European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke1

https://doi.org/10.1016/S0022-510X(96)00308-5Get rights and content

Abstract

In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose acetylsalicylic acid (ASA), modified-release dipyridamole, and the two agents in combination for secondary prevention of ischemic stroke. Patients with prior stroke or transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release dipyridamole alone (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years. Data from 6,602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for dipyridamole in reducing the risk of stroke (p ≤ 0.001) and stroke or death combined (p < 0.01). In pairwise comparisons, stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with combination therapy (p < 0.001). Risk of stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with dipyridamole alone (p = 0.015); and 24% with the combination (p < 0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p < 0.001) and dipyridamole (p < 0.01) for preventing TIA. The risk reduction for the combination was 36% (p < 0.001) in comparison with placebo. Headache was the most common adverse event, occurring more frequently in dipyridamole-treated patients. All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA in comparison to placebo or dipyridamole. We conclude that (1) ASA 25 mg twice daily and dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the secondary prevention of ischemic stroke and TIA; (2) when co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; (3) low-dose ASA does not eliminate the propensity for induced bleeding.

Introduction

In a recent review, Bonita (1992) describes stroke incidence and related mortality. Using selected studies from USA, New Zealand and Europe, she demonstrates that age-standardized incidence rates for first-ever stroke increase steeply from about 20 per 10,000 for people aged 50–64 year up to more than 200 per 10,000 for people aged 85 and over. Stroke mortality has been declining over the years but not necessarily stroke prevalence. In the same review, Bonita points out that an extrapolation from the Auckland Stroke Study suggests that in a population of 1 million, 1250 persons will have a first stroke each year and 350 will suffer a recurrent stroke. A large proportion of these people will remain handicapped and dependent. These factors together with a projected increase in the population older than 65 years, suggest a major burden on the community with respect to the care of stroke patients and the costs of acute and recurrent stroke.

Many investigators have sought to confirm that antiplatelet treatment would be of value for preventing secondary stroke and/or TIA with considerable uncertainty as to the outcome, including the trials named AICLA (Bousser et al., 1983), AITIA (Fields et al., 1977), UK-TIA (UK-TIA Study Group, 1991), SALT (SALT Collaborative Group, 1991) and ESPS-1 (ESPS Group, 1987). The Anti-platelet Trialists' Collaboration (1994a); Anti-platelet Trialists' Collaboration (1994b), Anti-platelet Trialists' Collaboration (1994c) performed a meta-analysis of all the randomized antiplatelet trials and demonstrated that ASA was efficacious in preventing recurrent thrombotic events and particularly in patients who had had prior myocardial infarction and prior cerebrovascular events. The analysis could not detect the merits of particular regimen, e.g. dose of ASA, usefulness of other agents etc., but the data did suggest that high doses of ASA were not more efficacious than lower doses. In addition, clinical pharmacological studies have suggested that very low doses of ASA may also be effective showing in healthy volunteers that 50 mg ASA per day and 400 mg dipyridamole per day significantly reduce ex vivo thrombus formation and have an additive effect in combination (Weisenberger, Nehmiz and Su, personal communication; Muller et al., 1990). Ticlopidine in two studies (Gent et al., 1989; Hass et al., 1989) has been shown to be effective in reducing risk of secondary stroke but is associated with significant adverse events and has not been universally approved for clinical use.

Two studies, from the American-Canadian Co-operative Study Group (1983) and AICLA (Bousser et al., 1983), on stroke secondary prevention involving a direct comparison of ASA alone to ASA combined with dipyridamole had been published. Neither of them did show a superiority of the combination over ASA alone. But both lacked the power to detect a small difference. Similarly the Anti-platelet Trialists' Collaboration (1988) failed to show a superiority of the combination over ASA alone in stroke prevention.

In 1987 the European Stroke Prevention Study was published (ESPS Group, 1987). In this trial dipyridamole at a daily dose of 225 mg (75 mg three times daily) was co-prescribed with ASA 990 mg daily (330 mg three times daily), for two years, in patients whose eligibility for the trial was determined by a prior ischemic stroke or TIA. The combination treatment showed a striking 38% reduction in secondary stroke over the group treated with placebo. This reduction was substantially more than that found in the analysis of trials using ASA alone.

In view of the conflicting data from the individual stroke prevention trials and the more recent debate with respect to the best dosing of ASA, it was felt by the study group that a placebo control arm could not be avoided for assessing this low dose (25 mg twice daily) of ASA. The ESPS-1 investigation had not shown the relative contribution of ASA and dipyridamole alone to the combination results. The protocol was considered and approved by the Ethics Committees of each participating centre and the central ethics review board.

The second European Stroke Prevention Study (ESPS-2) was designed to answer the following questions; (1) how effective are dipyridamole and ASA alone for prevention of secondary stroke, (2) is the combination of treatments superior to each agent given alone, (3) does ASA at the low dose of 50 mg eliminate the propensity to induce bleeding? ESPS-2 was a randomized, 2 × 2 factorial, double-blind, placebo-controlled, multicenter trial carried out at 59 sites in 13 countries between February 1989 and March 1995.

Section snippets

Patient recruitment and eligibility

Patients were eligible for the trial if they were more than 18 years old and had experienced a TIA (clinical neurological symptoms persisting for less than 24 h) or a completed ischemic stroke (clinical neurological deficit lasting more than 24 h), within the preceding three months. Diagnosis based on clinical neurological examination only was acceptable but computed tomography (CT) or magnetic resonance imaging (MRI) were recommended to confirm the diagnosis. General medical examination was

Demographic characteristics

The patients were recruited between February 1989 and March 1993 in 59 clinical centres from 13 European countries. The origin and the baseline characteristics of the ESPS-2 population have already been described in detail (Bertrand-Hardy et al., 1995). Data from 6,602 patients were analysed. There were no significant differences among the four treatment groups in terms of baseline characteristics, including age, sex, weight, nature and severity of qualifying event, concomitant diseases, and

Discussion

The second European Stroke Prevention Study has shown that dipyridamole modified-release formulation, 200 mg, given twice daily is effective in the secondary prevention of stroke and transient ischemic attack, when compared to placebo; further, that ASA 25 mg also given twice daily, a dose hitherto untested for clinical endpoints, is equally effective; that the co-prescription of the two agents provides a truly additive benefit, thus confirming the results of ESPS-1 (ESPS Group, 1987) a study

Acknowledgements

The study was supported by a grant from Boehringer Ingelheim.

References (22)

  • U. Alheid et al.

    Human endothelial cells inhibit platelet aggregation by separately stimulating platelet cyclic AMP and cyclic GMP

    Eur J Pharmacol

    (1989)
  • J.M. Bertrand-Hardy et al.

    European Stroke Prevention Study 2: Baseline data

    J Neurol Sci

    (1995)
  • R. Bonita

    Epidemiology of stroke

    Lancet

    (1992)
  • Persantin aspirin trial in cerebral ischemiaII: Endpoint results

    Stroke

    (1983)
  • Secondary prevention of vascular diseases by prolonged antiplatelet treatment

    Br Med J

    (1988)
  • Collaborative overview of randomized trials of antiplatelet therapyI: Prevention of death, myocardial infarction, and stroke by prolonged anti-platelet therapy in various categories of patients

    Br Med J

    (1994)
  • Collaborative overview of randomized trials of antiplatelet therapyII: Maintenance of vascular graft or arterial patency by antiplatelet therapy

    Br Med J

    (1994)
  • Collaborative overview of randomized trials of antiplatelet therapyIII: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients

    Br Med J

    (1994)
  • M.G. Bousser et al.

    ‘AICLA’ controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia

    Stroke

    (1983)
  • EAFT Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke....
  • ESPS Group. The European Stroke Prevention Study (ESPS): Principal endpoints. Lancet 1987; ii:...
  • Cited by (0)

    1

    ESPS-2 Writing Committee

    View full text