Combination Anticoagulant and Antiplatelet Therapy in Acute Stroke

The Cochrane group examined (a) whether the addition of UFH or LMWH to anti-platelet agents offers any net advantage over antiplatelet monotherapy for acute stroke, and (b) the effectiveness of anticoagulants compared to antiplatelets in acute ischemic stroke.17 They included 4 trials of 16,558 patients, each of which specified aspirin (160-333 mg daily) as the control, and all of which randomized patients within 14 days of stroke onset. The anticoagulants tested were UFH and LMWH. Almost 98% of the patients were followed up for 6 months.

Compared with aspirin monotherapy, anticoagulant treatment was associated with a small but significant increase in the number of deaths at the end of follow-up (OR 1.10, 95% CI 1.01-1.29), equivalent to 20 more deaths per 1000 patients treated with anticoagulants. Subgroup analysis showed that 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 0.56-1.03) and a marginally significant reduced risk of death at 14 days (OR 0.84, 95% CI 0.69-1.01), with no clear adverse effect on death at the end of follow-up.

As in previous reviews they also found an increased risk of sICH (OR 2.27, 95% CI 1.49-3.46), equivalent to 10 more (95% CI 0-10 more) sICHs per 1000 patients treated. An interaction by anticoagulant dose on sICH was observed (p = 0.01), with a greater risk in trials using high-dose anticoagulants (OR 3.24, 95% CI 2.09-5.04) as opposed to low-dose anticoagulants (OR 1.29, 95% CI 0.72-2.32). A similar dose-response relationship was observed when comparing UFH plus aspirin with aspirin monotherapy in the IST trial. Compared directly with aspirin, anticoagulants were associated with a nonsignificant increase in the risk of recurrent stroke (OR 1.20, 95% CI 0.99-1.46), equivalent to 10 more recurrent strokes per 1000 patients treated.

This was largely influenced by the high-dose UFH group in 1ST (OR 1.38, 95% CI 1.05-1.82). An interaction by UFH dose (p = 0.01) on recurrent stroke risk with combination UFH-aspirin therapy compared to aspirin monotherapy was observed, with a trend toward increased risk of recurrent stroke with high-dose UFH + aspirin (OR 1.22, 95% CI 0.92-1.62) and a trend toward reduced risk with low-dose UFH + aspirin (OR 0.75, 95% CI 0.56-1.03), equivalent to 10 fewer (95% CI 020 fewer) recurrent strokes per 1000 patients treated. They found a small, but significant benefit of LMWH over aspirin in the prevention of symptomatic DVT, equivalent to 10 (95% CI 0-30) fewer DVTs per 1000 patients treated. Compared with aspirin, anticoagulants were associated with nonsignificantly fewer symptomatic PEs (OR 0.85, 95% CI 0.55-1.32). There were fewer PEs with the combination of UFH and aspirin (OR 0.58, 95% CI 0.34-1.00), equivalent to 5 fewer (CI 0-10) PEs per 1000 patients treated. However, the overall incidence of symptomatic DVT and PE was low (1.1% and 0.7%).

Overall no evidence was found to support the claim that anticoagulants offer a net advantage over aspirin in patients with acute ischemic stroke. There was evidence, however, to suggest that combination anticoagulant and aspirin therapy was associated with a small increase in the number of deaths at the end of follow-up, equivalent to 20 more deaths per 1000 patients treated. This adverse effect can probably be attributed partly to the 10 extra sICHs, and the 5 extra major extracranial hemorrhages per 1000 patients treated with combination anticoagulant/ aspirin therapy.

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