Elsevier

The Lancet

Volume 349, Issue 9065, 31 May 1997, Pages 1569-1581
The Lancet

Articles
The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke*

https://doi.org/10.1016/S0140-6736(97)04011-7Get rights and content

Summary

Background

Only a few small trials have compared antithrombotic therapy (antiplatelet or anticoagulant agents) versus control in acute ischaemic stroke, and none has been large enough to provide reliable evidence on safety or efficacy.

Methods

The International Stroke Trial (IST) was a large, randomised, open trial of up to 14 days of antithrombotic therapy started as soon as possible after stroke onset. The aim was to provide reliable evidence on the safety and efficacy of aspirin and of subcutaneous heparin. Half the patients were allocated unfractionated heparin (5000 or 12 500 IU bd [twice daily]) and half were allocated “avoid heparin”; and, in a factorial design, half were allocated aspirin 300 mg daily and half “avoid aspirin”. The primary outcomes were death within 14 days and death or dependency at 6 months. 19 435 patients with suspected acute ischaemic stroke entering 467 hospitals in 36 countries were randomised within 48 hours of symptom onset.

Results

Among heparin-allocated patients, there were non-significantly fewer deaths within 14 days (876 [9·0%] heparin vs 905 [9·3%] no heparin), corresponding to 3 (SD 4) fewer deaths per 1000 patients. At 6 months the percentage dead or dependent was identical in both groups (62·9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 days (2·9% vs 3·8%) but this was offset by a similar-sized increase in haemorrhagic strokes (1·2% vs 0·4%), so the difference in death or non-fatal recurrent stroke (11·7% vs 12·0%) was not significant. Heparin was associated with a significant excess of 9 (SD 1) transfused or fatal extracranial bleeds per 1000. Compared with 5000 IU bd heparin, 12 500 IU bd heparin was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12·6% vs 10·8%). Among aspirin-allocated patients there were non-significantly fewer deaths within 14 days (872 [9·0%] vs 909 [9·4%]), corresponding to 4 (SD 4) fewer deaths per 1000 patients. At 6 months there was a non-significant trend towards a smaller percentage of the aspirin group being dead or dependent (62·2% vs 63·5%, 2p=0·07), a difference of 13 (SD 7) per 1000; after adjustment for baseline prognosis the benefit from aspirin was significant (14 [SD 6] per 1000, 2p=0·03). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2·8% vs 3·9%) with no significant excess of haemorrhagic strokes (0·9% vs 0·8%), so the reduction in death or non-fatal recurrent stroke with aspirin (11·3% vs 12·4%) was significant. Aspirin was associated with a significant excess of 5 (SD 1) transfused or fatal extracranial bleeds per 1000; in the absence of heparin the excess was 2 (SD 1) and was not significant. There was no interaction between aspirin and heparin in the main outcomes.

Interpretation

Neither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term.

Introduction

Every year, several million people worldwide are treated for acute ischaemic stroke1. If some widely practicable therapies could be reliably shown to prevent death or dependence for “just” 10 or 20 of every 1000 patients, it would, for every million stroke patients so treated, ensure that an extra 10 000 were alive and independent. If such benefits exist, they must not, therefore, be overlooked. Reliable assessment of them may, however, require randomised trials with tens of thousands of patients.2, 3 Two such candidates are heparin and aspirin.

Most strokes are caused by acute occlusion of a cerebral artery. Anticoagulants are widely used,4, 5, 6 to facilitate early clot lysis, to inhibit clot propagation in the cerebral arteries, and to prevent early arterial re-embolisation and venous thromboembolism originating in immobile limbs.2 However, there is little randomised evidence on the balance of risks and benefits of heparin in acute ischaemic stroke. Low-dose regimens of around 5000 IU twice daily of subcutaneous unfractionated heparin (or equivalent low-molecular-weight heparins or heparinoids) do reduce the risk of deep venous thrombosis,2, 7 but the effects of these and higher-dose regimens on the cerebral arterial circulation and on the risk of intracranial haemorrhage are unclear.2, 7 A medium-dose regimen of 12 500 IU subcutaneous unfractionated heparin twice daily prevents left-ventricular wall thrombus in acute myocardial infarction (AMI),8, 9 and proved feasible in two large trials,10, 11 but has not been tested in acute stroke.2, 7

Antiplatelet drugs such as aspirin can be effective in the secondary prevention of “serious vascular events” (stroke, AMI, and vascular death).12 Taken for a few years after a myocardial infarction, ischaemic stroke, or transient ischaemic attack (TIA), antiplatelet therapy typically avoids about 40 serious vascular events per 1000 patients treated.12 It also reduces the incidence of deep venous thrombosis and pulmonary embolism in high risk patients,13 and is effective in the treatment of AMI, preventing about 40 serious vascular events per 1000 patients treated for just one month.12 In acute ischaemic stroke there is substantial platelet activation, which can be inhibited by aspirin.14, 15 But there is no large-scale randomised evidence on aspirin in acute ischaemic stroke.2, 16

Aspirin and heparin have different mechanisms of action, so the combination might be more effective than either alone, although this might be offset by a greater risk of bleeding. In AMI, the combination of aspirin and heparin was not significantly more effective than aspirin alone,17, 18 but no trials have made this comparison in acute stroke.2, 7, 16

Given the uncertain balance of risk and benefit for heparin and for aspirin in acute stroke,2, 7, 12, 16 the uncertainty of many physicians about the safety and efficacy of these drugs in this setting4, 5, 6 and the wide variation in clinical practice,4, 5, 6 the IST was designed to assess the separate and combined effects of subcutaneous heparin (in twice daily doses of 5000 IU or 12 500 IU) and of aspirin (300 mg daily). Large numbers of patients were included in order to provide a reliable estimate of their effects on death and other major clinical events during the first 14 days after acute ischaemic stroke, and on death and dependency in activities of daily living at 6 months, as well as any adverse effects on intracranial haemorrhage and on transfused (or fatal) extracranial bleeds.

Section snippets

Patients

Eligibility A patient was eligible if, in the view of the responsible physician, there was evidence of an acute stroke (irrespective of severity) with onset less than 48 h previously, no evidence of intracranial haemorrhage (see below), and no clear indications for, or contraindications to, heparin or aspirin. The fundamental criterion for eligibility was simply that the physician was uncertain whether or not to administer either or both of the trial treatments to that particular patient.

Recruitment and follow-up

In the pilot phase 984 patients were recruited between January, 1991, and February, 1993,3 with 18 456 recruited between March, 1993, and May, 1996, in the main trial. 5 were entered in error, so no data were collected on these patients. Thus 19 435 patients were randomised, by 467 hospitals in 36 countries. Outcome data were 99·99% complete for 14-day outcome and 99·2% complete for 6-month outcome (figure 1).

Characteristics of patients

Large numbers and central randomisation (with minimisation21) ensured good balance

Heparin

Heparin (low and medium dose combined) did not significantly affect deaths at 14 days or death or dependency at 6 months. These results are consistent with overviews2, 7 of the short-term effects in other anticoagulant trials (figure 3). The 15 previous trials were small, and even in aggregate included only 1599 patients, so they contribute little information. 13 trials have not published results on death or dependency at final follow-up; of the two that did (figure 4), only one indicated a

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    *

    Details of members of the collaborating group, writing committee, and sources of support are given in the acknowledgment section

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