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ESPS2

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

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Year of Publication: 1996

Authors: H.C. Diener, L. Cunha, C. Forbes, ..., A. Lowenthal

Journal: Journal of the Neurological Sciences

Citation: Journal of the Neurological Sciences 143 (1996) 1-13

Link: https://doi.org/10.1016/s0022-510x(96)00308-5

Clinical Question

Are dipyridamole and acetylsalicylic acid (ASA) effective individually and in combination for secondary prevention of stroke in patients with prior TIA or ischemic stroke?

Bottom Line

Both ASA and dipyridamole individually reduce stroke risk, but combination therapy provides superior protection with 37.0% risk reduction compared to placebo, demonstrating additive beneficial effects.

Major Points

  • Large multicenter trial with 6,602 patients from 13 European countries
  • 2×2 factorial design comparing ASA, dipyridamole, combination, and placebo
  • ASA alone reduced stroke risk by 18.1% (p=0.013) compared to placebo
  • Dipyridamole alone reduced stroke risk by 16.3% (p=0.039) compared to placebo
  • Combination therapy reduced stroke risk by 37.0% (p<0.001) - significantly superior to either agent alone
  • Combination therapy showed additive protective effects without significant statistical interaction
  • Low-dose ASA (25 mg twice daily) was as effective as higher doses used in previous studies

Design

Study Type: Randomized, placebo-controlled, double-blind, 2×2 factorial trial

Randomization: 1

Blinding: Patients, investigators, and steering/monitoring committees were blinded to treatment assignment until the code was broken in August 1995

Enrollment Period: February 1989 to March 1993

Follow-up Duration: 2 years

Centers: 59

Countries: Belgium, Finland, France, Germany, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom

Sample Size: 6602

Analysis: Intention-to-treat principle with survival analysis (actuarial method, Wilcoxon-Gehan, Cox model); factorial analysis to assess statistical interaction between ASA and DP

Inclusion Criteria

  • Age >18 years
  • Experienced TIA with clinical neurological symptoms lasting <24 hours within preceding 3 months
  • OR completed ischemic stroke with clinical neurological deficit lasting >24 hours within preceding 3 months
  • Diagnosis based on clinical examination only (CT or MRI recommended but not required)

Exclusion Criteria

  • Recent history of peptic ulcer or other gastrointestinal bleeding
  • Hypersensitivity or intolerance to either study medication
  • Bleeding disorders or circumstances requiring anticoagulants
  • Life-threatening condition
  • Patients requiring continued use of ASA or anticoagulants

Baseline Characteristics

CharacteristicControlActive
Mean age66.6 years66.7-66.8 years across groups
Male57.7%57.9-58.3% across groups
Qualifying event - Stroke77.0%75.6-76.5% across groups
Qualifying event - TIA23.0%23.5-24.4% across groups
Hypertension62.0%59.4-61.2% across groups
Diabetes14.5%14.6-16.8% across groups
Current smokers23.5%23.5-25.6% across groups
Alcohol >5 units/day5.8%5.1-6.0% across groups

Arms

FieldASA groupDipyridamole groupCombination groupControl
InterventionAcetylsalicylic acid 25 mg twice dailyModified-release dipyridamole 200 mg twice dailyASA 25 mg twice daily plus modified-release dipyridamole 200 mg twice dailyMatched placebo tablets
Duration2 years2 years2 years2 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Three primary endpoints: (1) stroke (fatal and non-fatal); (2) death from all causes; (3) stroke and/or death together. In the combined stroke/death analysis the first event was counted to avoid double-counting.Primary
Transient ischemic attack (TIA)Secondary267/1622 (16.46%)ASA: 206/1631 (12.63%), DP: 215/1628 (13.21%), Combination: 172/1631 (10.55%)<0.001
Myocardial infarctionSecondary45/1649ASA: 39/1649, DP: 48/1654, Combination: 35/1650NS
Other vascular events (lung embolism, DVT, peripheral artery obstruction, retinal artery occlusion)Secondary54/1649ASA: 38/1649, DP: 35/1654, Combination: 21/1650<0.01
Ischemic events (stroke, MI, or sudden death)Secondary307/1649ASA: 266/1649, DP: 271/1654, Combination: 206/1650<0.001
Any adverse eventAdverse933/1649ASA: 990/1649, DP: 1034/1654, Combination: 1056/1650<0.001
Gastrointestinal eventsAdverse465/1649 (28.20%)ASA: 502/1649 (30.44%), DP: 505/1654 (30.53%), Combination: 541/1650 (32.80%)0.042
HeadacheAdverse534/1649ASA: 546/1649, DP: 615/1654, Combination: 630/1650<0.001
Bleeding any siteAdverse74/1649 (4.5%)ASA: 135/1649 (8.2%), DP: 77/1654 (4.7%), Combination: 144/1650 (8.7%)<0.001

Subgroup Analysis

No pre-specified subgroup analysis reported. Cox model identified prior cerebrovascular event (c=1.62), alcohol >5 units/day (c=1.51), smoking (c=1.51), diabetes (c=1.45), atrial fibrillation (c=1.67), and ischemic heart disease (c=1.50) as significant negative prognostic covariates.

Criticisms

  • Relatively high discontinuation rate due to adverse events (366 ASA, 485 DP, 479 DP-ASA vs 360 placebo)
  • Gastrointestinal side effects were more common in all active treatment groups
  • Bleeding risk increased with ASA-containing regimens (particularly combination)
  • Study was not powered to detect differences in mortality endpoints
  • Data from one center (438 patients) excluded before unblinding due to data-quality concerns

Funding

Supported by a grant from Boehringer Ingelheim

Based on: ESPS2 (Journal of the Neurological Sciences, 1996)

Authors: H.C. Diener, L. Cunha, C. Forbes, ..., A. Lowenthal

Citation: Journal of the Neurological Sciences 143 (1996) 1-13

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