Elsevier

The Lancet

Volume 380, Issue 9843, 25–31 August 2012, Pages 731-737
The Lancet

Articles
Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(12)60949-0Get rights and content

Summary

Background

Thrombolysis with intravenous alteplase is the only approved treatment for acute ischaemic stroke. After alteplase-induced recanalisation, reocclusion occurs in 14–34% of patients, probably because of platelet activation. Early administration of antiplatelet therapy after alteplase could reduce the risk of reocclusion and improve outcome. We compared the effects of early addition of intravenous aspirin to alteplase with standard alteplase without aspirin.

Methods

In this multicentre, randomised, open-label trial with blind-endpoint assessment, patients with acute ischaemic stroke treated with alteplase were randomly assigned to 300 mg intravenous aspirin within 90 min after start of alteplase treatment or to no additional treatment. In both groups, oral antiplatelet therapy was started 24 h after alteplase treatment. The primary endpoint was favourable outcome, defined as a score of 0–2 on the modified Rankin scale at 3 months. This trial is registered with the Netherlands Trial Register (NTR822).

Findings

Between July 29, 2008, and April 20, 2011, 642 patients (322 patients aspirin, 320 patients standard treatment) of the targeted 800 patients were enrolled. At that time, the trial was terminated prematurely because of an excess of symptomatic intracranial haemorrhage (SICH) and no evidence of benefit in the aspirin group. At 3 months, 174 (54·0%) patients in the aspirin group versus 183 (57·2%) patients in the standard treatment group had a favourable outcome (absolute difference −3·2%, 95% CI −10·8 to 4·2; crude relative risk 0·94, 0·82 to 1·09, p=0·42). Adjusted odds ratio was 0·91 (95% CI 0·66–1·26, p=0·58). SICH occurred more often in the aspirin group (14 [4·3%] patients) than in the standard treatment group (five [1·6%]; absolute difference 2·8%, 95% CI 0·2–5·4; p=0·04). SICH was more often the cause of poor outcome in the aspirin group compared with the standard treatment group (11 vs 1, p=0·006).

Interpretation

Early administration of intravenous aspirin in patients with acute ischaemic stroke treated with alteplase does not improve outcome at 3 months and increases the risk of SICH. The results of this trial do not support a change of the current guidelines, which advise to start antiplatelet therapy 24 h after alteplase.

Funding

The Dutch Heart Foundation.

Introduction

Intravenous thrombolysis with alteplase (or recombinant tissue plasminogen activator) is the only approved treatment for acute ischaemic stroke.1, 2 After thrombolysis, the overall recanalisation rate is 46%.3 Reocclusion after initial recanalisation occurs in 14–34% of patients and is associated with clinical deterioration and poor outcome.4, 5, 6 Reocclusion has been attributed to increased platelet aggregation caused by the local thrombus, endothelial injury, and probably the thrombolytic treatment itself.7, 8 Start of antiplatelet therapy early after alteplase might reduce the risk of reocclusion and thereby improve functional outcome. Indeed, previous use of antiplatelet therapy has been associated with higher rates of early recanalisation after thrombolysis.9 In the National Institute of Neurological Disorders and Stroke trial, clinical deterioration associated with poor outcome was less common in patients with previous use of antiplatelet therapy.10 In patients with acute myocardial infarction, the combination of antiplatelet therapy and thrombolysis reduces mortality substantially compared with thrombolysis alone.11

In the ARTIS (Antiplatelet therapy in combination with Rt-PA Thrombolysis in Ischemic Stroke) trial, we compared the effects of early addition of 300 mg intravenous aspirin to alteplase with standard alteplase without aspirin.

Section snippets

Study design and patients

ARTIS was a prospective, multicentre, randomised, open-label trial with blinded endpoint assessment (PROBE design). The rationale and the protocol of the study have been published.12, 13 The Department of Neurology of the Academic Medical Center (University of Amsterdam, Amsterdam, Netherlands) designed and coordinated the trial. 37 centres across the Netherlands participated (three academic hospitals, 20 non-academic teaching hospitals, and 14 non-teaching hospitals (see end of paper for ARTIS

Results

Between July 29, 2008, and April 20, 2011, 642 patients were included in the trial of whom 564 had reached 3 months follow-up (figure 1). At that time, inclusion was prematurely halted according to the recommendation of the DSMB because of a significant difference of reported SICHs between the groups, with more SICHs in the aspirin group (safety). To investigate the possible implications of this increased SICH rate, the results on the primary endpoint were revealed to the DSMB. On the basis of

Discussion

Our study shows that intravenous administration of 300 mg aspirin within 90 min after start of alteplase treatment does not improve functional outcome at 3 months but increases the risk of SICH.

A previous trial investigated the effect of combining aspirin (300 mg oral or 100 mg intravenous in case of swallowing difficulties) with intravenous thrombolysis using streptokinase instead of alteplase. This Multicenter Acute Stroke Trial–Italy study showed that the combination of early administration

References (29)

  • W Hacke et al.

    Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II)

    Lancet

    (1998)
  • KF Schulz et al.

    Multiplicity in randomised trials II: subgroup and interim analyses

    Lancet

    (2005)
  • Tissue plasminogen activator for acute ischemic stroke

    N Engl J Med

    (1995)
  • JH Rha et al.

    The impact of recanalization on ischemic stroke outcome: a meta-analysis

    Stroke

    (2007)
  • AV Alexandrov et al.

    Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator

    Neurology

    (2002)
  • M Rubiera et al.

    Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke

    Stroke

    (2005)
  • M Saqqur et al.

    Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: a multicenter transcranial Doppler study

    Stroke

    (2007)
  • JA Leopold et al.

    Platelet activation by fibrinolytic agents: a potential mechanism for resistance to thrombolysis and reocclusion after successful thrombolysis

    Coron Artery Dis

    (1995)
  • TK Nordt et al.

    Augmented platelet aggregation as predictor of reocclusion after thrombolysis in acute myocardial infarction

    Thromb Haemost

    (1998)
  • D Saňák et al.

    Prior use of antiplatelet therapy can be associated with a higher chance for early recanalization of the occluded middle cerebral artery in acute stroke patients treated with intravenous thrombolysis

    Eur Neurol

    (2012)
  • JC Grotta et al.

    Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial

    Stroke

    (2001)
  • Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2

    Lancet

    (1988)
  • SM Zinkstok et al.

    Antiplatelet therapy in combination with rt-PA thrombolysis in ischemic stroke (ARTIS): rationale and design of a randomized controlled trial

    Cerebrovasc Dis

    (2010)
  • SM Zinkstok et al.

    A randomised controlled trial of antiplatelet therapy in combination with Rt-PA thrombolysis in ischemic stroke: rationale and design of the ARTIS-Trial

    Trials

    (2010)
  • Cited by (0)

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