(Last Updated On: January 30, 2019)

We continue the series with Knowledge Bomb #22. The purpose and motivation for this series is outlined in the first entry and extensively in an ALiEM IDEA series blog entry.

Background

Ischemic stroke remains amongst the top five causes of death world wide impacting 6.2 million people annually¹. In the United States, 140K Americans die each year from stroke². A person’s risk of stroke is 3-15% after a transient ischemic attack (TIA) or minor ischemic event. Aspirin therapy alone has been proven to reduce stroke (CAST, IST, AHA/ASA guidelines). The CHANCE trial revealed the possibility that dual therapy could further reduce stroke risk. However, the trial had poor generalizability as it was performed primarily on one ethnic group in China.

Question

Does combination antiplatelet therapy, clopidogrel and aspirin, in acute minor ischemic stroke and high-risk TIA reduce the risk of recurrent stroke over the next 90 days?

Article

Johnston, M.D. et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. NEJM, 19 July 2018. [paper]

Study Design

Double blinded, placebo, randomized controlled trial at 269 sites in 10 countries in North America, Europe, Australia, and New Zealand. The majority of the patients (82.8%) were enrolled in the United States. Randomization occurred on a 1:1 basis and was assigned by trial website.

Trial medications were clopidogrel and placebo, which was same size, color and taste as clopidogrel tablets. The recommended dosing of medications was 600mg loading of clopidogrel followed by 75mg from days 2-90. Aspirin was dosed at 50mg to 325mg depending on the treating physician. First dosing was administered as soon as randomization was completed. Patients were subsequently followed for 90 days +/- 14 days.

Results

With aspirin and clopidogrel there was both a lower risk of major ischemic events (5.0% vs 6.5%, p=0.02) and a higher risk of major hemorrhage (0.9% vs 0.4%, p=0.02) than aspirin alone at 90 days.

Bomb!

Clopidogrel with aspirin for TIA and minor stroke significantly increases the risk of major hemorrhage, including intracranial hemorrhage, vs aspirin alone.

Discussion

This study will not change my daily practice in the ED. I will continue to start aspirin, but the decision for dual antiplatelet therapy should be considered on a case-by-case basis with involvement of neurology or primary care. These physicians will follow patients on a long term basis for re-evaluation and for therapy modifications.

This trial was stopped at 84% enrollment due to the adverse outcome of intracranial hemorrhage. This, in itself, gives one pause when starting a patient on dual antiplatelet therapy. Shared decision making with the patient will be of utmost importance given risk of intracranial hemorrhage. The number needed to treat to prevent one ischemic event was 66, while the number needed to harm was 200.

In addition, the trial did a poor job of keeping a uniform aspirin regimen, with dosing allowed to be determined by provider. The varying levels of aspirin dosing could have affected the benefits as well as the risks.

The study itself however did have significantly better generalizability than previous studies and the other components of the protocol seemed sound. Antiplatelet therapy remains a hot topic but for now, I will defer to my neurology colleagues for proper long term stroke management.

Angel Bermudez is an EM resident, class of 2020


Citations

¹ Global status report on noncommunicable diseases 2010. Geneva, World Health Organization, 2011.

² Kochanek KD, Xu JQ, Murphy SL, Arias E. Mortality in the United States, 2013. NCHS Data Brief, No. 178. Hyattsville, MD: National Center for Health Statistics, Centers for Disease Control and Prevention, Department of Health and Human Services; 2014.