Studies of Aspirin Soon After Stroke
ABSTRACTS & COMMENTARY
Sources: International Stroke Trial Collaborative Group. The International Stroke Trial (IST): A randomized trial of aspirin, subcutaneous heparin, both or neither among 19,435 patients with acute ischemic stroke. Lancet 1997;349:1569-1581; CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: Randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke. Lancet 1997;349:1641-1649.
The international stroke trial (ist) was a multinational, randomized, open trial of up to 14 days of antithrombotic therapy started within 48 hours after ischemic stroke onset. Half the patients were given unfractionated heparin, either 5000 IU or 12500 IU, subcutaneous bid, and half were allocated to receive aspirin 300 mg daily (see Table). The end points examined were deaths within 14 days and death or dependency at six months.
Effect of heparin vs. no heparin: At 14 days, there was no significant difference in deaths between heparin (9.0%) and no-heparin (9.3%) patients. At six months, the percentage dead or dependent (62.9%) was identical in both groups. Patients allocated to heparin had fewer recurrent ischemic strokes within 14 days (2.9% vs 3.8%; 2P = 0.005), but this was offset by an increase in hemorrhagic strokes (1.2% vs 0.4%; 2P < 0.00001). Heparin treatment was associated with an excess (9 per 1000) of transfused or fatal extracranial bleeds. Higher dose heparin (12500 IU vs 5000 IU, sq bid) treatment was associated with more intra- and extracranial hemorrhages, and more deaths and non-fatal strokes within 14 days (12.6% vs 10.8%; 2P < 0.00001).
Effect of Aspirin: Among aspirin-treated patients, there were non-significant trends toward fewer deaths within 14 days and, at six months, toward a smaller percentage of the aspirin group being dead or dependent (62.2% vs 63.5%). Aspirin-allocated patients had numerically significantly fewer recurrent ischemic strokes within 14 days (2.8% vs 3.9%; 2P < 0.001) with no excess of hemorrhagic strokes. Therefore, the reduction in death or non-fatal recurrent stroke with aspirin (11.3% vs. 12.4%; 2P = 0.02) became significant. No significant increase in extracranial bleeds affected persons on aspirin, and no interaction between aspirin and heparin was apparent in the main outcomes.
Table
Randomized Allocations of IST Patients (n = 19,435)
Treatment Groups Number of Patients
Aspirin 300 mg + heparin 12,500 IU 2430
Aspirin 300 mg + heparin 500 IU 2432
Aspirin 300 mg + no hepari4858
No aspirin + heparin 12,500 IU 2426
No aspirin + heparin 5000 IU 2429
CAST was a large, randomized, placebo-controlled trial of aspirin treatment (160 mg/d) started within 48 hours of suspected ischemic stroke (87% of 21,106 patients had a CT scan before randomization) and continued in hospital for up to four weeks. The primary end points were death from any cause during the four-week treatment period and death or dependence at discharge. Patients at 413 Chinese hospitals were randomized to aspirin (n = 10,554) or placebo (n = 10,552). There was a significant (14 ± 7%; mean ± SD) proportional reduction in mortality during the treatment period: among aspirin allocated patients, the death rate was 3.3% vs. 3.9% among the placebo group (2P = 0.04). There were fewer recurrent ischemic strokes in the aspirin group than in the placebo group (1.6% vs. 2.1%; 2P = 0.01) but a slightly higher percentage of hemorrhagic strokes (1.1% vs. 0.9%; NS). For the combined end points of death or non-fatal stroke, at four weeks there was a 12 ± 6% proportional risk reduction with aspirin (5.3% vs 5.9%; 2P = 0.03), an absolute difference of 6.8 ± 3.2 fewer cases per 1000. At discharge, 30.5% of the aspirin-allocated patients and 31.6% of the placebo-allocated patients had died or were dependent, corresponding to 11.4 ± 6.4 fewer cases per 1000, a trend in favor of aspirin (NS).
COMMENTARY
IST did not show a significant benefit from aspirin on death from any cause during the treatment period or on death or dependency at six months. CAST found a reduction in mortality during the treatment period. Both studies found that the absolute number of recurrent ischemic strokes dropped by 1.1% in IST and by 0.5% in CAST, but the risk of severe extracranial bleeding increased by 0.5% in IST. In both studies, when a combined end point of death or non-fatal recurrent stroke within 14 days (IST) or four weeks (CAST) was used, aspirin significantly reduced the absolute number of adverse outcomes by 1.1% and 0.6%, respectively. In IST, there was no significant increase in the percentage of patients making a full recovery.
In IST, heparin sq did not affect the number of deaths at 14 days or the number of deaths or dependent victims at six months. In general, heparin reduced the number of recurrent ischemic strokes, but the effect was offset by an equal increase in the number of hemorrhagic strokes.
In contrast to aspirin, heparin produced this benefit without a significant excess of serious extracranial bleeds. The effect of heparin to reduce stroke recurrence did not depend on the presence of atrial fibrillation (AF). Among approximately 3000 patients with AF in IST, the average rate of recurrent ischemic stroke within 14 days for control subjects with AF was only 4.9% vs. 3.6% for controls without AF (NS).
Although IST does not support the routine use of subcutaneous heparin in acute ischemic stroke, recent guidelines have recommended low-dose heparin as prophylaxis against deep vein thrombosis and pulmonary embolism in stroke patients, especially those at higher risk due to hemiplegia (Neuro Alert 1997;15:83-84). The rate of pulmonary embolism in IST was low (0.8%) even among patients allocated to no heparin and not significantly different in heparin-treated patients. This low rate of non-fatal pulmonary embolism may represent underreporting, as the authors acknowledge. The IST results do argue against the routine use of any heparin regimen greater than 500 IU bid during the first two weeks after stroke onset, when the risks of cerebral bleeding are highest. Obviously, intravenous heparin or oral warfarin anticoagulation can be even more dangerous than heparin sq. Nevertheless, clinical experience indicates that they can be used both safely and effectively.
IST and CAST showed that aspirin is effective for the early prevention of death and recurrent ischemic stroke but does not affect death or dependency at six months. Aspirin was not beneficial as acute treatment for stroke because it did not increase the number of patients making a full recovery. The results of these large studies are disappointingthe mountains have labored, and a mouse was born. jjc
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