Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack

Wang, Yongjun; Wang, Wenjuan; Liu, Liping; Wang, David; Wang, Chunxue; Wang, Chen; Li, Hao; Meng, Xia; Cui, Liying; Jia, Jianping; Dong, Qiang; Xu, Anding; Zeng, Jinsheng; Li, Yansheng; Wang, Zhimin; Xia, Haiqin; Johnston, S. Claiborne

doi:10.1056/nejmoa1215340

Cited by 1,456 publications

(1,143 citation statements)

References 29 publications

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“…The CHANCE trial was a randomized, double‐blind, controlled trial that enrolled 5170 patients within 24 hours after onset of minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3) or high‐risk TIA (ABCD 2 ≥4) from 114 clinical centers in China 18, 19, 20. In total, 73 (64%) of 114 participating hospitals voluntarily participated in the serum biomarker substudy in the CHANCE trial.…”

Section: Methodsmentioning

confidence: 99%

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Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus

Chen

Pan

Jing

et al. 2017

JAHA

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BackgroundWe aimed to determine the risk conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High‐risk patients with Acute Non‐disabling Cerebrovascular Events) trial.Methods and ResultsIn total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society (CDS) and International Diabetes Foundation (IDF) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS, 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow‐up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89–3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98–3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke (P=0.82 for interaction in the fully adjusted model of CDS) was observed. Using the METS (IDF) criteria demonstrated similar results.ConclusionsConcurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack.

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Section: Methodsmentioning

confidence: 99%

“…The primary efficacy outcome was a new stroke (ischemic or hemorrhagic) within 90 days 18. Recurrent stroke was defined by the presence of a sudden new symptomatic neurological deficit on a background of stability or improvement after the presenting event 22.…”

Section: Methodsmentioning

confidence: 99%

Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus

Chen

Pan

Jing

et al. 2017

JAHA

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“…Early and short‐term use of two agents appears to be superior to monotherapy, as suggested by observational studies (EXPRESS, SOS 1, 2), small trials (FASTER, EARLY) 24, 25, and a post hoc subgroup analysis of the PRoFESS mega‐trial 26. These findings were strengthened by the large CHANCE trial that showed that the combination of aspirin + clopidogrel was superior to aspirin alone in reducing stroke recurrence 23. Indeed, it appears in meta‐analyses that any pair of antiplatelets is superior to any single agent 27, 28.…”

Section: Introduction and Rationalementioning

confidence: 96%

“…While oral anticoagulants are established therapy after cardioembolic stroke and TIA 11, 12, 13, 14, the majority of patients with acute and chronic ischemic stroke or TIA need antiplatelets 15, 16, 17, 18, 19, 20, 21, 22, 23.…”

Section: Introduction and Rationalementioning

confidence: 99%

Safety and Efficacy of Intensive vs. Guideline Antiplatelet Therapy in High-Risk Patients with Recent Ischemic Stroke or Transient Ischemic Attack: Rationale and Design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) Trial (ISRCTN47823388)

2015

International Journal of Stroke

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RationaleThe risk of recurrence following a stroke or transient ischemic attack is high, especially immediately after the event.HypothesisBecause two antiplatelet agents are superior to one in patients with non‐cardioembolic events, more intensive treatment might be even more effective.Sample size estimatesThe sample size of 4100 patients will allow a shift to less recurrence, and less severe recurrence, to be detected (odds ratio 0·68) with 90% power at 5% significance.Methods and design Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (ISRCTN47823388) is comparing the safety and efficacy of intensive (combined aspirin, clopidogrel, and dipyridamole) vs. guideline antiplatelet therapy, both given for one‐month. This international collaborative parallel‐group prospective randomized open‐label blinded‐end‐point phase III trial plans to recruit 4100 patients with acute ischemic stroke or transient ischemic attack. Randomization and data collection are performed over a secure Internet site with real‐time data validation and concealment of allocation. Outcomes, serious adverse events, and neuroimaging are adjudicated centrally with blinding to treatment allocation.Study outcomeThe primary outcome is stroke recurrence and its severity (‘ordinal recurrence’ based on modified Rankin Scale) at 90 days, with masked assessment centrally by telephone. Secondary outcomes include vascular events, functional measures (disability, mood, cognition, quality of life), and safety (bleeding, death, serious adverse events).DiscussionThe trial has recruited more than 50% of its target sample size (latest number: 2399) and is running in 104 sites in 4 countries. One‐third of patients presented with a transient ischemic attack.

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“…For example, GpIIb/IIIa inhibitors do not lead to an improvement in functional outcome compared to aspirin alone, perhaps because they increase the risk of intracranial haemorrhage. However, when clopidogrel and aspirin were targeted to Chinese patients with a particularly high risk of recurrent ischemic stroke, and low risk of haemorrhage – patients with recent TIA – the more intensive regime led to a net clinical benefit: fewer ischemic strokes, with no increase in intracranial haemorrhage 2. This hypothesis is of great interest in recent TIA, and being explored in different populations (Platelet Orientated Inhibition in New TIA, POINT, NCT00991029) and with more intensive antiplatelet regimes (Triple Antiplatelets for Reducing Dependence After Ischaemic Stroke, TARDIS, ISRCTN47823388).…”

Section: Introductionmentioning

confidence: 99%

Targeting Aspirin in Acute Disabling Ischemic Stroke: An Individual Patient Data Meta-Analysis of Three Large Randomized Trials

Thompson

Murray

Candelise

et al. 2015

International Journal of Stroke

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BackgroundAspirin is of moderate overall benefit for patients with acute disabling ischemic stroke. It is unclear whether functional outcome could be improved after stroke by targeting aspirin to patients with a high risk of recurrent thrombosis or a low risk of haemorrhage.AimsWe aimed to determine whether patients at higher risk of thrombotic events or poor functional outcome, or lower risk of major haemorrhage had a greater absolute risk reduction of poor functional outcome with aspirin than the average patient.MethodsWe used data on individual ischemic stroke patients from three large trials of aspirin vs. placebo in acute ischemic stroke: the first International Stroke Trial (n = 18 372), the Chinese Acute Stroke Trial (n = 20 172) and the Multicentre Acute Stroke Trial (n = 622). We developed and evaluated clinical prediction models for the following: early thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis and pulmonary embolism); early haemorrhagic events (significant intracranial haemorrhage, major extracranial haemorrhage, or haemorrhagic transformation of an infarct); and late poor functional outcome. We calculated the absolute risk reduction of poor functional outcome (death or dependence) at final follow‐up in: quartiles of early thrombotic risk; quartiles of early haemorrhagic risk; and deciles of poor functional outcome risk.ResultsIschemic stroke patients who were older, had lower blood pressure, computerized tomography evidence of infarct or more severe deficits due to stroke had increased risk of thrombotic and haemorrhagic events and poor functional outcome. Prediction models built with all baseline variables (including onset to treatment time) discriminated weakly between patients with and without recurrent thrombotic events (area under the receiver operating characteristic curve 0·56, 95% CI:0·53–0·59) and haemorrhagic events (0·57, 0·52–0·64), though well between patients with and without poor functional outcome (0·77, 0·76–0·78) in the International Stroke Trial. We found no evidence that the net benefit of aspirin increased with increasing risk of thrombosis, haemorrhage or poor functional outcome in all three trials.ConclusionsUsing simple clinical variables to target aspirin to patients after acute disabling stroke by risk of thrombosis, haemorrhage or poor functional outcome does not lead to greater net clinical benefit. We suggest future risk stratification schemes include new risk factors for thrombosis and intracranial haemorrhage.

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Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack

Cited by 1,456 publications

References 29 publications

Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus

Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus

Safety and Efficacy of Intensive vs. Guideline Antiplatelet Therapy in High-Risk Patients with Recent Ischemic Stroke or Transient Ischemic Attack: Rationale and Design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) Trial (ISRCTN47823388)

Targeting Aspirin in Acute Disabling Ischemic Stroke: An Individual Patient Data Meta-Analysis of Three Large Randomized Trials

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