1Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Trust, London, UK
2National Heart and Lung Institute, Imperial College of Science Technology and Medicine, London, UK
3Division of Cardiology, University of Alberta, Edmonton, Canada
4Faculty of Medicine, University of Sydney, Sydney 2006, Australia
5Department of Cardiology, University Hospital, Groningen, The Netherlands
6Institute of Cardiology, Academy of Science of Ukraine, Kiev, Ukraine
7Hungarian Institute of Cardiology, Budapest, Hungary
8Service de Cardiologie, Hôpital Beaujon, Clichy, France
9University of Pharmacy and Medicine, Cluj Napoca, Romania
10Department of Cardiology, University of Ferrara, Ferrara, Italy
11Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS, Gussago, Italy
12Service de Pharmacologie, Hôpital Pitie-Salpetrière, Paris, France
13Cardiology Division, Hospital General Vall d'Hebron, Barcelona, Spain
14Department of Cardiology, IRCCS Policlinico San Matteo, Pavia, Italy
151st Department of Medicine, Masaryk University Hospital, Brno, Czech Republic
16Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Homburg/Saar, Germany
17Department of Cardiology, Charité Campus Virchow-Klinikum, Berlin, Germany
18Medical Research Council Biostatistics Unit, Cambridge, UK
Received 26 November 2004; revised 10 December 2004; accepted 15 December 2004; online publish-ahead-of-print 9 January 2005.
* Corresponding author. Tel: +61293514579; fax +61293516645. E-mail address: ajscoats{at}aol.com
See page 203 for the editorial comment on this article (doi:10.1093/eurheartj/ehi118)
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Abstract |
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Methods and results We randomly assigned 2128 patients aged 70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction
35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placebo. The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). Analysis was by intention to treat. Mean duration of follow-up was 21 months. Mean age was 76 years (SD 4.7), 37% were female, mean ejection fraction was 36% (with 35% having ejection fraction >35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.740.99; P=0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.711.08; P=0.21).
Conclusion Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.
Key Words: Heart failure Elderly Beta-blocker Nebivolol Randomized trial Ejection fraction
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Introduction |
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Heart failure is characterized by changes in many neurohormonal mechanisms, but notably activation of the sympathetic and reninangiotensinaldosterone systems. Inhibition of these two systems is the mainstay of current treatment.7 Beta-blockers have been shown to reduce adrenergic drive, improve autonomic balance, and reduce ventricular wall stress.8,9 Several large randomized trials and meta-analyses have shown that in patients with a low ejection fraction, beta-blockers reduce hospital admissions for worsening heart failure and the risk of death by 30%.1014
The average age of patients in these previous placebo-controlled mortality and morbidity studies of beta-blockers in heart failure has been 63 years, and patients with an ejection fraction >40% were excluded.14 In a community-based study, the average age of new incident cases of heart failure was 76 years.3 The lack of evidence from a representative sample of elderly patients with heart failure has raised doubts about extrapolating the current evidence for beta-blockers to patients in the community. More relevant evidence from randomized trials is needed to clarify the balance of risk and benefit of beta-blockers in elderly patients with a broad range of ventricular function.
Nebivolol is a beta-1-selective blocker with vasodilating properties related to nitric oxide modulation.1517 This effect may improve tolerability in elderly patients with heart failure, where endothelial vasodilator reserve may be limited. There is also evidence that nebivolol may have advantages in patients with diastolic dysfunction.18 The SENIORS Study (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) was undertaken to determine the effect of nebivolol on mortality and morbidity in elderly patients with heart failure, regardless of ejection fraction.
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Methods |
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Patients
To be eligible, patients had to be aged 70 years, provide written informed consent, have a clinical history of chronic heart failure with at least one of the following features: documented hospital admission within the previous 12 months with a discharge diagnosis of congestive heart failure or documented left ventricular ejection fraction
35% within the previous 6 months. The main exclusion criteria were new drug therapy for heart failure in the 6 weeks prior to randomization, any change in cardiovascular drug therapy in the 2 weeks prior to randomization, heart failure due primarily to uncorrected valvular heart disease, contraindication or previous intolerance to beta-blockers (e.g. heart rate <60 beats/min or systolic blood pressure <90 mmHg), current use of beta-blockers, significant hepatic or renal dysfunction, cerebrovascular accidents within the previous 3 months, and being on a waiting list for percutaneous coronary intervention or cardiac surgery or other major medical conditions that may have reduced survival during the period of the study.
Screening and randomization
Patients were screened for eligibility at participating centres by checking hospital outpatient lists and admissions for heart failure within the previous year. Patients underwent echocardiography after entry into the study but prior to administration of the study drug. A master randomization list stratified by centre was prepared and held securely. Randomization to nebivolol or placebo on a 1:1 basis was carried out by telephone call to a central office (Clinical Data Care, Lund, Sweden). Patients were allocated a treatment number which corresponded to the appropriate study treatment packs.
Study medication
Nebivolol or placebo tablets were provided in identical packaging and tablet appearance. The initial dose was 1.25 mg once daily, and, if tolerated, this was increased to 2.5 and 5 mg, respectively, every 12 weeks, reaching a target of 10 mg once daily over a maximum of 16 weeks. Dose titration was performed during a visit to the hospital or clinic, and patients were observed for up to 2 h after taking the new dose to assess tolerability. Up-titration could be stopped or delayed depending on symptoms, possible side-effects, or at the judgement of the local investigator.
Patient follow-up
Following the titration phase, the next two visits were scheduled at 4 and 6 months after randomization, and further visits at 3-monthly intervals until the end of the study. A 30-day safety follow-up visit was planned for all patients after the last study drug administration to document any post-treatment adverse effects. The initial protocol specified a minimum observation period of 6 months for all patients, but this was amended to a minimum of 12 months by the Steering Committee in March 2003 when it was observed in blinded analysis that the composite primary event rate was below the expected rate. The end of the observation period for all patients was set at 15 November 2003. In those patients who did not attend their end of observation follow-up visit, vital status was determined by direct enquiry, national registers of death, and review of practice records.
Monitoring, data management, and reporting of adverse events
Study monitoring and data management were performed by the contract research organization Parexel GmbH (Berlin, Germany) under the supervision of the Sponsor. Patient data were recorded on paper case report forms. At regular intervals validation of data was undertaken and all resulting queries were resolved with investigators. Serious adverse events, other than those defined as clinical outcome events, were reported by investigators in an expedited manner and reviewed centrally. An independent and experienced Data and Safety Monitoring Committee regularly examined unblinded data prepared by an independent statistician. In all four interim unblinded analyses,19 no reason was found for safety concerns.
Independent supervision of the study
The protocol was developed by an independent Steering Committee in collaboration with the Sponsor. The Steering Committee comprised cardiologists from hospitals and academic centres in the participating countries. The responsibilities of the Steering Committee included overseeing the scientific conduct of the study, independent statistical analysis, presentation of the results at scientific meetings, and preparation of manuscripts for publication. The independent Data and Safety Monitoring Committee was responsible for reviewing unblinded study data at regular intervals and ensuring that the Steering Committee was informed of any safety concerns or efficacy issues during the course of the study. All reported deaths and hospital admissions were referred to the independent Clinical Events Review Committee, blinded to treatment, for review of medical records and any other documentation and for final classification of events.
Study outcomes and definitions
The primary outcome was the composite of all cause mortality or cardiovascular hospital admission (time to first event). This outcome was chosen to reflect the potential effect of nebivolol on quality of life in elderly patients in addition to an effect on the risk of death. Secondary outcomes included all cause mortality, the composite of all cause mortality or all cause hospital admissions, all cause hospital admissions, cardiovascular hospital admissions, cardiovascular mortality, the composite of cardiovascular mortality or cardiovascular hospital admissions (time to first event for all of them), functional capacity by New York Heart Association (NYHA) class assessment, and 6-min walk test at 6 months. Deaths were sub-classified by the Clinical Event Review Committee into cardiovascular deaths, non-cardiovascular deaths, or deaths of unknown cause. Hospital admissions were defined as admissions to hospital involving a stay of at least 24 h (excluding hospital admissions planned before randomization and planned admissions for study-related procedures). Cardiovascular admissions included those for cardiac causes (e.g. worsening heart failure, acute coronary syndromes), cerebrovascular causes, or other cardiovascular causes. All other causes of hospital admission were classified as non-cardiovascular or unknown, if relevant information was missing.
Statistical methods
On the basis of previous studies, it was estimated that a sample size of 1700 patients observed for an average 1.5 years (2 years for recruitment and a minimum follow-up of 0.5 years) would provide 90% power to detect a proportional difference of 25% between nebivolol and placebo with a two-sided significance level of 0.05. This assumed a mean annual rate for the primary outcome of 25% in the placebo group and an overall non-compliance rate of 20% in the nebivolol group. To allow for the possibility of lower than expected event rates and higher levels of non-compliance, and losses to follow-up, a total sample of 2000 patients was specified. The sample size was estimated using a time-driven rather than an event-driven approach. The statistical analysis was carried out using the intention to treat according to a plan drawn up before the outcome data were available. The pre-specified primary outcome was analysed using a Cox proportional hazards model with randomized treatment as the major covariate adjusted for baseline age, gender, and ejection fraction. A further analysis was performed with treatment as the sole covariate. Similar analyses were carried out for secondary outcomes unadjusted for multiple comparisons. Whether the effect of nebivolol varied according to five pre-specified risk factors of major interest (Figure 4) was assessed by tests of interaction in Cox-proportional hazard regression analyses adjusted for age, gender, and ejection fraction. A two-sided significance level of 0.05 was specified. Seven exploratory analyses that were not pre-specified in the statistical analysis plan are reported and are clearly labelled as such.
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Results |
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Haemodynamics
Mean (SD) systolic blood pressure, diastolic blood pressure, and heart rate at the first maintenance visit (4 months), taking the last observation available for patients with missing data, were 132.3 (19.9) and 135.2 (20.3) mmHg, 76.3 (10.4) and 78.1 (10.2) mmHg, and 68.8 (12.5) and 77.4 (13.6) beats/min in the nebivolol and placebo groups, respectively. Changes from baseline [mean (SD)] in the nebivolol and placebo groups, respectively, for systolic blood pressure were 6.3 (18.2) and 4.3 (17.9) mmHg, for diastolic blood pressure 4.2 (10.6) and 2.4 (10.0) mmHg, and for heart rate 10.3 (14.3) and 1.5 (14.0) beats/min.
Primary outcome
The proportion of patients who suffered death or cardiovascular hospital admission in the nebivolol group was 31.1% compared with 35.3% in the placebo group [hazard ratio (HR) 0.86, 95% CI 0.740.99; P=0.039; Table 3]. The unadjusted analysis showed an HR of 0.85 with the same CI (P=0.034; Table 3). The absolute risk reduction is 4.2%, suggesting that 24 patients would need to be treated for 21 months to avoid one event. The KaplanMeier plot (time to event) suggests that the curves for nebivolol-treated patients compared with placebo for the primary outcome separate after about 6 months and continue to diverge for the duration of follow-up (Figure 3A).
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All cause mortality
The proportion of deaths was 15.8 and 18.1% in the nebivolol and placebo groups, respectively (HR 0.88, 95% CI 0.711.08; P=0.21; Table 3). Time to all cause death is shown in Figure 3B. The proportion of cardiovascular deaths which might be considered sudden deaths was 36% in the nebivolol group and 48% in the placebo group.
Other secondary outcomes
The proportions of cardiovascular hospital admissions were 24.0 and 26.0% in the nebivolol and placebo groups, respectively (HR 0.90, 95% CI 0.761.06). Other secondary outcomes including total mortality, cardiovascular mortality, or all cause mortality and all cause hospitalization are shown in Table 3.
Analyses which were not pre-specified
In order to put the results of SENIORS in the context of previous beta-blocker trials, which recruited younger patients and excluded patients with higher ejection fractions, we identified the subgroup of patients most similar to the previous major outcome trials. In this subgroup, defined as patients of less than median age (75.2 years) with an ejection fraction 35% (n=342 for nebivolol and n=342 for placebo), the HR for the primary outcome was 0.73 (95% CI 0.560.96). For all cause mortality alone, the HR was 0.62 (95% CI 0.430.89). This suggests an efficacy for nebivolol similar to that seen in similar patient cohorts for metoprolol-controlled release, bisoprolol, and carvedilol. If an ejection fraction threshold of 40% rather than 35% was used, there was no material difference to the results for the subgroup comparisons. For the primary endpoint, in the population with ejection fraction
40%, HR=0.86 (95% CI 0.731.03; P=0.095) and for ejection fraction >40%, HR=0.83 (95% CI 0.621.11; P=0.203). As age was a particular focus of the SENIORS trial, we also analysed patient cohorts between median age (75.2 years) and 85 years (n=459 for nebivolol and n=482 for placebo) where the HR for the primary endpoint was 0.91 (95% CI 0.741.13) and for patients >85 years (n=69 for nebivolol and n=54 for placebo) where the HR was 1.32 (95% CI 0.732.37). There was no difference between the groups for hospitalization for heart failure [placebo 144 (13.7%), nebivolol 145 (13.9%), HR=0.99 (95% CI 0.791.25; P=0.95)].
Adverse events
Adverse events are shown in Table 4. There were no differences other than those expected of a beta-blocker, namely, an increased incidence of bradycardia and a decrease of angina pectoris and unstable angina. Bradycardia was associated with withdrawal from blinded treatment in 18 and 4 nebivolol and placebo treated patients, respectively.
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Discussion |
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Several large randomized trials and meta-analyses of previous trials have shown that beta-blockers reduce the risk of death or hospitalization in patients with heart failure.1014 In those studies the mean age was 63 years and the estimated mean ejection fraction was 25% (most studies had an upper limit for ejection fraction of 35 or 40%). Subgroup analyses of some of the large studies indicated this benefit was present in patients>65 years,13,20,21 but there was little information in those >70 years and those patients with ejection fraction >35%. The need for additional data has been emphasized.8,11,22,23 SENIORS extends the evidence of benefit of beta-blockade to a broad range of elderly patients with heart failure including those with mild left ventricular dysfunction or preserved ventricular function. The patients in the SENIORS study more closely resemble the general population of patients with heart failure, where the mean age is 76 years.2,3 Other observational studies have assessed the effects of beta-blockers in elderly patients24,25 but no previous randomized controlled trial has had the power to demonstrate efficacy in elderly heart failure patients specifically.
The estimated HR for the primary outcome in SENIORS was 0.85, suggesting a lesser degree of risk reduction compared with previous large trials. Nevertheless, both components of the primary outcome (all cause mortality and cardiovascular hospital admission) show a similar and consistent effect indicating that the results are robust with a 15% proportional and 4% absolute reduction in risk. We undertook a subanalysis which was not pre-specified (age less than median and ejection fraction 35%) in order to determine the result for patients most similar to those recruited in previous trials. The findings were similar to the results from previous trials, with significant 27 and 38% reductions in the primary composite endpoint and all cause mortality, respectively, indicating that nebivolol has beneficial effects of a magnitude similar to those of other beta-blockers proved to have major outcome benefits in heart failure.
SENIORS explored the effects of nebivolol in several clinically important subgroups of patients. Given the overall P-value for the primary endpoint of 0.039 there was, of course, limited power to detect potential interactions. Despite advanced age being an inclusion criterion one important potential interaction was still that of age itself. The increased risk of dying from a natural cause in the elderly may compete with the potential benefits of a treatment. Thus, it is plausible that there is a threshold of biological age, rather than chronological age, beyond which the benefit of treatment is difficult to show. Although the benefits of nebivolol appeared to be less in patients >75 years, age as a continuous variable did not significantly affect the treatment effect. It is possible that beta-blockers, or indeed any treatments, are in reality less effective in the very elderly.
Heart failure with preserved systolic function is common in population samples of heart failure patients, especially in the older age groups.26 Previous mortality and morbidity studies both for ACE inhibitors and for beta-blockers have typically excluded such patients. One trial within the CHARM programme27 investigating the effects of candesartan did not show a significant effect on its primary endpoint. SENIORS showed both a significant overall treatment effect and a virtually identical point estimate of risk reduction for patients with low and preserved ejection fraction. This is the best evidence to date of a treatment likely to be effective in the substantial proportion of the elderly population with heart failure who have a broad range of ventricular dysfunction, and suggests the beta-blocker nebivolol can be recommended for heart failure, irrespective of ejection fraction.
Nebivolol is a beta-1-selective blocker with vasodilator properties which appear to be due to modulation of nitric oxide release that reduces peripheral vascular resistance.1517 Nebivolol has been extensively investigated in hypertension and has received approval in many jursidictions for this indication. The exact mechanisms of benefit in heart failure are not known, but may include reduction in ventricular wall stress,28 reduction in adverse neurohormonal stimulation, and reduction in incidence of acute coronary events, especially as half of the patients had a prior myocardial infarction. In SENIORS, patients were started on a dose of 1.25 mg once daily and titrated to a target dose of 10 mg over a mean of 7 weeks. Elderly patients are at higher risk of hypotension, bradycardia, and other side-effects of beta-blockers when compared with younger patients. Nevertheless, 68% of patients in the nebivolol group reached the maximum dose, with only 6% not tolerating any dose. This good tolerability may, in part, be related to the vasodilating properties of nebivolol so that results may not be generalizable to other beta-blockers when used in elderly heart failure patients. Previous studies have raised the possibility that beta-blockers in heart failure need to be evaluated separately and the effects of one cannot be extrapolated to another.29,30 It has been estimated that the probability of receiving beta-blocker therapy is substantially lower in the elderly31,32 and the most quoted reasons for this are concerns that physicians are less convinced by the body of evidence in this age group.33,34 The SENIORS study should allay this concern.
The SENIORS trial shows that the beta-1-selective vasodilating beta-blocker nebivolol is well tolerated and effective in reducing mortality and morbidity in patients of age >70 years with heart failure, regardless of the initial ejection fraction. Nebivolol can be used in this common group of patients for the treatment of heart failure.
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Acknowledgements |
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Appendix |
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Data Safety and Monitoring Committee
Alberto Zanchetti (chair), Università di Milano and Instituto Auxologico, Italy; Basil Lewis, Lady Davis Carmel Medical Center, Haifa, Israel; Markku Nieminen, Helsinki University Central Hospital, Helsinki, Finland; Peter Sleight, University of Oxford, Oxford, UK; Simon Thompson, Medical Research Council Biostatistics Unit, Cambridge, UK. Independent statistical analyses for the Data Safety and Monitoring Committee and for the manuscript were provided by Tony Brady (Sealed Envelope Ltd, London, UK). (S.T. has overseen the data analysis and approved the final version of this manuscript.)
Clinical Event Review Committee
Kristian Thygesen (chair), Aarhus University Hospital, Denmark; Michael Frenneaux, University of Wales, UK; Michal Tendera, Silesian School of Medicine, Katowice, Poland; Marcelo Shibata (representative of the Steering Committee), Division of Cardiology, University of Alberta, Edmonton, Canada; Gianfranco Sinagra, Ospedale Maggiore, Trieste, Italy.
Study Co-ordination
Menarini Ricerche SpA (study no. MR/01-99/01-Nhf): Angela Capriati (corporate clinical research director), Ines Koch (study manager), Kai Schumacher (study physician), Giacomo Mordenti (statistician), Maria Mercede Brunetti (quality assurance), Isabel Paredes (drug safety unit)
Parexel GmbH: Stephan Jung (senior project manager), Barbara Veprek (project manager), Werner Wierich (senior director biostatistics and programming)
Clinical Trials and Evaluation Unit (Secretariat to Steering Committee): Marcelo Shibata, Nicola Delahunty, Anil Taneja, Marcus Flather, Jean Booth
Investigators
Czech Republic: Prof. Michael Aschermann, MUDr Jiri Carda, MUDr Bohuslav Cernosek, MUDr Jaroslav Doubravsk, Prim. MUDr Bohumil Filipensk
, Prof. Pavel Gregor, MUDr Petr Kovár, MUDr Josef Kroupa, MUDr Milena Kubicková, MUDr Igor Macel, MUDr Frantisek Padour, MUDr Antonin Pavelka, MUDr Lubomir Pollák, MUDr Jana Popelová, MUDr Karel Pospisil, MUDr Petr Reichert, Prof. Borivoj Semrad, MUDr Hana Skalická, As. MUDr Rudolf Spacek, Doc. MUDr Jindrich Spinar, Prof. Lenka Spinarova, MUDr Dag Tichy, Prof. Jiri Toman, MUDr Petr Vales
France: Prof. Pierre Bareiss, Dr Hassan Belfaqih, Prof. Joel Belmin, Dr Patrick Bocquet, Dr Jean-Patrick Bousser, Dr Francois Funck, Prof. Michel Galinier, Dr Eric Garbarz, Dr Richard Isnard, Prof. Guillaume Jondeau, Dr Jean-Claude Kahn, Dr Khalifé Khalife, Dr Pierre Larrieu, Dr André Marquand, Dr Yannick Neuder, Dr Jean-Francois Thébaut
Germany: Prof. Michael Böhm, PD Dr Uwe Desaga, Prof. Stephan Holmer, Dr Detlev Nunberger, Prof. Burkert Pieske, Dr Andreas Schreckenberg, Dr Walter Sehnert, Prof. Wolfram Voelker, Dr Jürgen Wachter
Hungary: Prof. József Borbola, Dr Béla Herczeg, Prof. Pál Kárpáti, Dr Béla Öze, Dr Béla Pálossy, Dr László Regós, Dr Aladár Rónaszéki, Dr Mátyás Sereg, Dr Sándor Tímár, Dr Csaba Tóth, Dr Károly Tóth, Dr József Ványi, Dr István Varga, Prof. Gabor Veres
Italy: Dr Aldo Carbonari, Dr Giuseppe Castiglioni, Prof. Roberto Ferrari, Dr Antonio Grieco, Dr Francesco Ippolito, Dr Danilo Neglia, Dr Gianfranco Parati, Dr Roberto Pedretti, Dr Gianni Rovelli, Dr Franco Russo, Dr Vito Santoro, Prof. Luigi Tavazzi, Dr Massimo Uguccioni
Netherlands: Dr Adriaan Bredero, Dr Jeroen Bucx, Dr Eugene Buys, Dr P.A.R. de Milliano, Dr Anita Derks, Dr Peter Dunselman, Dr Erwin Göbel, Dr B. Hamer, Dr J.A. Henneman, Dr Walter R.M. Hermans, Dr G.M. Jochemsen, Dr Hans Kragten, Dr T. Gie Liem, Dr G.C.M. Linssen, Dr Angela Maas, Dr M. Nagelsmit, Dr J. Posma, Dr Brian van den Berg, Dr Pieter van der Burgh, Dr Louis Van Kempen, Dr Rudolf A.M. van Langenveld, Prof. Dirk Jan van Veldhuisen, Dr Leen Van Wijk, Dr Jan C.L. Wesdorp, Dr Adrie Withagen
Romania: Prof. Ioan Victor Bruckner, Prof. Alexandru Campeanu, Prof. Radu Capalneanu, Conf. Dr Emilian Carasca, Dr Zorita Ciulea-Prepelita, Dr Mihail Crisu, Dr Sabina Diaconescu, Prof. Maria Dorobantu, Sef lucrari Dan Dumitrascu, Conf. Dr Carmen Ginghina, Prof. Alexandru Ioan, Dr Ferencz Jeszenszky, Dr Dorina Leasu, Conf. Dr Ioan Manitiu, Dr Constanta Motoc-Moarcas, Dr Codin Olariu, Dr Eugen Panturu, Prof. Mariana Radoi, Dr Marcela Rau, Conf. Dr Crina Sinescu, Dr Nicolae Stanciu, Sef lucrari Dr Mihail Stefanescu, Conf. Dr Cristina Tanaseanu, Dr Rodica Tataru, Dr Gabriel Tatu-Chitoiu, Dr Sebastian Toma, Dr Lacramioara Topolnitchi, Dr Alina Tudose, Conf. Dr Marius Vintila
Spain: Dr Fernando Alonso, Dr Julián Bayón, Dr Jordi Bruguera, Dr Román Calvo-Jambrina, Dr Jose M. Cruz-Fernandez, Dr Alfonso del Río, Dr Miguel Angel de Miguel, Dr Enrique Galve, Dr Amador López-Granados, Dr Ramón Martos, Dr Juan Motero, Dr Miguel Ribas, Dr Antonio Salvador, Dr Luis Sosa, Prof. Mariano Valdés, Dr Vicente Valle, Dr José A. Velasco
Switzerland: Prof. Augusto Franco Gallino, Prof. Tiziano Moccetti
Ukraine: Prof. Ekaterina Amosova, Dr Olga Barna, Dr Andrey Basylevych, Dr Nikolay Demeshko, Prof. Aleksandr Djadyk, Dr Boris Goloborodko, Prof. Tatjana Khomazyuk, Dr Sergiy Kolomiets, Prof. Yuriy Koltchin, Acad. Oleg Korkuschko, Prof. Volodymyr Kovalenko, Dr Igor Kovalskiy, Dr Igor Krayz, Prof Volodymyr Kubyshkin, Dr Svetlana Lichkanenko, Prof. Yuriy Mostovoy, Prof. Vasil Netyazhenko, Prof. Aleksandr Parkhomenko, Dr Mikhaylo Perepelyca, Prof. Tatyana Pertseva, Dr Roman Petrovskiy, Prof. Sergiy Polyvoda, Prof. Mykola Rishko, Dr Leonid Rudenko, Dr Yurii Rudyk, Prof. Ivan I. Sakharchuk, Prof. Viktor Syvolap, Dr Susanna Tikchonova, Dr Larisa Vasiljeva, Prof. Nikolay Vatutin, Prof. Vadim Vizir, Dr Andreiy Yahenskiy, Dr Anatoliy Zavgorodniy, Dr Vladymir Zhelezniy, Dr Alexey Zhumro
United Kingdom: Dr G.B. Ambepitiya, Dr Allan Bridges, Dr Kevin Channer, Dr Piers Clifford, Prof. Andrew Coats, Dr I.N. Findlay, Dr Robert Greenbaum, Dr Derek Harrington, Dr Sarfraz R. Khan, Prof. Gregory Lip, Dr Donald MacLeod, Dr Hugh F. McIntyre, Dr M. Millar-Craig, Dr Dave L. Murdoch, Dr Olusola Odemuyiwa, Dr Susan Pound, Dr Roxy Senior, Dr J.D. Stephens, Dr Jonathan Swan, Dr J.T. Walsh, Dr Clive Weston
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Footnotes |
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The Institutions of the Investigators are listed in the Appendix.
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References |
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