ArticlesTinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial
Introduction
Acute ischaemic stroke is characterised in most cases by large-vessel thromboembolic occlusion or small-vessel occlusion, and may be complicated by local thrombus extension, peripheral venous thromboembolism, and ischaemic cardiac events. Anticoagulation with heparin might reduce the likelihood of these events and improve functional outcome. Although unfractionated heparin is commonly recommended and used in the management of acute ischaemic stroke,1, 2, 3 randomised controlled trials have not found it to be safe or effective in improving functional outcome.4, 5, 6 However, studies in other vascular disorders, especially in the prevention and treatment of deep-vein thrombosis and pulmonary embolism, have found that low-molecular-weight (LMW) heparins are superior to unfractionated heparin in terms of both efficacy and safety.7, 8, 9 Clinical differences between LMW and unfractionated heparins are likely to result from differences in their pharmacokinetic profile and activity:10 LMW heparins have higher and more consistent bioavailability, a longer half-life, less protein binding, and dose-independent clearance, thereby producing a more predictable anticoagulant response. LMW heparins also have less antiplatelet activity than unfractionated heparin and do not increase vascular permeability, resulting in less bleeding. Finally, LMW heparins have greater antifactor-Xa activity than unfractionated heparin, which preferentially inhibits anti-factor-IIa through activation of antithrombin.
Ten randomised controlled trials of LMW heparins or heparinoids in acute ischaemic stroke have been reported,10 although only three of these11, 12, 13 were designed to test the hypothesis that these drugs decrease the risk of death and disability after stroke. Only the small Fraxiparine in Ischaemic Stroke (FISS) study of nadroparin, with 312 patients, found positive results on its primary outcome11 but this finding was not confirmed in the larger FISS bis trial (767 patients).13 The Trial of Org 10172 in Acute Stroke Treatment (TOAST) reported, in a post-hoc analysis, that danaparoid increased the odds of a favourable outcome in patients with stroke secondary to presumed large-artery (atherosclerotic) disease.12 A systematic review of these ten trials found that LMW heparins lowered the frequency of deep-vein thrombosis and pulmonary embolism but increased the risk of significant bleeding;14 there was a non-significant decrease in the combined outcome of death and disability with LMW heparins, an effect that became significant in an exploratory analysis of the trials in which treatment could be started beyond 24 h after the onset of stroke.14
Tinzaparin sodium is a LMW heparin (peak molecular mass about 4500 Da) prepared by enzymatic degradation of porcine mucosal heparin. It is licensed for the prevention and treatment of deep-vein thrombosis and pulmonary embolism. One small pilot trial of tinzaparin in acute ischaemic stroke showed that the drug reduced the frequency of deep-vein thrombosis (Leo Pharmaceutical Products, unpublished). We report here the findings of a randomised aspirin-controlled trial assessing the safety and efficacy of tinzaparin in improving functional outcome after acute ischaemic stroke.
Section snippets
Participants
TAIST was a prospective randomised, multicentre, double-blind, aspirin-controlled trial that took place from July, 1997, in ten countries in Europe (Belgium, Denmark, Finland, France, Germany, Ireland, the Netherlands, Norway, Sweden, and the UK) and Canada. Recruitment was completed in June 1999, and follow-up in January 2000. The study was run according to the principles of the Declaration of Helsinki and the International Conference on Harmonisation of Good Clinical Practice. Study approval
Discussion
The use of anticoagulation in acute ischaemic stroke remains controversial. Although the results of previous trials have been inconsistent and inconclusive, many physicians continue to administer LMW heparins to patients with acute ischaemic stroke. In this trial, the largest to date of a LMW heparin in acute stroke, we found that neither high-dose nor medium-dose tinzaparin improved the proportion of patients achieving independence, assessed as a Rankin score of 0–2, compared with aspirin.
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