Journal of

Neurology

Editorial

© Springer-Verlag1992 J Neurol (1992) 239 : 299-301

Second European Stroke Prevention Study ESPS-2 Working Group* Received December 21, 1990 / Received in revised form March 26, 1991 / Accepted August 26, 1991

Summary. The computerized design, aims, organization, and structure of the E u r o p e a n Stroke Prevention Study 2 (ESPS-2) are presented. This clinical trial will investigate the effect of single and combination regimens of low-dose acetylsalicylic acid (50 mg daily) and dipyridamole (400 mg daily) versus placebo in secondary prevention of stroke and death.

Key words: Brain ischaemia - Prevention - Dipyridamole - Acetylsalicylic acid * List of participating centres: Belgium Algemeen Ziekenhuis Middleheim, Antwerp (Dr. Lowenthal, Chairman, Coordinating Committee) (Dr. DeDeyn); Cliniques Universitaires St. Luc, Brussels (Dr. Laterre); Universitair Ziekenhuis Gasthuisberg, Leuven (Dr. Carton); Centre Hospitalier Universitaire, Li4ge (Dr. Franck) Federal Republic of Germany Kliniken Schnarrenberg, Tiibingen (Dr. Diener); Rhein-Ruhr-Rehabilitationsklinik, Essen (Dr. Schtitt); Neurologische Universit~itsklinik, Essen (Dr. Diener); Albertinen Haus, Hamburg (Dr. MeierBaumgartner); Kliniken St. Antonius, Verbert (Dr. Ftisgen); Neurologische Universit~itsklinik, Mainz (Dr. Kr~imer);Diakoniekrankenhaus Rotenburg, Rotenburg/Wtimme (Dr. Hagenah); Nordwest-Krankenhaus Sanderbusch, Sande (Dr. Rohkamm) Finland University of Kuopio, Kuopio (Dr. Riekkinen, Dr. Sivenius); Savonlinnan Keskussairaala, Savonlinna (Dr. Kilpelainen); Turku University Central Hospital, Turku (Dr. Rinne, Chairman, Steering Committee) France C.H.U. de Montpellier, Montpellier (Dr. Blard); C.H.U. de la Timone, Marseille (Dr. Khalil) Ireland Cork Regional Hospital, Cork (Dr. Galvin, member Steering Committee); University College Hospital, Galway (Dr. Moran) Italy Istituto delle Malattie del Sistema Nervoso, Universita di Ancona, Torrette di Ancona (Dr. Provinciali) Norway University Hospital, Trondheim (Dr. Sjaastad); Haukeland Sykehus, Bergen (Dr. Thomassen) Portugal Hospital de Santa Maria, Lisboa (Dr. Ferro); Servico de Neurologia dos Hospitais de Universidade de Coimbra, Coimbra (Dr.

Introduction The first E u r o p e a n Stroke Prevention Study (ESPS-1) was a randomized, placebo-controlled, double-blind trial organized by Dutch, British, and Belgian neurologists and carried out at 16 centres in six countries. The trial, which was completed in 1985, enrolled 2,500 patients with a previous cerebrovascular event: transient ischaemic attack (TIA), 33.4% ; reversible ischaemic neurological deficit (RIND), 65%; stroke, 60.1%. Cunha); Servico de Neurologia de Hospital de San Antonio, Porto (Dr. Castro Lopes) Sweden Huddinge Sjukhus, Huddinge (Dr. Ersmark, Dr. G. Bovim); Karolinska Sjukhuset, Stockholm (Dr. Wahlgren) Switzerland Universit~itsspital, Ziirich (Dr. Baumgartner) Spain Hospital de la Santa Cruz y San Pablo, Barcelona (Dr. Escartin); Hospital General Valle de Hebron, Barcelona (Dr. Molins Girbau); University Hospital San Juan, San Juan-Alicante (Dr. Matias Guiu); Hospital de la S.S. La Fe, Valencia (Dr. Yaya Huaman) The Netherlands St. Ignatius Ziekenhuis, Breda (Dr. Stroy); Streekziekenhuis Helmond-Deurne, Helmond (Dr. Dijkstra); St. Laurentius Ziekenhuis, Roermond (Dr. van Gool); St. Gemini Ziekenhuis, Den Helder (Dr. van der Heyde); Maasland Ziekenhuis, Sittard (Dr. Hogenhuis); Scheper Ziekenhuis, Emmen (Dr. ten Napel); St. Josef Ziekenhuis, Kerkrade (Dr. Pasmans); Prot. Ziekenhuis "Willem Alexander", 's Hertogenbosch (Dr. Peperkamp); St. Elisabeth Ziekenhuis, Venray (Dr. Wiezer); Streekziekenhuis, Almelo (Dr. Gelmers) United Kingdom Ninewells Hospital and Medical School, Dundee (Dr. Forbes); Cardiff Royal Infirmary, Cardiff (Dr. Pathy, Dr. Woodhouse, Dr. Sastry); Derbyshire Royal Infirmary, Derby (Dr. Mishra); Oldchurch Hospital, Romford (Dr. Capildeo); Orsett Hospital, Orsett (Dr. Capildeo); Manor Park Hospital, Bristol (Dr. Windsor); St. Michael's Hospital, Norfolk (Dr. Fulcher); Royal Infirmary, Glasgow (Dr. Lowe); Jersey General Hospital, Jersey (Dr. Martin); Crawley Hospital, Crawley (Dr. Bailey); Bolton General Hospital, Bolton (Dr. Banerjee); Leeds Royal Infirmary, Leeds (Dr. Prentice); Woodend Hospital, Aberdeen (Dr. Hamilton); North Staffs Royal Infirmary, Stoke-on-Trent (Dr. Scarpello): St. Woolos Hospital, Newport (Dr. Brown) Correspondence to: A. Lowenthal, Jan Van Rijswijcklaan, 106, B-2018 Antwerp, Belgium

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Table 1. First European Stroke Prevention Study: side effects, significant differences

Stomach pains Vomiting Dyspepsia Peptic ulcer Paraesthesiae Bleeding

DP-ASAa

Placebo

171 26 223 13 8 91

96 8 155 2 1 48

P < 0.0001 P < 0.01 P < 0.001 P < 0.1 P < 0.05 P < 0.001

a DP, Dipyridamole; ASA, acetylsalicylic acid

Patients received either placebo or an active regimen consisting of 330 mg acetylsalicylic acid (ASA) and 75 mg dipyridamole (DP) three times a day for 2 years. Trial end-points were a reduction in stroke or death from any cause. When the data were analysed on an intention-to-treat basis, they showed a 33.5% reduction in stroke/death among those in the active trial arm as compared with the placebo patients [1, 2]. This is the greatest risk reduction demonstrated in any clinical trial published to date. Two issues, however, arising from the ESPS-1 trial remain to be addressed: 1. Of patients in the active arm, 34.1% dropped out of treatment or were lost to follow-up (29.9% dropped out of the placebo arm). These drop-outs from the active arm, in some cases occurring as late as the 2nd year of follow-up, were occasioned by drug side effects, which were reported by 13.1% in the active group (6.7% in the placebo group). Most frequently cited were adverse gastrointestinal reactions characteristic of A S A (see Table 1). The question asked, therefore, is whether lowering the dosage of A S A would reduce the drop-out rate while maintaining the efficacy of the combination regimen in secondary prevention of stroke. 2. Over the years, the relative roles of A S A and DP in secondary prevention have been questioned, and the existence of synergy between the two agents has been debated. For these reasons, a new clinical trial, ESPS-2, has been organized. The aims of the trial are to determine: 1. Whether the risk reduction observed in ESPS-1 can be achieved with a lower dose of ASA, thereby preventing the high indicence of ASA-related adverse effects seen in the first trial. 2. Whether an increased dosage of D P can compensate for the reduced dosage of ASA. 3. Whether A S A or D P given alone, rather than in combination, can achieve a significant reduction in cerebrovascular events. 4. Whether the combination of A S A and D P can produce greater efficacy than either agent alone. 5. Whether the cited drug regimens can produce a significant reduction in risk not only of secondary stroke,

but also in vascular disease in general, and myocardial infarction in particular.

Methodology ESPS-2 is a randomized, placebo-controlled, doubleblind, multicentre trial of risk reduction in patients experiencing a vascular ischaemic accident up to 3 months prior to enrolment. "Ischaemic vascular accident" is defined as neurological deficit due to involvement of the brain or brain stem without symptoms or signs of haemorrhage or tumour. Patients will receive one of four treatment regimens: placebo; ASA, 25 mg twice a day; slow-release DP, 200 mg twice a day; slow-release DP, 200mg twice a day, plus ASA, 25 mg twice a day. The end-points are stroke (fatal or non-fatal) and mortality from any cause (including fatal strokes). The incidence of TIAs, myocardial infarction, and all other vascular events will also be analysed. Statistical analyses will be performed only on an intention-to-treat basis. Therefore, inclusion criteria and data collection have been computerized - to minimize violation of inclusion criteria and misdiagnoses that might diminish the power of the study. A total of 5,000 patients will be recruited 1,250 for each of the four treatment groups. Sample size was established through computer simulation. The aim was a trial with 80% power to detect a significant difference at the 5% level. Computer simulations evaluated the appropriateness of four treatment groups with 1,600 patients per group, the same drop-out rate as was observed in ESPS-1, the same survival curves for placebo and combination treatment groups, and intermediate surivival curves for the two new treatment groups. Sensitivity analysis was performed by varying all parameters to reproduce as closely as possible the values observed in ESPS-1; 30% and 35% reduction in end-points were considered; and follow-up periods of 2 and 3 years were evaluated. After studying 100 computer simulations, it was determined that a sample size of 1,250 patients each for the four treatment groups would be appropriate, and that a 3-year follow-up period would merely increase the trial workload without increasing the trial's statistical power to detect differences. Computer simulations were used because the classical methods are based on amplifying hypotheses that we do not expect to be satisfied by our data. Nevertheless, the results of the simulations were similar to those obtained by those cruder methods, in which mortality and dropouts are approximated by exponential distribution.

Organization ESPS-2 is being managed by four different committees: 1. The Ethics Committee consists of five academic physicians not participating in the trial; their role is to monitor the safety of the trial.

301 2. The Steering Committee includes one representative of each of the 16 countries taking part in the study. 3. The Coordinating Committee consists of a permanent chairman and three physicians (internists or neurologists) who oversee the progress of the trial, assisted by the Technical Support unit (TSU) and the Morbidity and Mortality Assessment Group (MMAG). The TSU is in charge of day-to-day management, data collection, and on-site and in-house monitoring. The MMAG reviews all patients reaching an end-point or a relevant event. This committee also reviews diagnosis or eligibility questions raised by the TSU. 4. The Protocol and Publishing Committee, composed of representatives of the participating clinical centres, a statistician, and a representative of the sponsor, drew up the trial protocol and will deal with any changes in the protocol, should they prove necessary. This committee is also responsible for the publication policy.

Monitoring and data handling The computerized centre where randomization of patients takes place is located in Brussels and is part of the European Organization for Research and Treatment of Cancer (EORTC). All clinical centres participating in ESPS-2 are provided with a computer terminal connected with the randomization centre. Prior to actual randomization of any individual patient, clinical centres must answer a set of questions relating to patient eligibility. As part of the quality control of the data-handling process, all original data record sheets are stored, and only photocopies are handled. Data are entered into a computer twice, by different individuals. Computerized programs check the entry for missing data, incorrect entry, and inconsistencies within each entry. All forms are reviewed by two different physicians who ensure that the errors and inconsistencies are re-

ported on a special form that is dispatched to the clinical centre. To put it another way, the computerized system handles: automatic transfer of randomization data from the randomization centre to the TSU computer and statistical-center computer; double entry of data and a check for missing data, errors, and inconsistencies; control of all data sheets arriving in the TSU office; control of the special forms dispatched and responses received; ordering of drug samples and maintenance of sample inventory; scheduling of follow-up appointments; status of recruitment; all adverse reaction reports. The Laboratory of Medical Statistics at Brussels University is providing statistical support.

Status of the trial The ESPS-2 began in February 1989. By May 1991, more than 3,900 patients had been recruited by 55 clinical centres in 11 countries. Recruitment is expected to reach 5,000 patients by the end of 1991 or early in 1992. Allowing for a 2-year follow-up period, initial results will be available in 1994-1995.

Acknowledgements. We wish to thank: Dr. Bertrand-Hardy, Dr. Goossens, Dr. Hoeven, and Dr. Schapira for their help in writing this paper; the Laboratory for Medical Statistics, School of Public Health, Universit6 Libre de Bruxelles, Brussels, Belgium (Dr. P. Smets, P. Valente); the European Organizationfor Research and Treatment of Cancer, Brussels, Belgium; and our sponsor, Boehringer Ingelheim GmbH, Ingelheim am Rheim, FRG (Dr.Welhers).

References 1. The ESPS Group (1987) The European Stroke Prevention Study (ESPS) Principal endpoints. Lancet II : 1351-1354 2. The ESPS Group (1990) European Stroke Prevention Study. Stroke 21 : 1122-1130

Second European Stroke Prevention Study. ESPS-2 Working Group.

The computerized design, aims, organization, and structure of the European Stroke Prevention Study 2 (ESPS-2) are presented. This clinical trial will ...
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