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Special Article |

Dipyridamole Plus Aspirin in Cerebrovascular Disease

Janet L. Wilterdink, MD; J. Donald Easton, MD
Arch Neurol. 1999;56(9):1087-1092. doi:10.1001/archneur.56.9.1087.
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Background  The second European Stroke Prevention Study (ESPS-2) recently reported a substantial benefit of dipyridamole combined with aspirin over aspirin alone in the prevention of stroke. This appears to be at odds with previous studies suggesting that dipyridamole adds nothing to aspirin alone.

Objectives  To review and compare the results of ESPS-2 and previous studies of dipyridamole plus aspirin and aggregate them in a meta-analysis.

Methods  We combined the detailed data provided by the Antiplatelet Trialists' Collaboration on the previous studies of dipyridamole plus aspirin with the results from ESPS-2. The data on the previous trials were listed in the appendix of the 1994 publication of the Antiplatelet Trialists' Collaboration.

Results  The results of our meta-analysis demonstrate that for the outcome of nonfatal stroke, ESPS-2 overwhelms previous data, which, even in the aggregate, did not include enough patients or outcome events to exclude efficacy for the combination of dipyridamole and aspirin. Differences between ESPS-2 and previous studies, which may have contributed to different results, include the doses and preparations of aspirin and dipyridamole.

Conclusions  The ESPS-2 showed that dipyridamole alone prevents stroke. More importantly, it showed a substantial benefit for dipyridamole combined with aspirin over aspirin alone. When the ESPS-2 data are aggregated with the 14 previous trials of dipyridamole combined with aspirin over aspirin alone, the combination reduces the risk of stroke by 23% over aspirin alone. Nevertheless, important questions remain unanswered. We conclude that another randomized clinical trial showing a significant benefit of the combination of dipyridamole plus aspirin over aspirin alone may be needed before the addition of dipyridamole to aspirin is widely accepted for prevention of stroke.

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Figures

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Figure 1.

Direct comparison of proportional effects of dipyridamole plus aspirin vs aspirin on vascular events and nonvascular deaths: outcome events in the 14 Antiplatelet Trialists' Collaboration trials (5317 patients). MI indicates myocardial infarction. "Vascular death" represents any death that cannot be confidently attributed to a nonvascular cause; "all vascular events" includes nonfatal stroke, nonfatal MI, and vascular deaths. When the confidence interval includes unity (1.0), the difference in treatments is not statistically significant.

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Figure 2.

Direct comparison of proportional effects of dipyridamole plus aspirin vs aspirin on vascular events and nonvascular deaths: outcome events in the 3 Antiplatelet Trialists' Collaboration cerebrovascular trials (1574 patients). Abbreviation and terms are defined in the legend to Figure 1.

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Figure 3.

Direct comparison of proportional effects of dipyridamole plus aspirin vs aspirin on vascular events and nonvascular deaths: outcome events in the 14 Antiplatelet Trialists' Collaboration trials plus the second European Stroke Prevention Study (8616 patients). Abbreviation and terms are defined in the legend to Figure 1.

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Figure 4.

Direct comparison of proportional effects of dipyridamole plus aspirin vs aspirin on vascular events and nonvascular deaths: outcome events in the 3 Antiplatelet Trialists' Collaboration cerebrovascular trials plus the second European Stroke Prevention Study (4873 patients). Abbreviation and terms are defined in the legend to Figure 1.

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Figure 5.

Direct comparison of proportional effects of dipyridamole plus aspirin vs aspirin on nonfatal strokes: all antiplatelet trials, excluding trials in which no strokes occurred or in which stroke outcome was not studied. PARIS I indicates the first Persantine-Aspirin Reinfarction Study; TIA, transient ischemic attack; AICLA, Accidents, Ischemiques Cerebraux Lies à l'Atherosclerose; ACCSG, American-Canadian Cooperative Study Group; VACoopCABG, Veterans Administration Cooperative Study; and ESPS-2, the second European Stroke Prevention Study.

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Figure 6.

Direct comparison of proportional effects of dipyridamole plus aspirin vs aspirin on nonfatal strokes: trials in patients with cerebrovascular disease (CVD). Other abbreviations are defined in the legend to Figure 5.

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