Preventive treatment of patients after non-disabling cerebral ischaemia of presumed arterial origin; comparative randomized study with intensive anticoagulant therapy or aspirin treatment

Objective. Because aspirin is ischaemia, the efficacy in the secondary prevention after cerebral ischaemia, the efficacy and safety of 30 mg aspirin daily and oral anticoagulation (international normalized ration (INR): 3.0- 4.5) was studied in the Stroke prevention in reversible ischaemia trial (SPIRIT). Design. Open, randomised, controlled study. Setting. 58 hospitals: 52 in the Netherlands and 6 in other countries. Methods. Patients referred to a neurologist in one of 58 collaborating centres because of a transient ischaemic attack or minor ischaemic stroke (Rankin grade ≤ 3) were eligible. Randomization was concealed, treatment assignment was open, and assessment of outcome events was masked. Treatment was with oral anticoagulants (INR: 3.0- 4.5) or with 30 mg of aspirin. The primary measure of outcome was the composite event 'death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or non-fatal major bleeding complication. Result. A total of 1316 patients participated; their mean follow-up was 14 months. The trial was stopped at the first interim analysis: there was an excess of the primary outcome event in the anticoagulated group (81/651) versus 36/665 in the salicylate group (hazard ratio: 2.3;95% confidence interval (95% CI): 1.6-3.5). This excess could be attributed to 53 major bleeding complications (27 intracranial; 17 fatal) during anticoagulant therapy versus 6 on aspirin (3 intracranial; 1 fatal). The bleeding incidence increased by a factor of 1.43 (95% CI: 0.96-2.13) for each 0.5 unit increase of the achieved INR. Conclusion. Anticoagulant therapy with INR range 3.0-4.5 in patients after cerebral ischaemia of presumed arterial origin is not safe. The efficacy of a lower intensity anticoagulation regimen remains to be determined.