Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.,The Lancet

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Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.
The Lancet ( IF 98.4 ) Pub Date : 2017-12-20 , DOI: 10.1016/s0140-6736(17)32849-0
Philip M Bath ₁ , Lisa J Woodhouse ₂ , Jason P Appleton ₁ , Maia Beridze ₃ , Hanne Christensen ₄ , Robert A Dineen ₅ , Lelia Duley ₆ , Timothy J England ₇ , Katie Flaherty ₂ , Diane Havard ₂ , Stan Heptinstall ₂ , Marilyn James ₈ , Kailash Krishnan ₁ , Hugh S Markus ₉ , Alan A Montgomery ₆ , Stuart J Pocock ₁₀ , Marc Randall ₁₁ , Annemarei Ranta ₁₂ , Thompson G Robinson ₁₃ , Polly Scutt ₂ , Graham S Venables ₁₄ , Nikola Sprigg ₁ ,

Affiliation

Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK; Stroke, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Hospital of War Veterans, Tbilisi, Georgia.
Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Department of Neurology, Copenhagen, Denmark.
Radiological Sciences, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, UK.
Vascular Medicine, Division of Medical Sciences & GEM, University of Nottingham, Nottingham, UK.
Health Economics, Division of Rehabilitation and Ageing, University of Nottingham, Nottingham, UK.
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Department of Neurology, Wellington Hospital and University of Otago, Wellington, New Zealand.
Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Research Centre, University of Leicester, Leicester, UK.
Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.

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.

中文翻译：

阿司匹林、氯吡格雷和双嘧达莫抗血小板治疗与单用氯吡格雷或阿司匹林和双嘧达莫治疗急性脑缺血 (TARDIS) 患者的比较：一项随机、开放标签的 3 期优效性试验。

背景对于预防急性脑缺血患者的复发事件，使用三种药物的强化抗血小板治疗可能比指导治疗更有效。我们的目的是比较强化抗血小板治疗（联合阿司匹林、氯吡格雷和双嘧达莫）与基于指南的抗血小板治疗的安全性和有效性。方法我们对发病 48 小时内患有缺血性中风或短暂性脑缺血发作 (TIA) 的成年参与者进行了一项国际、前瞻性、随机、开放标签、盲态终点试验。使用计算机随机化将参与者按 1:1 的比例分配，接受负荷剂量，然后接受 30 天的强化抗血小板治疗（联合阿司匹林 75 mg、氯吡格雷 75 mg 和双嘧达莫 200 mg，每日两次）或基于指南的治疗（包括氯吡格雷单独或组合阿司匹林和双嘧达莫）。随机分组按国家和指数事件进行分层，并尽量减少预后基线因素、药物使用、随机分组时间、中风相关因素和溶栓治疗。顺序主要结局是 90 天内任何复发性卒中（缺血性或出血性；使用改良 Rankin 量表评估）或 TIA 的综合发生率和严重程度，通过中心电话随访评估，并掩盖治疗分配，并按意图进行分析来治疗。该试验已在 ISRCTN 注册中心注册，注册号为 ISRCTN47823388。结果 2009 年 4 月 7 日至 2016 年 3 月 18 日期间，从四个国家的 106 家医院招募了 3096 名受试者（强化抗血小板治疗组 1556 名，指南抗血小板治疗组 1540 名）。根据研究人员的建议，该试验提前停止。数据监测委员会。强化治疗和指南治疗之间，复发性卒中或 TIA 的发生率和严重程度没有差异（93 名 [6%] 参与者 vs 105 名 [7%]；调整后常见比值比 [cOR] 0·90，95% CI 0·67-1 ·20，p=0·47)。相比之下，强化抗血小板治疗会导致更多、更严重的出血（调整后的 cOR 2·54，95% CI 2·05-3·16，p<0·0001）。解释在近期发生脑缺血的患者中，强化抗血小板治疗并没有降低复发性卒中或 TIA 的发生率和严重程度，但确实显着增加了大出血的风险。三联抗血小板治疗不应用于常规临床实践。资助美国国立卫生研究院健康技术评估计划、英国心脏基金会。

更新日期：2018-03-02

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