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

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.

Critique on the Use of Early Short-Term Dual Antiplatelet Therapy Following Minor Acute Cerebral Ischemic Events

“…S1), yet substantially fewer major hemorrhages (Fig. S4) in comparison to triple therapy [23]. Rates of serious (fatal/major/ moderate) hemorrhages in the "guideline" ASA + DP or Clo only group (> 2%) were again notably discrepant to those of CHANCE and POINT, again questioning the veracity and generalizability of the CHANCE and POINT findings and conclusions.…”

“…The Triple Antiplatelets for Reducing Dependency after Ischemic Stroke (TARDIS) trial randomized 3,096 patients with cerebral infarct or TIA within 48 h to a combination of ASA, Clo and dipyridamole (DP), or to "guideline" therapy consisting of ASA + DP, or Clo alone [23]. At 90 days, no advantage was observed for triple antiplatelet therapy in the primary outcome of recurrent infarct or TIA, whereas triple therapy substantially increased severe (fatal and major; p = 0.0063) and intracerebral hemorrhages (p = 0.04).…”

Predictors and Management of Antiplatelet-Related Bleeding Complications for Acute Coronary Syndrome in Chinese Elderly Patients

“…In this regard, approximately half of the major bleeds in patients aged 75 years or older are gastrointestinal bleeding (GIB) [8], an uncommon but devastating complication of regular antiplatelet use is intracerebral haemorrhage (ICH) [9]. An increasing number of data indicates that the Asian population that present with ACS or undergo PCI display highly variable risk profiles for bleeding when compared with the Western population [10].…”

The use of cilostazol for secondary stroke prevention: isn’t it time it’s evaluated in Western countries?

“…In a recent metaanalysis comprising 18 randomized controlled trials involving 15,515 patients of non-cardioembolic, transient or ischemic stroke, it has been observed that there is no significant difference between aspirin+dipyridamole versus aspirin alone on stroke recurrence, composite vascular events and major bleeding [4]. Lately, usefulness of combined intensive therapy comprising aspirin + clopidogrel + dipyridamole is compared with either clopidogrel alone or aspirin + dipyridamole in acute cerebral ischemia, which has revealed that intensive therapy does not reduce incidence and severity of ischemic stroke or transient ischemic stroke [23]. Several controlled randomization trials, which tested the efficiency of dipyridamole in combination with aspirin versus other antiplatelet drugs are summarized in Table 2.…”