doi: 10.1161/01.STR.0000023102.03179.30
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(Stroke. 2002;33:2138.)
© 2002 American Heart Association, Inc.
Controversies in Stroke |
Aspirin Therapy Should Be First-Line Treatment in Secondary Prevention of Stroke—Against
From the Department of Neurology, University Essen, Essen, Germany.
Correspondence to Dr Hans-Christoph Diener, Department of Neurology, University Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail h.diener{at}uni-essen.de
Key Words: aspirin • clopidogrel • dipyridamole • stroke prevention • ticlopidine
Patients with transient ischemic attack (TIA) are at high risk for an ischemic stroke,1 and patients who have already suffered a stroke are at high risk for stroke recurrence. Aspirin leads only to a modest reduction both in the risk of stroke (23%) and in reducing the combined end point of stroke, myocardial infection (MI), or vascular death (18%).2
Ticlopidine is more effective than aspirin. A large multicenter trial compared a daily dose of 500 mg ticlopidine and 1300 mg/d aspirin in 3069 patients with TIA or minor stroke.3 This study was associated with a statistically significant 21% reduction (P=0.024) in fatal or nonfatal stroke risk at 3 years in patients who received ticlopidine versus aspirin. The relative risk reduction of the combined outcome of stroke, MI, or vascular death was reduced by 9% in favor of ticlopidine, which was not statistically significant. Ticlopidine, however, can lead to neutropenia in up to 0.8% of patients3,4 and therefore is no longer the drug of choice.
Clopidogrel is an antiplatelet agent that is chemically related to ticlopidine. A pivotal randomized, blinded, international trial, Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE), examined the relative safety and efficacy of daily doses of 75 mg clopidogrel versus 325 mg aspirin in nearly 20 000 patients with stroke, MI, or peripheral arterial disease.5 The results of the trial showed that clopidogrel was more effective than aspirin in preventing a combined end point of ischemic stroke, MI, or vascular death. The trialists found a significant 8.7% reduction in relative risk (P=0.043) for clopidogrel versus aspirin. Although the CAPRIE trial was not powered to detect treatment differences within patient subgroups, a subgroup analysis, which was not part of the original design, was performed. Overall, when the results for these subgroups were examined, there was no significant difference between clopidogrel and aspirin in patients with stroke or MI. There was, however, a significant benefit favoring clopidogrel in patients with peripheral arterial disease.
The combination of aspirin plus slow-release dipyridamole was investigated in the Second European Stroke Prevention Study (ESPS-2).6 ESPS-2 analyzed 6602 stroke or TIA patients who were randomly assigned to 4 treatment arms: placebo; aspirin alone (25 mg twice daily); extended-release dipyridamole alone (200 mg twice daily); or aspirin (25 mg twice daily) plus extended-release dipyridamole (200 mg twice daily). The trial showed additive effects of aspirin and dipyridamole. The aspirin-plus-dipyridamole regimen of ESPS-2 produced a statistically significant 37% reduction (P=0.00l) in risk of fatal or nonfatal stroke over 2 years compared with placebo, similar to the risk reduction of the earlier ESPS-1 trial (38%).7 Neither aspirin nor dipyridamole or the combination reduced mortality.8
Taken together, these study results show that the combination of aspirin plus dipyridamole is superior to aspirin alone in the prevention of stroke after TIA or stroke. The bleeding risk is not higher than with aspirin alone.6 Therefore, aspirin plus dipyridamole is the first-line treatment for secondary prevention of stroke. Clopidogrel is superior to aspirin for a combined end point of stroke, MI, and vascular death and is first-line treatment for high-risk patients with multiple vascular risk factors (eg, peripheral arterial disease). Whether the combination of clopidogrel plus aspirin is superior to aspirin alone is under investigation (MATCH trial).
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
1. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000; 284: 2901–2906.
2. Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J. 1994; 308: 81–106.
3. Hass WK, Easton JD, Adams HP, Pryse-Phillips W, Molony BA, Anderson S, Kamm B. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke. N Engl J Med. 1989; 321: 501–507.[Abstract]
4. Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW, Panak E, Roberts RS, Sicurella J, Turpie AGG. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet. 1989; 1: 1215–1220.[Medline] [Order article via Infotrieve]
5. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996; 348: 1329–1339.[CrossRef][Medline] [Order article via Infotrieve]
6. Diener HC, Cuhna L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143: 1–13.[CrossRef][Medline] [Order article via Infotrieve]
7. The ESPS Group. The European Stroke Prevention Study (ESPS): principal end- points. Lancet. 1987; 2: 1351–1354.[CrossRef][Medline] [Order article via Infotrieve]
8. Diener HC, Forbes C, Riekkinen PJ, Sivenius J, Smets P, Lowenthal A, and the ESPS Group. European Stroke Prevention Study 2: efficacy and safety data. J Neurol Sci. 1997; 151 (suppl): S1–S77.
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