The Journal of Informed Pharmacotherapy 2001;5:213-215.
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Reviewer: Susan C. Fagan, Pharm.D., BCPS, FCCP
Reviewer's email address: email@example.com
Reviewer's profession/specialty: Pharmacotherapy/Stroke
International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997;349:1569-81. PubMed Cit
The IST was a large (n=19,435) international study designed to determine the safety and efficacy of two widely used treatments for acute ischaemic stroke: unfractionated heparin and aspirin. Patients with acute stroke were eligible if they could be enrolled within 48 hours after a negative CT scan to receive either heparin 5000 u sc q12h (n=2,426) or heparin 12500 u sc q12h (n=2,432) or aspirin 300 mg daily (n=2,430), both heparin and aspirin (n=2,430), or neither drug (4,860). The major endpoints of the study were death and other clinical events at 14 days, death and dependency at 6 months and intracranial and other hemorrhage.
1. Was assignment of patients randomized?
Unknown. The breakdown of patient characteristics by treatment group at the beginning of the trial was not given. The authors stated that groups were similar.
The use of non-trial treatments (including anti-edema, surgery and thrombolysis) was well balanced according to the authors (data not given). Thirty-six different countries may have lead to regional differences in co-intervention. However, strict randomization protocol should have taken care of any differences. The compliance rates were good (88-94% for heparin and 93% for aspirin) but it was not broken out by region.
1. How large was the treatment effect?
Patients who received aspirin had an absolute reduction in stroke recurrence at 14 days of 1.1% and there was no difference in hemorrhagic strokes. Death or nonfatal stroke at 14 days was significantly less in the aspirin group (11.3% vs. 12.4%, p=0.02, NNT=91).
Patients who received heparin experienced a significant reduction in stroke recurrence within 14 days by 0.9%. However, patients who received heparin also experienced an increase in hemorrhagic strokes by 0.8%(absolute)in the same time frame. The increase in hemorrhagic strokes was dose-related. There was no difference in the incidence of death or dependency at 6 months in the heparin group.
2. How precise was the estimate of the treatment effect?
Unable to extract confidence intervals from the paper.
2. Were all clinically important outcomes considered?
Yes. Recurrent ischaemic stroke, hemorrhagic stroke, death or nonfatal stroke, pulmonary embolism and major extracranial bleed were all assessed at 14 days. At six months, death and dependency were assessed.
When the results of the IST are combined with the results of the Chinese Acute Stroke Trial (1), one can support the recommendation to begin aspirin in all eligible acute ischemic stroke patients within 48 hours of symptom onset. The use of unfractionated heparin remains controversial. There is a strong-voiced minority who state that the IST study is flawed and patients who needed heparin were excluded (this was an exclusion criteria for this study). Also, a small number of patients did not have a CT scan prior to enrolling. This may have led to an overestimation of the risk of heparin. Even when a more easily dosed and theoretically safer "heparinoid" compound was subsequently tried in ischaemic stroke in the TOAST trial, a similar result was obtained. (2) The heparinoid did not offer any benefit, but was associated with increased risk. Despite the fact that there is still no evidence to support the use of heparin in acute ischemic stroke, it remains in use and proponents favour further clinical trials to test immediate (i.e. within 6 hours) anticoagulation with this product. (3)
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