TY - JOUR

T1 - Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS)

T2 - a randomised, open-label, phase 3 superiority trial

AU - TARDIS Investigators

AU - Bath, Philip M

AU - Woodhouse, Lisa J

AU - Appleton, Jason P

AU - Beridze, Maia

AU - Christensen, Hanne

AU - Dineen, Robert A

AU - Duley, Lelia

AU - England, Timothy J

AU - Flaherty, Katie

AU - Havard, Diane

AU - Heptinstall, Stan

AU - James, Marilyn

AU - Krishnan, Kailash

AU - Markus, Hugh S

AU - Montgomery, Alan A

AU - Pocock, Stuart J

AU - Randall, Marc

AU - Ranta, Annemarei

AU - Robinson, Thompson G

AU - Scutt, Polly

AU - Venables, Graham S

AU - Sprigg, Nikola

AU - Emsley, Hedley

N1 - Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

PY - 2018/3/3

Y1 - 2018/3/3

N2 - BACKGROUND: Intensive 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.METHODS: We 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.FINDINGS: 3096 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).INTERPRETATION: Among 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.FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

AB - BACKGROUND: Intensive 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.METHODS: We 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.FINDINGS: 3096 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).INTERPRETATION: Among 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.FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

KW - Acute Disease

KW - Aged

KW - Aspirin/administration & dosage

KW - Brain Ischemia/drug therapy

KW - Denmark/epidemiology

KW - Dipyridamole/administration & dosage

KW - Drug Therapy, Combination

KW - Female

KW - Georgia/epidemiology

KW - Hemorrhage/chemically induced

KW - Humans

KW - Ischemia/drug therapy

KW - Ischemic Attack, Transient/chemically induced

KW - Male

KW - Middle Aged

KW - New Zealand/epidemiology

KW - Platelet Aggregation Inhibitors

KW - Prospective Studies

KW - Recurrence

KW - Research Design/standards

KW - Risk Assessment

KW - Stroke/drug therapy

KW - Thrombolytic Therapy/methods

KW - Ticlopidine/administration & dosage

KW - Treatment Outcome

KW - United Kingdom/epidemiology

U2 - 10.1016/S0140-6736(17)32849-0

DO - 10.1016/S0140-6736(17)32849-0

M3 - Journal article

C2 - 29274727

VL - 391

SP - 850

EP - 859

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10123

ER -