The International Stroke Trial - IST
The goal of this study was to assess the safety and efficacy of aspirin and heparin among patients with acute ischemic stroke.
Anticoagulation and antiplatelet therapy with heparin and aspirin would be associated with improved clinical outcomes without a prohibitive risk of bleeding complications.
Patients Enrolled: 19,435
Mean Follow Up: Six months
Patients with clinical evidence of an acute stroke (irrespective of severity) with onset less than 48 hours previously, and no clear indications for, or contraindications to, heparin or aspirin
A small likelihood of worthwhile benefit (e.g., the symptoms seemed likely to resolve completely within a few hours or the patient was severely disabled before the stroke); a high risk of adverse effects (e.g., hypersensitivity to aspirin, active peptic ulceration, or recent gastrointestinal bleeding; or already on long-term oral anticoagulants); and hemorrhagic stroke
Death from any cause within 14 days and death or dependency (i.e., needing help from another person with daily activities) at six months
Symptomatic intracranial hemorrhage within 14 days (including any recurrent stroke definitely due to hemorrhage or symptomatic hemorrhagic transformation of the original infarct) that was confirmed by computed tomography, magnetic resonance imaging, or autopsy; ischemic stroke within 14 days (including any recurrent stroke of ischemic or unknown type); major extracranial hemorrhage (including any bleed that required transfusion or caused death within 14 days); other major events within 14 days such as pulmonary embolism; death from any cause by six months; and dependence in activities of daily living or incomplete recovery from the stroke at six months
Eligible patients were randomized to receive either heparin or placebo and aspirin or placebo using a factorial design. Heparin was given as either low dose (5000 IU) or medium dose (12,500 IU) or placebo injections subcutaneously every 12 hours so that one-quarter of the patients received low dose heparin, one-quarter received medium dose heparin, and one-half received placebo. Aspirin (300 mg PO or PR, or 100 mg IV daily) was given to half of the patients, and the other half received placebo.
In the heparin group, there was no significant difference in mortality within 14 days (9.0% vs. 9.3%). At six months, the percentage of patients dead or dependent was identical in both groups (62.9%). Patients randomized to receive heparin had significantly fewer recurrent ischemic strokes within 14 days (2.9% vs. 3.8%, p=0.005), but they also had an increase in the incidence of hemorrhagic strokes (1.2% vs. 0.4%, p<0.00001), so that the difference in death or nonfatal recurrent stroke (11.7% vs. 12.0%) was not significant.
Heparin was associated with an increase in transfusions or fatal extracranial bleeds as well (1.3% vs. 0.4%, p<0.00001). Compared with 5000 IU bid heparin, 12,500 IU bid heparin was associated with significantly more transfusions or fatal extracranial bleeds (2.0% vs. 0.6%, p<0.00001), more hemorrhagic strokes (1.8% vs. 0.7%, p<0.00001), and more deaths or nonfatal strokes within 14 days (12.6% vs. 10.8%, p=0.03).
In the aspirin group, there was no significant difference in mortality within 14 days (9.0% vs. 9.4%). At six months, there was a nonsignificant trend toward a smaller percentage of the aspirin group being dead or dependent (62.2% vs. 63.5%, p=0.07). Aspirin-allocated patients had significantly fewer recurrent ischemic strokes within 14 days (2.8% vs. 3.9%, <0.001), with no significant excess of hemorrhagic strokes (0.9% vs. 0.8%). There was a significant reduction in death or nonfatal recurrent stroke with aspirin (11.3% vs. 12.4%, p=0.02). Aspirin was associated with an increase in the incidence of transfusions or fatal extracranial bleeds (1.1% vs. 0.8%, p=0.004). However, in the absence of heparin, this increase was not significant.
There was no interaction between aspirin and heparin in the main outcomes.
Among patients with acute ischemic stroke, heparin provided no significant survival benefit at six months and was associated with an increase in the need for transfusion and in the incidence of fatal extracranial bleeds, especially at the higher of the two doses used. Aspirin was associated with reduction in death or nonfatal recurrent stroke without a significant increase in the incidence of major bleeding complications when used in the absence of heparin. These findings suggest that aspirin should be initiated early in patients with symptoms of ischemic stroke and that heparin, if used, should be administered at low doses.
The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997;349:1569-81.
Clinical Topics: Anticoagulation Management
Keywords: Stroke, Platelet Aggregation Inhibitors, Heparin
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