Anticoagulants Versus Antiplatelet Agents for Acute Ischemic Stroke
Antiplatelet agents produce a small but worthwhile benefit in long-term functional outcome and survival, and have become standard treatment for acute ischemic stroke. Anticoagulants are often used as an alternative treatment, despite evidence that they are ineffective in producing long-term benefits.
We wanted to review trials, which have directly compared anticoagulants and antiplatelet agents, to assess whether any anticoagulant regimen offers net advantages over antiplatelet agents, overall or in some particular category of patients (eg, patients with atrial fibrillation). We also wanted to assess whether there is any evidence to suggest that the addition of anticoagulants to antiplatelet agents offers any net advantage over antiplatelet agents alone.
We searched the Cochrane Stroke Group Trials Register, the Cochrane Controlled Trials Register (Central/CCTR), the trials register held by the Antithrombotic Therapy Trialists’ Collaboration, MEDLINE (1966 to 2000), and EMBASE (1980 to 2000).
We sought to identify truly unconfounded, randomized controlled trials comparing anticoagulants with antiplatelet agents, or anticoagulants and antiplatelet agents with antiplatelet agents alone, given within 14 days of onset of presumed or confirmed ischemic stroke.
The searches retrieved about 5000 references, of which 4 trials met the eligibility criteria: Pince 1981, IST 1997, HAEST 2000, and TAIST 2001. The anticoagulants tested were unfractionated heparin (UFH) and low-molecular-weight heparin. Aspirin was used as control in all trials. A total of 16 558 patients contributed to the analyses. Overall, there was no evidence that anticoagulants were superior to aspirin in reducing “death or dependency” at long-term follow-up (odds ratio [OR] 1.07, 95% CI 0.98 to 1.15; Figure). Compared with aspirin, anticoagulants were associated with a small but significant increase in the number of deaths at the end of follow-up (OR 1.10, 95% CI 1.01 to 1.29), equivalent to 20 more deaths (95% CI 0 to 30) per 1000 patients treated; a significant increased risk of symptomatic intracranial hemorrhage (OR 2.35, 95% CI 1.49 to 3.46); and a nonsignificant increased risk of “any recurrent stroke” during treatment (OR 1.20, 95% CI 0.99 to 1.46). These neutral or adverse effects outweighed a small but significant effect on symptomatic deep vein thrombosis (OR 1.20, 95% CI 0.07 to 0.58), equivalent to 10 fewer (95% CI 0 to 30) deep vein thromboses by 14 days per 1000 patients treated with anticoagulants instead of aspirin. Subgroup analysis could not identify any type, dose, or route of administration of anticoagulants associated with net benefit, or any benefit in patients with atrial fibrillation.
Overall, the combination of UFH and aspirin did not appear to be associated with a net advantage over aspirin alone. A subgroup analysis showed that, compared with aspirin, the combination of low-dose UFH and aspirin was associated with a marginally significant reduced risk of “any recurrent stroke” (OR 0.75, 95% CI 0.56 to 1.03) and a marginally significant reduced risk of death at 14 days (OR 0.84, 95% CI 0.69 to 1.01), and with no clear adverse effect on death at end of follow-up (OR 0.98, 95% CI 0.85 to 1.12).
In conclusion, anticoagulants offered no net advantages over antiplatelet agents in acute ischemic stroke. Antiplatelet agents should therefore be the antithrombotic agent of first choice. The combination of low-dose UFH and aspirin appeared in a subgroup analysis to be associated with net benefits over aspirin alone, and this might be worth testing in further large-scale randomized controlled trials.
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- Received December 18, 2002.
- Accepted January 3, 2003.