The International Stroke Trial (IST): a Randomised Trial of Aspirin, Subcutaneous Heparin, Both, Or Neither Among 19 435 Patients with Acute Ischaemic Stroke
Total Page：16
File Type：pdf, Size：1020Kb
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 International Stroke Trial Collaborative Group* Summary significant (14 [SD 6] per 1000, 2p=0·03). Aspirin- allocated patients had significantly fewer recurrent Background Only a few small trials have compared ischaemic strokes within 14 days (2·8% vs 3·9%) with no antithrombotic therapy (antiplatelet or anticoagulant significant excess of haemorrhagic strokes (0·9% vs agents) versus control in acute ischaemic stroke, and 0·8%), so the reduction in death or non-fatal recurrent none has been large enough to provide reliable evidence stroke with aspirin (11·3% vs 12·4%) was significant. on safety or efficacy. Aspirin was associated with a significant excess of 5 (SD Methods The International Stroke Trial (IST) was a large, 1) transfused or fatal extracranial bleeds per 1000; in the randomised, open trial of up to 14 days of antithrombotic absence of heparin the excess was 2 (SD 1) and was not therapy started as soon as possible after stroke onset. significant. There was no interaction between aspirin and The aim was to provide reliable evidence on the safety heparin in the main outcomes. and efficacy of aspirin and of subcutaneous heparin. Half Interpretation Neither heparin regimen offered any clinical the patients were allocated unfractionated heparin (5000 advantage at 6 months. The results suggest that if or 12 500 IU bd [twice daily]) and half were allocated heparin is given in routine clinical practice, the dose “avoid heparin”; and, in a factorial design, half were should not exceed 5000 IU subcutaneously twice daily. allocated aspirin 300 mg daily and half “avoid aspirin”. For aspirin, the IST suggests a small but worthwhile The primary outcomes were death within 14 days and improvement at 6 months. Taking the IST together with death or dependency at 6 months. 19 435 patients with the comparably large Chinese Acute Stroke Trial, aspirin suspected acute ischaemic stroke entering 467 hospitals produces a small but real reduction of about 10 deaths or in 36 countries were randomised within 48 hours of recurrent strokes per 1000 during the first few weeks. symptom onset. Both trials suggest that aspirin should be started as soon Results Among heparin-allocated patients, there were as possible after the onset of ischaemic stroke; previous non-significantly fewer deaths within 14 days (876 [9·0%] trials have already shown that continuation of low-dose heparin vs 905 [9·3%] no heparin), corresponding to 3 aspirin gives protection in the longer term. (SD 4) fewer deaths per 1000 patients. At 6 months the Lancet 1997; 349: 1569–81 percentage dead or dependent was identical in both See Commentary page 1564 groups (62·9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 Introduction days (2·9% vs 3·8%) but this was offset by a similar-sized Every year, several million people worldwide are treated increase in haemorrhagic strokes (1·2% vs 0·4%), so the for acute ischaemic stroke1. If some widely practicable difference in death or non-fatal recurrent stroke (11·7% therapies could be reliably shown to prevent death or vs 12·0%) was not significant. Heparin was associated dependence for “just” 10 or 20 of every 1000 patients, it with a significant excess of 9 (SD 1) transfused or fatal would, for every million stroke patients so treated, extracranial bleeds per 1000. Compared with 5000 IU bd ensure that an extra 10 000 were alive and independent. heparin, 12 500 IU bd heparin was associated with If such benefits exist, they must not, therefore, be significantly more transfused or fatal extracranial bleeds, overlooked. Reliable assessment of them may, however, more haemorrhagic strokes, and more deaths or non-fatal require randomised trials with tens of thousands of strokes within 14 days (12·6% vs 10·8%). Among aspirin- patients.2,3 Two such candidates are heparin and aspirin. allocated patients there were non-significantly fewer Most strokes are caused by acute occlusion of a deaths within 14 days (872 [9·0%] vs 909 [9·4%]), cerebral artery. Anticoagulants are widely used,4-6 to corresponding to 4 (SD 4) fewer deaths per 1000 facilitate early clot lysis, to inhibit clot propagation in patients. At 6 months there was a non-significant trend the cerebral arteries, and to prevent early arterial towards a smaller percentage of the aspirin group being re-embolisation and venous thromboembolism dead or dependent (62·2% vs 63·5%, 2p=0·07), a originating in immobile limbs.2 However, there is little difference of 13 (SD 7) per 1000; after adjustment for randomised evidence on the balance of risks and benefits baseline prognosis the benefit from aspirin was of heparin in acute ischaemic stroke. Low-dose regimens of around 5000 IU twice daily of subcutaneous *Details of members of the collaborating group, writing committee, and unfractionated heparin (or equivalent low-molecular- sources of support are given in the acknowledgment section weight heparins or heparinoids) do reduce the risk of 2,7 Correspondence to: Dr PAG Sandercock, Department of Clinical deep venous thrombosis, but the effects of these and Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK higher-dose regimens on the cerebral arterial circulation (e-mail: [email protected]) and on the risk of intracranial haemorrhage are Vol 349 • May 31, 1997 1569 THE LANCET unclear.2,7 A medium-dose regimen of 12 500 IU comatose patient could be randomised before CT. For those subcutaneous unfractionated heparin twice daily allocated active treatment, the initial doses could be given while prevents left-ventricular wall thrombus in acute the CT was being arranged, but treatment was stopped if myocardial infarction (AMI),8,9 and proved feasible in intracranial haemorrhage was found (which it rarely was). Classification and predicted prognosis Neurological deficits two large trials,10,11 but has not been tested in acute recorded at telephone randomisation were used to classify the 2,7 stroke. infarct as: total anterior circulation, partial anterior circulation, Antiplatelet drugs such as aspirin can be effective in posterior circulation, lacunar, or other, by means of a computer the secondary prevention of “serious vascular events” algorithm.19 Prognosis was predicted by a validated model,20 (stroke, AMI, and vascular death).12 Taken for a few using baseline data to calculate the probability of a poor years after a myocardial infarction, ischaemic stroke, or outcome (see statistical methods). transient ischaemic attack (TIA), antiplatelet therapy typically avoids about 40 serious vascular events per Planned interventions and their timing 1000 patients treated.12 It also reduces the incidence of After informed consent had been obtained (the procedure deep venous thrombosis and pulmonary embolism in varied to conform to local ethical committee requirements), high risk patients,13 and is effective in the treatment of patients were entered by telephoning the central randomisation AMI, preventing about 40 serious vascular events per service at the Clinical Trial Service Unit (CTSU), Oxford, UK. 1000 patients treated for just one month.12 In acute After the baseline data had been entered and checked for range and consistency, the computer allocated the study treatment(s) ischaemic stroke there is substantial platelet activation, (a minimisation algorithm was used to reduce any imbalance in 14,15 which can be inhibited by aspirin. But there is no recorded prognostic features between treatment groups).21 At large-scale randomised evidence on aspirin in acute that point the patient was irrevocably included in the study. ischaemic stroke.2,16 Clinicians could depart from the randomly allocated treatment Aspirin and heparin have different mechanisms of if a clear reason to do so had arisen, but they could not action, so the combination might be more effective than withdraw a patient from follow-up even if the patient turned either alone, although this might be offset by a greater out not to have had a stroke or did not receive the treatment risk of bleeding. In AMI, the combination of aspirin and allocated. heparin was not significantly more effective than aspirin Heparin Half of the patients were randomly allocated to receive 17,18 subcutaneous unfractionated heparin (one-quarter 5000 IU alone, but no trials have made this comparison in twice daily [low-dose] and one-quarter 12 500 IU twice daily 2,7,16 acute stroke. [medium-dose]); and half were allocated to “avoid heparin”. Given the uncertain balance of risk and benefit for Heparin was supplied by the hospital, and sodium heparin heparin and for aspirin in acute stroke,2,7,12,16 the could be used if calcium heparin was not available. In more uncertainty of many physicians about the safety and than 30 000 patients with AMI (most of whom also received efficacy of these drugs in this setting4-6 and the wide fibrinolytic therapy and aspirin) 12 500 IU twice daily had been variation in clinical practice,4-6 the IST was designed to fairly safe without routine monitoring of coagulation times,10,11 assess the separate and combined effects of so such monitoring was optional in the IST. Aspirin subcutaneous heparin (in twice daily doses of 5000 IU Using a factorial design, half of all patients were allocated to 300 mg aspirin daily and half to “avoid aspirin”. If or 12 500 IU) and of aspirin (300 mg daily). Large a patient could not swallow safely, aspirin was to be given by numbers of patients were included in order to provide a nasogastric tube, per rectum (300 mg suppository), or reliable estimate of their effects on death and other intravenously (100 mg lysine salt in 100 mL normal saline over major clinical events during the first 14 days after acute 60 min).