ArticlesAlteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study
Introduction
The recombinant tissue plasminogen activator alteplase is the only medical treatment currently approved for acute ischaemic stroke. Although it significantly improves the likelihood of disability-free recovery, alteplase has restricted fibrinolytic efficacy, achieving arterial recanalisation in fewer than 50% of patients.1 Of those patients who recanalise, only about half do so within 2 h of drug administration.2 Tenecteplase is a modified recombinant tissue plasminogen activator molecule engineered to improve efficacy3 through increased affinity binding to fibrin, greater resistance to inactivation by plasminogen activator inhibitor-1, no procoagulant effects, and longer free plasma half-life. In animal models, it has achieved significantly shorter time to reperfusion, with greater recanalisation and reduction of thrombus burden compared with alteplase.4 In acute myocardial infarction, tenecteplase showed equal therapeutic efficacy and lower risk of bleeding compared with alteplase,5 with non-significant evidence of improved early reperfusion.6
Investigation of new thrombolytic drugs for acute stroke has, until recently, concentrated on extending the window beyond 4·5 h from symptom onset established for alteplase. Dose-ranging studies of tenecteplase in acute stroke have been reported.7, 8 Parsons and colleagues9 reported superiority of tenecteplase over alteplase in terms of both imaging-defined reperfusion and clinical outcomes in a selected group of patients with large artery occlusion and favourable brain perfusion patterns defined on CT scan. However, how the effect sizes reported in a highly selected population will translate into the general population is unclear. In the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study, we aimed to compare alteplase with tenecteplase, using imaging criteria as exploratory outcome measures rather than selection criteria, to define possible effect sizes in a general stroke population eligible for intravenous thrombolysis.
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Study design and participants
In this single-centre, phase 2, prospective, randomised, open-label, blinded endpoint study, patients were recruited from The Institute of Neurological Sciences, Glasgow, Scotland. Patients were eligible if they had clinically diagnosed supratentorial acute ischaemic stroke with measurable deficit on the National Institutes of Health stroke scale (NIHSS),10 were within 4·5 h of symptom onset, were aged 18 years or older, were living independently pre-stroke, and were considered eligible for
Results
Between Jan 1, 2012, and Sept 7, 2013, 355 patients were screened (figure 1), of whom 157 were eligible for intravenous thrombolysis and 104 were enrolled. 52 patients were assigned to receive tenecteplase and 52 to receive alteplase. Reasons for exclusion are detailed in figure 1. Eight patients ultimately had a diagnosis other than stroke and were excluded from the protocol-defined analysis. Groups were well-balanced for clinical baseline characteristics and comorbidities (table 1), had
Discussion
Neither radiological nor clinical outcomes differed significantly with intravenous tenecteplase 0·25 mg/kg compared with alteplase 0·9 mg/kg, the present standard of care. We did not note any difference in our primary endpoint of penumbral salvage, an exploratory measure selected owing to its established relation to early clinical change.26 Safety outcomes did not differ, notably intracerebral haemorrhages of all kinds, and parenchymal haematomas, the complication most strongly associated with
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