by patients who prematurely stopped study treatment required a recalculation of the necessary number of fatal events [25]. This recalculation determined that 1020 fatal events are required to detect with at least 80% power a risk reduction of 20% with the three following assumptions:

• premature discontinuations lead to a dilution effect of the anticipated risk reduction in mortality by 20%.
  
• an aggregate one year mortality rate of 8.1%.
  
• the overall type I error of =0.05 is split, 0.04 for ‘all cause mortality’ and 0.01 for ‘all cause hospitalisation and all cause mortality’.
  

The last fatal event is now expected by November 2002, assuming a constant hazard rate in both treatment groups and a proportional hazard ratio over time. For the combined endpoint of ‘all cause hospitalisation and all cause mortality’ approximately 2400 events are expected. With 80% power a risk reduction of 15% at a significance level of 0.01 can be detected. For this power calculation the above-mentioned dilution effect caused by premature discontinuations of treatment is considered.

5.2. Evaluation of patients
All randomised patients treated with at least one dose of study drug will be included in the intent-to-treat (ITT) analyses of efficacy and safety. All patients will be followed to the end of the study, even after premature discontinuation of study treatment. Patients who are lost to follow-up will be regarded as censored for the respective analysis at time of last follow-up.

5.3. Analysis of the primary variable
The primary variables will be analysed by log-rank tests without stratification. The relative risk reduction (hazard ratio and corresponding 95% confidence interval) will be obtained using a Cox Proportional Hazard model. In addition, the treatment effect will be estimated for the following sub-groups: (1) age; (2) male or female; (3) baseline NYHA class; (4) CHF aetiology (ischaemic, non-ischaemic); (5) baseline ACE-inhibition; (6) baseline heart rate ( or > median) (7) baseline diabetes, (8) baseline spironolactone and (8) baseline angiotensin receptor blockade.

5.4. Analysis of secondary variables
The most important secondary endpoints are:

• Time to first of cardiovascular hospitalisation or all-cause mortality.
  
• Time to first event: cardiovascular death, non-fatal acute myocardial infarction, heart transplantation or worsening of heart failure.
  
• Time to first cardiovascular death.
  
• NYHA class.
  
• Time to worsening of heart failure.
  
• Time to first cardiovascular hospitalisation or all cause mortality in elderly patients (>65 years).
  
• Time to first cardiovascular hospitalisation or all cause mortality in NYHA IV patients.
  

All time-to-event variables will be analysed with the same statistical methods as the primary endpoints. The NYHA class will be analysed using the baseline assessment as the stratification variable with patients who have died being assigned the worst rank.

	6. Study organisation

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
The organisation of COMET is overseen by four committees: (1) Steering Committee; (2) Data and Safety Monitoring Committee; (3) Endpoint Committee; and (4) the Technical Committee. Each has specific roles and responsibilities throughout the trial.

6.1. Steering Committee
The membership is Philip Poole-Wilson (UK, Chairman), John Cleland (UK), Marco Metra (Italy), Peter Hanrath (Germany) Michel Komajda (France), Andrea DiLenarda (Italy), Willem J. Remme (The Netherlands), Karl Swedberg (Sweden), Christian Torp-Pedersen (Denmark), Allan Skene (Nottingham Clinical Research Group) and representatives of the Sponsor. The Committee is responsible for the scientific direction of the trial, protocol design, scientific policies, monitoring of trial progress, sub-studies, co-operation with the Data and Safety Monitoring Committee, and for the reporting and publication of trial results. The Committee meets at least once per year during the trial, and is informed regarding trial progress, protocol adherence and other aspects as necessary.

6.2. Data and safety monitoring committee (DSMC)
The membership is Jacobus Lubsen (Switzerland, Chairman), Lars Wilhelmsen (Sweden), Hansjörg Just (Germany). The DSMC, thus, consists of one statistician and two cardiologists who are not trial investigators. The chairman of the DSMC is responsible for all communications on safety issues and reports to the Chairman of the Steering Committee. The DSMC has the principal responsibility of protecting the safety of patients in the trial. The DSMC may recommend early termination of the study in the event of safety concerns. Meetings are held immediately in the case of potential safety issues.

6.3. Endpoint Committee (EC)
The membership is John Cleland (UK, Chairman), Leif Erhardt (Sweden), Willem J. Remme (The Netherlands). The EC consists of three cardiologists who assign mode-of-death categorisations.

6.4. Technical Committee
The Technical Committee includes representatives of the Sponsor and the clinical trial data co-ordinator. This committee is responsible for protocol preparation, design of case record forms and for assessment, on a day-to-day basis, of scientific policy and operational issues which do not require the attention of the full Steering Committee.

6.5. Independent statistical centre
The independent clinical trial data centre is the Nottingham Clinical Research Group (NCRG), Nottingham, UK. The study database will be maintained by NCRG, who will also be responsible for providing monthly safety reports to the DSMC and for drug distribution to the investigating centres.

The principal investigators of each country represent their country on the Steering Committee and help the local selection of investigator sites and patient recruitment. Good clinical practice (GCP) is observed throughout the trial. Monitoring and GCP compliance is the responsibility of Roche affiliates in each participating country.

6.6. Sponsor
The sponsor is Roche Pharmaceuticals

	7. Clinical implications and conclusions

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
The beta-blocking agents proven to be effective in chronic heart failure (carvedilol, bisoprolol, metoprolol) differ both with respect to the extent of adrenergic receptor blockade as well as in terms of the presence or absence of other ancillary properties. The clinical relevance of these pharmacological differences has not been determined. The increased mortality with xamoterol [26] and the recent disappointing result with bucindolol in the Beta-Blocker Evaluation of Survival Trial (BEST) [13] further highlight that not only are the mechanisms of beta-blockers different but the clinical outcomes may also differ.

A number of small studies have shown differences between carvedilol and metoprolol in terms of the effect on ejection fraction and haemodynamics. A recent publication reported on 150 patients with heart failure who were randomly assigned to carvedilol or metoprolol [23]. Carvedilol caused greater anti-adrenergic effects than metoprolol, larger increases in left ventricular ejection fraction, and greater decreases in mean pulmonary artery and pulmonary wedge pressure. Both drugs improved symptoms, submaximal exercise tolerance, and quality of life to a similar degree. Similar findings emerged from a meta-analysis [24]. Left ventricular ejection fraction may be a surrogate parameter for outcome in chronic heart failure patients, but the question ultimately remains whether these hemodynamic differences in favour of carvedilol will result in an advantageous effect on mortality or hospitalisation in these patients.

A major difficulty when embarking on a trial comparing two drugs is the choice of dose. Attempting to undertake a dose response study in addition to a drug comparison is impractical. One basis for comparing beta-blocking agents is the effect on heart rate. Heart rate is a major determinant of myocardial oxygen consumption and cardiac workload. An elevated heart rate is frequently seen in patients with congestive heart failure and is in large part the result of increased sympathetic activity and decreased parasympathetic activity. In the Metoprolol Dilated Cardiomyopathy (MDC) trial [27] the metoprolol target dose was 100–150 mg daily, depending on body weight, age, heart rate, and blood pressure. The mean dose of metoprolol used was 108 (S.D. 51) mg daily and the mean heart rate reduction in the metoprolol group was 15 beats/min. The formulation of metoprolol used was metoprolol tartrate. In the US carvedilol heart failure study program, patients received a mean daily dose of 45 (S.D. 27) mg carvedilol and heart rate was reduced by 13 beats/min after a median treatment time of 6.5 months [9]. At the time when COMET was planned, Gilbert et al. [28] reported the results from a MDC sub-study, in which 48 patients had a mean dose of metoprolol tartrate of 127 (S.D. 38) mg and a heart rate reduction of 15 beats/min at rest and 22 beats/min during exercise. This would correspond to 0.12–0.17 bpm/mg decrease. Using the results of the MDC trial and calculating the bpm/dose decrease in the same way, the respective figure would be 0.14 bpm/mg for metoprolol. From the US carvedilol program [9] this figure would be 0.29 bpm/mg. A comparison of doses twice as high for metoprolol (25, 50 and 100 mg per day) on a milligram basis as compared to carvedilol (12.5, 25 and 50 mg per day) appeared to be reasonable. The target dose of carvedilol in COPERNICUS [12] was 25 mg bid. The Steering Committee selected 25 mg bid for carvedilol and 50 mg bid for metoprolol tartrate to be used as target doses in COMET to achieve a comparable degree of beta-blockade in each group.

In 1988 Sandberg et al. [29] compared a new multiple-unit, controlled release formulation of metoprolol, metoprolol succinate, with the conventional metoprolol tartrate tablets and demonstrated that the multiple-unit CR formulation showed a 30–35% reduced systemic availability. When COMET was initiated, the MERIT-HF trial was already ongoing. The maximal and mean doses of metoprolol succinate used in MERIT-HF were respectively 200 and 159 mg, representing 130 and 100 mg, respectively, of the salt (metoprolol tartrate) used in COMET. Thus, differences in target dose are unlikely to account for any differences in clinical outcome observed in this comparative trial.

COMET is a randomised, double-blind clinical trial directly comparing two different beta-blocking agents, carvedilol and metoprolol, and is powered to detect a difference in mortality or morbidity between these agents.

	Appendix A. List of Principal Investigators by country

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 
Austria Prim. Univ Prof Dr H. Drexler, Prof. F. Hoppichler, Prim. Dr H. Wimmer, Prof. D. Geissler, Prof. B. Schneeweiss, Univ. Prof. Dr W. Klein, Prim. Dr D. Brandt, Prim. Prof. F. Skrabal, Prim. Dr Georg Gaul, Prof. Dr T. Stefenelli, Univ Doz Dr F. Stockenhuber, Prim. Dr F. Wilhelm. Belgium Dr D. Duprez, Dr J. Creplet, Professor B. Marchandise, Dr R. Geukens, Dr V. Hamoir, Dr Henuzet, Dr Missault, Dr J.M. Chaudron, Dr Philippart, Dr Melchior, Dr B. Boland, Dr Gregorie, Dr Boxho, Dr M. Leonard, Dr B. Van Frachen, Dr Laruelle, Dr Vanwelden. Switzerland PD Dr Med Georg Noll, Prof. Dr. T. Moccetti, PD Dr A. Gallino, Dr L. Finci, Dr K. Weber, Dr P. Vulliemin. Germany Dr H. Herrmann, Prof. Dr R. Simon, Dr F. Hartmann, Dr C.J. Wick, PD Dr A. Jaeckle, Dr R.K. Klocke, Dr H. Nordbeck, Dr A. Nötges, Dr H.J. Arndt, Dr T. Schärtels, Dr W. Sehnert, Prof. Dr B. Lösse, Prof. Dr H.J. Trappe, Prof. P. Schuster, Dr P. Lenga, Dr R. Sack, PD Dr B. Krämer, Prof. Dr J. Nitsch, Dr T. Horacek, Dr J. Wübbelt, Prof. Dr P. Hanrath, Prof. Dr F. Saborowski, Dr P. Wacker, Prof. Dr M. Böhm, PD Dr R. Schwinger, Dr F.R. Althoff, PD Dr H. Darius, Prof. Dr H.P. Nast, Prof. Dr R. Hopf, Dr H. Riedel, Dr R. Stöhring, Prof. Dr B. Maisch, Dr E. Jagodzinski, Dr K.E. Hauptmann, Dr C. Bergmeier, PD Dr M.M. Borst, Dr B. Haaff, Dr F. Höltermann, Prof. Dr C. Holubarsch, Dr H. Wirth, Prof. Dr H. Sigel, Prof. Dr T. Risler, Prof. Dr R. Zimmerman, Dr J. Hetzel. Dr P. Kratochvil, Prof. Dr J. Cyran, PD Dr A. Schmidt, Dr H.J. Frielitz, Prof. Dr L. Neyses, Dr H. Beyer, Dr F. Freytag, Prof. Dr R. Uebis, Dr K. Bergmann, Prof. Dr M.G. Gottwik, Prof. Dr G. Schmidt, Dr Stempfle, Prof. Dr C. Angermann-Gerhardt, Prof. Dr W. von Scheidt, Prof. Dr O.J. Titlbach, Prof. Dr C. Nienaber, Prof. Dr W. Urbaszek, Dr F. Richter, Dr S. Marbach, Dr C. Weirich, Dr J. Krülls-Münch, Dr K. Herrmann, Dr F. Menzel, Prof. Dr Landgraf, Prof. Dr H.U. Klein, Dr R. Zotz, Dr S. Spitzer, Dr E. Altmann, Prof. Dr D. Pfeiffer, Prof. Dr H.R. Figulla. Denmark Prof. C. Torp-Pedersen, Dr Per Hildebrandt, Dr Torben Glud, Dr A. Deding, Dr B. Engby, Dr J. Markenvard, Dr A. Thomassen, Dr M. Scheibel. Spain Dr I. Mínguez Enríquez de Salamanca, Dr I. González Maqueda, Dr C. Saenz de la Calzada, Dr L. Martínez Elbal, Dr L. Plaza Celemín, Dr A. Grande Ruiz, Dr J.E. Muñoz Moral, Dr C. Martín Luengo, Dr L. Rodríguez Padial, Dr F. Fernández Avilés, Dr E. de Teresa Galvan, Dr F. Malpartida Torres, Dr J. Azpitarte Almagro, Dr V. López García-Aranda, Dr J. Burgos Cornejo, Dr A. Martínez M, Dr J. Beltrán Rodríguez, Dr C. Piñero Gálvez, Dr J.C. Vargas Machuca, Dr V. Nieto Lago, Dr I. Laynez Cerdeña, Dr I. Ferreira Montero, Dr J.M.^a Aguirre Salcedo, Dr P. Montes Orbe, Dr A. Llácer Escorihuela, Dr J.A. de Velasco Ramis, Dr F. Sogorb Garri, Dr J.J. Poveda Sierra, Dr J.L. Rodríguez Lambert, Dr A. Castro Beiras, Dr C. Pallarés Monleón, Dr C. Ridao García, Dr J. Bruguera Cortada, Dr A. Francino Batlle, Dr E. Galve Basilio, Dr L. Saenz Cusí, Dr V. Valle Tudela, Dr H. Pérez Hernández. Finland Dr H. Leinonen, Dr L.M. Voipio-Pulkki, Dr A. Palomäki, Dr M. Ikäheimo, Dr P. Kettunen, Dr S. Pohjola-Sintonen, Dr E. Koskela, Dr K. Soininen, Dr J. Melin, Dr L. Hämäläinen. France Dr Hagege, Dr P. Duc, Dr R. Dimitrou, Dr H. Mann, Dr G. Baradat, Dr P. Dugrand, Dr P. Coulon, Dr Y. Chotard, Dr Nitel, Dr P. Sultan, Dr A. Julliard, Dr M. Burdin, Dr Roncalli, Dr Armengaud, Prof. Y. Juilliere, Prof. Preiss, Dr Pinzani, Dr Fournie, Dr Lorie, Dr Deshayes, Dr J.P. Bertinchant, Dr Wuillermin, Dr Aleil, Dr Brandt, Dr Ledain, Dr Valy, Dr De Groote, Dr N. Lucke, Dr V. Lucke, Dr S. Baleynaud, Dr Le Potier, Prof. P. Bareiss, Dr Doutreleau, Prof. Roul, Pr Le Marec, Dr Trochu, Dr Delhoume, Dr Lande, Dr Chedru, Dr Hossle, Dr A. Bieth, Dr Pathé, Dr Marchand, Dr Lipiecki, Dr Reboud, Dr Rossignol, Dr Dujardin, Dr Coisne, Dr Christiaens, Dr A. Verdun, Dr Heitz, Dr Allard-Latour, Dr Abrieu, Dr Chassing, Dr Caron, Dr Camier, Dr E. Decoulx, Dr Chartier, Dr L. Genet, Dr N. Guillard, Dr Haddad, Dr Duval, Dr Lallemant, Dr F. Leroy, Dr Dujardin, Dr Raczka, Dr Demarcq, Prof. Habib, Dr Garcia, Dr Estampes, Dr Discazeaux. Hungary Prof. Dr L. Cserhalmi, Prof. Dr I. Preda. Italy Prof. C. Brunelli, Dr M. Orlandi, Prof. S. Pirelli, Dr P Zonzin, Prof. A Branzi, Prof. S. Iliceto, Prof. S. Vassanelli, Prof. Klugmann, Dr A. Di Lenarda, Dr A. Murrone, Prof. C Fiorentini, Prof. G.P. Trevi, Prof. S. Coglitore, Dr M. Mariani, Dr L. Tantalo, Dr S. Forconi, Prof. G. Mattioli, Dr D. Scrutinio, Prof. L. Dei Cas, Dr E. Adornato, Dr G. Giuffrida, Prof. G. Gensini, Prof. F. Fedele, Prof. B. Tucillo. The Netherlands Dr H.W. Vliegen, Dr J.C.A. Hoorntje, Dr M.P. Freericks, Dr B.J. van den Berg, Dr D.J.A. Lok, Dr J.R.M. Peters, Dr L.H.J. van Kempen, Dr J.H. Cornel, Dr J.L. Posma, Dr A.H.E.M. Maas, Dr H.R. Michels, Dr D.P. Hertzberger, Dr W. Jaarsma, Dr A.J.A.M. Withagen, Dr P.E. Polak, Dr M.C.G. Daniels, Dr J.A. Kragten, Dr B.J.B. Hamer, Dr T.B. Tan, Dr A.H.M.M. Balk, Dr J.H. Kirkels, Dr C.M. Leenders, Dr J.C. Chin, Dr G. Hoedemaker, Dr L.H. Savalle, Dr S.A.M. Said. Norway Dr PK Rönnevik, Dr K. Dickstein, Dr S. Njålla, Dr B. Wik. Portugal Prof. Dr L. Providência, Prof. Dr R. Ferreira, Prof. Dr R. Gonçalves, Dra I. Mendonça, Prof.^a Dra F. Ceia, Dr N. Lousada, Prof.^a Dra C Vagueiro. Sweden Prof. K. Swedberg, Dr A. Stjerna, Dr J. Jonsson, Dr T. Kellerth, Dr L. Klintberg, Dr G. Agert, Dr C. Dahlén, Dr L. Åström, Dr G. Gustafsson, Dr J. Ellström, Dr S. Ekdahl, Dr I. Ödmansson, Dr B. Möller, Dr B. Pettersson, Dr T. Messner, Dr C. Höglund, Dr U. Dahlström, Dr O. Nilsson, Dr B. Malmros, Dr E. Pantev, Dr O. Lövheim, Dr K. Boman, Dr A. Zingmark, Dr U. Ahremark, Dr A. Kirkegaard, Dr K.E. Karlberg, Dr B. Ullman, Dr C. Wettervik, Dr B. Karlsson, Dr S. Thorsén, Dr F. Rücker, Dr P. Kvidahl, Dr K. Tolagen, Dr D. Lundblad, Dr C. Cline, Dr M. Ali. United Kingdom Dr N.H. Brooks, Dr D.H. Roberts, Dr K.G. Oldroyd, Dr T.G. Trouton, Dr A. Brady, Dr S. Odemuyiwa, Dr B.A. Gould, Dr P. Das Gupta, Dr J. Dhawan, Dr I. Squire, Dr I. Hudson, Dr S. Walton, Dr I.N. Findlay, Dr M.N. Al-Khafaji, Dr P.S. Lewis, Dr A.D. Timmis, Dr J.S. Birkhead.

^aList includes centres which recruited at least 1 patient

	References

Top Abstract 1. Introduction 2. Study design and... 3. Endpoints 4. Study procedures, patient... 5. Statistical design and... 6. Study organisation 7. Clinical implications and... Appendix A. List of... References

 

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