ESPS2
European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke
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://www.urmc.rochester.edu/MediaLibr...ents/ESPS-2.pdf
PDF: https://www.urmc.rochester.edu/MediaLibr...ents/ESPS-2.pdf
PDF: 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% 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 trial
Randomization: 1
Blinding: Patients, investigators, and steering/monitoring committees were blinded to treatment assignment until study completion
Enrollment Period: February 1989 to March 1995
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 using Cox model, factorial analysis to assess statistical interaction
Inclusion Criteria
- Age >18 years
- Experienced TIA with clinical neurological deficit 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 not required but acceptable)
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
| Characteristic | Control | Active |
|---|---|---|
| Mean age | 66.7 years | 66.6-66.8 years across groups |
| Male | 58.3% | 57.9-58.1% across groups |
| Qualifying event - Stroke | 76.5% | 75.6-76.3% across groups |
| Qualifying event - TIA | 23.5% | 23.7-24.4% across groups |
| Hypertension | 61.2% | 59.6-61.1% across groups |
| Diabetes | 16.8% | 13.5-16.6% across groups |
| Current smokers | 23.9% | 22.7-25.6% across groups |
| Alcohol >5 units/day | 6.0% | 5.1-5.3% across groups |
Arms
| Field | ASA group | Dipyridamole group | Combination group | Control |
|---|---|---|---|---|
| Intervention | Acetylsalicylic acid 25 mg twice daily | Modified-release dipyridamole 200 mg twice daily | ASA 25 mg twice daily plus modified-release dipyridamole 200 mg twice daily | Matched placebo tablets |
| Duration | 2 years | 2 years | 2 years | 2 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Stroke (fatal and non-fatal strokes, death from any cause allowed first event to be counted for 'survival' analysis but avoided patient being counted twice) | Primary | 250/1649 (15.2%) | ASA: 206/1649 (12.5%), DP: 211/1654 (12.8%), Combination: 157/1650 (9.5%) | ASA: 0.819 (0.67-0.99), DP: 0.837 (0.69-1.02), Combination: 0.630 (0.52-0.76) | ASA: 0.013, DP: 0.039, Combination: <0.001 |
| Stroke or death | Secondary | 378/1649 (22.9%) | ASA: 330/1649 (20.0%), DP: 321/1654 (19.4%), Combination: 286/1650 (17.3%) | ASA: 0.87, DP: 0.85, Combination: 0.75 | ASA: 0.056, DP: 0.073, Combination: <0.001 |
| Death | Secondary | 202/1649 (12.3%) | ASA: 182/1649 (11.0%), DP: 188/1654 (11.4%), Combination: 185/1650 (11.2%) | ASA: 0.89, DP: 0.92, Combination: 0.90 | All non-significant |
| Gastrointestinal events | Adverse | 465/1649 | ASA: 990/1649, DP: 1034/1654, Combination: 1056/1650 | <0.001 for all active groups | |
| Bleeding any site | Adverse | 74 patients | ASA: 135, DP: 77, Combination: 144 | <0.001 |
Subgroup Analysis
TIA occurrence was recorded in 860 patients during follow-up. Factorial analysis indicated that when ASA and DP were co-prescribed, protective effects were additive with combination being significantly more effective than either agent alone
Criticisms
- Relatively high discontinuation rate due to adverse events
- Gastrointestinal side effects were significantly more common in all active treatment groups
- Bleeding risk increased with active treatments, particularly combination therapy
- Study was not powered to detect differences in mortality endpoints
- No formal sample size calculation reported in the paper
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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