Abstract
SummaryBackgroundIntensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.MethodsWe did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001).InterpretationAmong patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.FundingNational Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.
Highlights
The risk of recurrence after ischaemic stroke and transient ischaemic attack (TIA) is highest immediately after the event and declines over the following weeks.[1]
Recruitment commenced on April 7, 2009, and on the advice of the independent data monitoring committee was halted on March 18, 2016, after enrolment of 3096 participants (76% of the planned target of 4100; figure 1). 28 patients in the intensive treatment group and 30 in the guideline treatment group were classified as inpatients in hospital—participants who were already admitted to hospital when they had their qualifying event
In this cohort of patients with acute, non-cardioembolic ischaemic stroke or TIA, a regimen of intensive anti platelet therapy did not reduce stroke recurrence or its severity when compared with guideline antiplatelet therapy with either clopidogrel alone or combined aspirin and dipyridamole
Summary
The risk of recurrence after ischaemic stroke and transient ischaemic attack (TIA) is highest immediately after the event and declines over the following weeks.[1]. If two dual agents in inhibiting platelet aggregation, platelet– leucocyte conjugation, and leucocyte activation in vitro[7] and ex vivo in healthy volunteers and participants with previous stroke or TIA.[8,9] A small trial in participants with chronic stroke reported that combined aspirin, clopidogrel, and dipyridamole (compared with aspirin alone) was feasible to administer for up to 24 months, bleeding was increased with intensive treat ment.[10] In a case series, long-term administration of triple treatment appeared to be useful in participants at very high risk of recurrence, defined as recurrence on dual antiplatelet therapy.[11]. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy
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