Elsevier

The Lancet Neurology

Volume 14, Issue 4, April 2015, Pages 368-376
The Lancet Neurology

Articles
Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study

https://doi.org/10.1016/S1474-4422(15)70017-7Get rights and content

Summary

Background

In most countries, alteplase given within 4·5 h of onset is the only approved medical treatment for acute ischaemic stroke. The newer thrombolytic drug tenecteplase has been investigated in one randomised trial up to 3 h after stroke and in another trial up to 6 h after stroke in patients selected by advanced neuroimaging. In the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST), we aimed to assess the efficacy and safety of tenecteplase versus alteplase within 4·5 h of stroke onset in a population not selected on the basis of advanced neuroimaging, and to use imaging biomarkers to inform the design of a definitive phase 3 clinical trial.

Methods

In this single-centre, phase 2, prospective, randomised, open-label, blinded end-point evaluation study, adults with supratentorial ischaemic stroke eligible for intravenous thrombolysis within 4·5 h of onset were recruited from The Institute of Neurological Sciences, Glasgow, Scotland. Patients were randomly assigned (1:1) to receive tenecteplase 0·25 mg/kg (maximum 25 mg) or alteplase 0·9 mg/kg (maximum 90 mg). Treatment allocation used a mixed randomisation and minimisation algorithm including age and National Institutes of Health Stroke Scale score, generated by an independent statistician. Patients were not informed of treatment allocation; treating clinicians were aware of allocation but those assessing the primary outcome were not. Imaging comprised baseline CT, CT perfusion, and CT angiography; and CT plus CT angiography at 24–48 h. The primary endpoint was percentage of penumbra salvaged (CT perfusion-defined penumbra volume at baseline minus CT infarct volume at 24–48 h). Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT01472926.

Findings

Between Jan 1, 2012, and Sept 7, 2013, 355 patients were screened, of whom 157 were eligible for intravenous thrombolysis, and 104 patients were enrolled. 52 were assigned to the alteplase group and 52 to tenecteplase. Of 71 patients (35 assigned tenecteplase and 36 assigned alteplase) contributing to the primary endpoint, no significant differences were noted for percentage of penumbral salvaged (68% [SD 28] for the tenecteplase group vs 68% [23] for the alteplase group; mean difference 1·3% [95% CI −9·6 to 12·1]; p=0·81). Neither incidence of symptomatic intracerebral haemorrhage (by SITS-MOST definition, 1/52 [2%] tenecteplase vs 2/51 [4%] alteplase, p=0·55; by ECASS II definition, 3/52 [6%] vs 4/51 [8%], p=0·59) nor total intracerebral haemorrhage events (8/52 [15%] vs 14/51 [29%], p=0·091) differed significantly. The incidence of serious adverse events did not differ between groups (32 in the tenecteplase group, three considered probably or definitely related to drug treatment; 16 in the alteplase group, five were considered drug-related).

Interpretation

Neurological and radiological outcomes did not differ between the tenecteplase and alteplase groups. Evaluation of tenecteplase in larger trials of patients with acute stroke seems warranted.

Funding

The Stroke Association.

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.

Section snippets

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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