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Antiplatelet Agents for Preventing Early Recurrence of Ischemic Stroke or Transient Ischemic Attack

Reduced recurrent strokes but increased major hemorrhages

Benefits in NNT

40
1 in 40 were helped (reduced stroke recurrence)
None were helped (vascular death)
40
2.5% reduction in recurrent stroke

Harms in NNT

91
1 in 91 were harmed (major hemorrhage)
91
1.1% increase in major hemorrhage
View As:

Efficacy Endpoints

Stroke recurrence and vascular death. Secondary outcomes included myocardial infarction, vascular death, and death from all causes

Harm Endpoints

Intracranial and extracranial hemorrhage

Narrative

Ischemic strokes range in severity from minor to debilitating. Minor strokes and transient ischemic attacks (TIA) may be followed by recurrent strokes, with the highest risk in the first 48 hours.1 Approximately 30% of strokes are recurrent.2 Antiplatelet agents may reduce the risk of recurrence and prevent disability, but may also increase the risk of hemorrhage.2, 3, 4 The purpose of this summary is to update and refine a prior summary examining the effect of adding clopidogrel to aspirin after atherothrombotic acute ischemic stroke or TIA.

The Cochrane review from which we extracted this information included randomized controlled trials (RCTs) evaluating patients taking any combination of multiple antiplatelet agents versus fewer agents within 72 hours of an atherothrombotic acute ischemic stroke or TIA and followed up for at least one month.5 The primary outcome was stroke during follow up of at least 3 months. Secondary outcomes included myocardial infarction, intracranial hemorrhage, extracranial hemorrhage, and death. When there was more than one follow-up period, the authors included outcomes at one week, one month, three months, and six months. Here we focus on the comparison of aspirin plus clopidogrel versus aspirin alone.

The meta-analysis authors included 5 RCTs of 10739 subjects comparing aspirin plus clopidogrel versus aspirin alone.3, 6, 7, 8, 9 All medications were administered orally, and most utilized a loading dose of clopidogrel 300 mg. Dosing of aspirin ranged from 75-300 mg. Follow-up time points ranged from 30 days to 1 year.

Dual antiplatelet therapy with aspirin plus clopidogrel was associated with less recurrent stroke when compared to aspirin alone (6.5% versus 9%; absolute risk reduction [ARR]: 2.5%; number needed to treat [NNT]: 40; risk ratio [RR]: 0.7; 95% confidence interval [CI]: 0.6-0.8). There was no difference in vascular death (RR 1.4; 95% CI: 0.6-2.9) or myocardial infarction (RR 1.5; 95 CI: 0.6-3.4). Extracranial hemorrhage was higher with aspirin plus clopidogrel (1.4% versus 0.3%; absolute risk increase: 1.1%; number needed to harm [NNH]: 91; RR 4.8; 95% CI: 2.2-10.6), while intracranial hemorrhage was not statistically different (RR: 1.3; 95% CI: 0.6-2.9). The risk of hemorrhage significantly increased after 3 months of therapy.

Caveats

There are several limitations associated with this meta-analysis. A single trial conducted in China (CHANCE) accounted for the majority of data concerning aspirin plus clopidogrel versus aspirin alone.3 However, exclusion of this study did not significantly change the primary or secondary outcomes. Several studies report data from before 2010, and stroke care has significantly changed since this period.4 Only three studies reported intracranial hemorrhage data, and just two reported extracranial hemorrhage data.3, 6, 7, 8, 9 Four trials included patients with TIA or non-disabling stroke (defined by a The National Institutes of Health Stroke Scale ≤3), while one included strokes regardless of severity.3, 6, 7, 8, 9 Other adverse outcomes such as myocardial infarction were also reported in only a few studies. Another significant consideration is that the results apply to atherothrombotic and not cardioembolic strokes. Finally, duration of therapy is an important consideration. Included patients received at least 1 month of antiplatelet therapy, and follow up was 3 months in most studies.

Broadly, the Cochrane review summarized here found a strategy of multiple antiplatelet agents initiated within 72 hours of the event compared to a single agent reduced stroke in the short term, while increasing major hemorrhage.5 This finding is consistent with results from trials adding clopidogrel to aspirin.3, 6, 7, 8, 9 Based on this evidence, we have assigned a color recommendation of Green (benefit >harm) for the use of aspirin plus clopidogrel versus aspirin alone after atherothrombotic ischemic stroke or TIA. While further study is needed, the CHANCE trial suggests a duration of 21 days to 1 month is appropriate.3 Further data are needed to better evaluate adverse events, cardioembolic events, and specific durations of therapy.

Author

Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

February 3, 2021

References:

Coull AJ, Lovett JK, Rothwell PM, Oxford Vascular Study. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ. 2004;328(7435):326.
Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline [published correction appears in Stroke. 2007 Jan;38(1):207]. Stroke. 2006;37(6):1583-1633.
Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19.
Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association [published correction appears in Stroke. 2019 Dec;50(12):e440-e441]. Stroke. 2019;50(12):e344-e418.
Naqvi IA, Kamal AK, Rehman H. Multiple versus fewer antiplatelet agents for preventing early recurrence after ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev. 2020;8(8):CD009716.
Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379(3):215-225.
Hankey GJ, Johnston SC, Easton JD, et al. Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial. Int J Stroke. 2011;6(1):3-9.
Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):961-969.
Petrovska-Cvetkovska D, Baneva N, Trencev R, Georgievska A, Radulovic-Bekarovska S. Efficacy and tolerability of aspirin, aspirin plus clopidogrel and statins in prevention after transient ischemic attacks. Int J Stroke. 2008;3 Suppl 1:314 (Abst.PO02-192).

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