Indications for Early Aspirin Use in Acute Ischemic Stroke: A Combined Analysis of 40 000 Randomized Patients From the Chinese Acute Stroke Trial and the International Stroke Trial

Abstract

Background and Purpose —Long-term daily aspirin is of benefit in the years after ischemic stroke, and 2 large randomized trials (the Chinese Acute Stroke Trial [CAST] and the International Stroke Trial [IST]), with 20 000 patients in each, have shown that starting daily aspirin promptly in patients with suspected acute ischemic stroke also reduces the immediate risk of further stroke or death in hospital and the overall risk of death or dependency. However, some uncertainty remains about the effects of early aspirin in particular categories of patient with acute stroke. Methods —To assess the balance of benefits and risks of aspirin in particular categories of patient with acute stroke (eg, the elderly, those without a CT scan, or those with atrial fibrillation), a prospectively planned meta-analysis is presented of the data from 40 000 individual patients from both trials on events that occurred in the hospital during the scheduled treatment period (4 weeks in CAST, 2 weeks in IST), with 10 characteristics used to define 28 subgroups. This represents 99% of the worldwide evidence from randomized trials. Results —There was a highly significant reduction of 7 per 1000 (SD 1) in recurrent ischemic stroke (320 [1.6%] aspirin versus 457 [2.3%] control, 2 P <0.000001) and a less clearly significant reduction of 4 (SD 2) per 1000 in death without further stroke (5.0% versus 5.4%, 2 P =0.05). Against these benefits, there was an increase of 2 (SD 1) per 1000 in hemorrhagic stroke or hemorrhagic transformation of the original infarct (1.0% versus 0.8%, 2 P =0.07) and no apparent effect on further stroke of unknown cause (0.9% versus 0.9%). In total, therefore, there was a net decrease of 9 (SD 3) per 1000 in the overall risk of further stroke or death in hospital (8.2% versus 9.1%, 2 P =0.001). For the reduction of one third in recurrent ischemic stroke, subgroup-specific analyses found no significant heterogeneity of the proportional benefit of aspirin (χ 2 18 =20.9, NS), even though the overall treatment effect (χ 2 1 =24.8, 2 P <0.000001) was sufficiently large for such subgroup analyses to be statistically informative. The absolute risk among control patients was similar in all 28 subgroups, so the absolute reduction of ≈7 per 1000 in recurrent ischemic stroke does not differ substantially with respect to age, sex, level of consciousness, atrial fibrillation, CT findings, blood pressure, stroke subtype, or concomitant heparin use. There was no good evidence that the apparent decrease of ≈4 per 1000 in death without further stroke was reversed in any subgroup or that in any subgroup the increase in hemorrhagic stroke was much larger than the overall average of ≈2 per 1000. Finally, there was no significant heterogeneity between the reductions in the composite outcome of any further stroke or death (χ 2 18 =16.5, NS). Among the 9000 patients (22%) randomized without a prior CT scan, aspirin appeared to be of net benefit with no unusual excess of hemorrhagic stroke; moreover, even among the 800 (2%) who had inadvertently been randomized after a hemorrhagic stroke, there was no evidence of net hazard (further stroke or death, 63 aspirin versus 67 control). Conclusions —Early aspirin is of benefit for a wide range of patients, and its prompt use should be routinely considered for all patients with suspected acute ischemic stroke, mainly to reduce the risk of early recurrence.