International Stroke Trial

International Stroke Trial
Name	International Stroke Trial
Other names	IST
Start date	1991
Completion date	1997
Phase	III
Design	randomized controlled trial
Interventions	aspirin, heparin
Primary outcome	death or dependency at 6 months
Sample size	19,435
Countries	United Kingdom, France, Germany, Italy, Spain, Australia, China, India, Poland, Russia

International Stroke Trial was a large, multicenter, randomized controlled trial that evaluated antithrombotic strategies in acute ischemic cerebrovascular accident patients. The study compared early administration of acetylsalicylic acid and heparin regimens to standard care across a broad international network including centers in United Kingdom, France, Germany, Italy, Spain, Australia, China, India, Poland, and Russia. Designed during the era following results from trials such as those led by investigators in Oxford University and National Institutes of Health, it aimed to resolve controversies about routine antithrombotic use in acute stroke care.

Background and objectives

At the time of trial initiation, conflicting data from trials in United States, Scotland, and Sweden had left clinicians uncertain about the benefits and risks of early antiplatelet and anticoagulant therapy after ischemic stroke. Interest from organizations including the World Health Organization, European Stroke Organisation, Royal College of Physicians, and research groups at Cambridge and Imperial College London led to a collaborative effort. Primary objectives were to determine whether early administration of aspirin reduced death and dependency and whether heparin reduced recurrent cerebrovascular disease or improved outcomes, with secondary objectives addressing hemorrhagic complications, early recurrent transient ischemic attack, and subgroup effects by infarct subtype as classified by systems used in Glasgow and Oxford cohorts.

Methods

The trial used randomized allocation with factorial design across emergency departments and stroke units affiliated with institutions such as Addenbrooke's Hospital, St Thomas' Hospital, Royal Melbourne Hospital, and major tertiary centers in Beijing and Mumbai. Inclusion criteria mirrored diagnostic pathways from Magnetic Resonance Imaging and Computed Tomography protocols established at Mayo Clinic and Harvard Medical School partner hospitals, enrolling patients with clinically confirmed acute ischemic events within 48 hours. Treatment arms included low-dose acetylsalicylic acid versus no acetylsalicylic acid and early subcutaneous unfractionated heparin versus no heparin, with masking of outcome assessment modeled on methods developed at Johns Hopkins and analytic plans influenced by statisticians from London School of Hygiene and Tropical Medicine and University of Oxford. Primary outcome measurement at six months used dependency scales analogous to those validated by researchers at Stanford University and University College London.

Results

The trial enrolled 19,435 participants and reported that early aspirin reduced the combined endpoint of death or dependency at six months, with effects consistent across subgroups including patients from centers in Italy, Spain, Poland, and Australia. Heparin reduced early recurrent ischemic stroke in selected high-risk cohorts but did not significantly improve overall functional outcomes and increased rates of symptomatic intracranial hemorrhage in some sites such as those modeled after protocols from Moscow and Beijing centers. Results echoed and contrasted findings from contemporaneous trials at NIH and Oxford and influenced guideline panels at organizations including the American Heart Association, European Society of Cardiology, and Stroke Association in the United Kingdom.

Safety and adverse events

Safety analyses documented increased major bleeding, including intracranial hemorrhage, associated with heparin arms, particularly in older cohorts and in settings with limited routine Computed Tomography availability as experienced in some centers in India and China. Aspirin was associated with small increases in gastrointestinal bleeding documented in datasets similar to surveillance from Centers for Disease Control and Prevention and hospital registries at Guy's Hospital and Royal Infirmary of Edinburgh, but overall net benefit favored aspirin when balancing mortality and dependency outcomes. Adverse event monitoring procedures were informed by pharmacovigilance standards from European Medicines Agency and trial safety committees with expertise from World Health Organization advisors.

Interpretation and impact

Investigators concluded that routine early low-dose aspirin for most acute ischemic stroke patients provided a modest but important reduction in death and dependency, while routine early use of heparin should be reserved for specific high-risk subgroups due to bleeding risk. The findings influenced clinical decision-making at stroke units established following models from Stroke Unit Trialists' Collaboration and hospitals such as Addenbrooke's Hospital and Royal Melbourne Hospital. The trial's international scope, large sample size, and pragmatic design helped reconcile differing practices between centers in Europe, North America, and Asia and provided evidence that shaped acute stroke pathways in multidisciplinary services linked to rehabilitation medicine and vascular neurology departments at institutions including Mayo Clinic and Massachusetts General Hospital.

Subsequent research and influence on guidelines

Following publication, the trial prompted secondary analyses and meta-analyses led by investigators at University of Oxford, Harvard Medical School, Johns Hopkins, and University College London; these syntheses informed guideline updates by the American Heart Association, European Stroke Organisation, National Institute for Health and Care Excellence, and national stroke societies in Australia and Canada. Subsequent randomized trials and pooled analyses investigated optimal antiplatelet combinations, timing of anticoagulation in cardioembolic stroke related to atrial fibrillation, and tailored strategies integrating advanced imaging from Massachusetts General Hospital and Mayo Clinic. The trial remains cited in guideline documents, textbook chapters from Cambridge University Press and Oxford University Press, and policy advisories from the World Health Organization.

Category:Clinical trials Category:Stroke research Category:Antithrombotic therapy