2023 Top Story in Neurology: Effectiveness of Dual Antiplatelet Therapy vs Alteplase in Patients With Minor Non-disabling Acute Ischemic Stroke
There have been a number of advances in stroke care this year, including studies showing the benefits of thrombectomy, even in patients with large core infarcts,1 and new indications or longer time windows for thrombolysis. However, the study that may change management the most worldwide is the ARAMIS trial.2 This was a double-blind randomized trial comparing the effectiveness of dual antiplatelet therapy with that of thrombolysis in 760 patients with acute ischemic stroke and mild deficits. Mild deficits were defined as 1) NIHSS scores of 5 or less; 2) NIHSS scores of 1 or less on the items of vision, language, neglect, and weakness in a single limb; and 3) a score of 0 on the item of consciousness. The dual antiplatelet regimen included 300 mg of clopidogrel on the first day, 75 mg of clopidogrel daily for the next 12 [±2] days, and 100 mg of aspirin daily for 13 [±2] days, followed by single antiplatelet therapy or aspirin 100 mg plus clopidogrel 75 mg based on guidelines until 90 days. Thrombolysis involved the administration of the standard weight-based dose of alteplase. The authors found that the incidence of the primary outcome measure, excellent neurologic function at 90 days (defined as a modified Rankin Scale score of 0 or 1), was not significantly different between the two groups. The primary outcome was observed in 93.8% of patients in the dual antiplatelet therapy group and 91.4% of patients in the intravenous alteplase group. Not only did the difference meet the prespecified noninferiority margin of −4.5%, but the outcome was also better in the dual antiplatelet group. These results mirror those of the earlier PRISMS trial,3 which indicated no difference in the outcome between patients randomized to aspirin and those randomized to alteplase but a higher risk of intracranial hemorrhage in patients who received alteplase. However, the results of that trial were not considered to be definitive because the trial was terminated very early, after only 313 of a planned 948 patients were enrolled. The trial was terminated by the sponsor (Genentech) before unblinding because of failure to meet patient enrollment targets (a financial decision).
This study is important because it provides definitive evidence that alteplase should not be used to treat minor nondisabling stroke. It confirms the results of the PRISMS trial, showing that administration of antiplatelets is just as effective as, and less harmful than, administration of alteplase in these patients. These findings will change management by many stroke clinicians. The results are especially important for clinicians in middle- and low-income countries, where alteplase is prohibitively expensive. Even in high-income countries, it is critical to reduce the cost of healthcare. The cost of the initial dose of alteplase is $4500 to $5000, and patients on alteplase also require close monitoring (usually in a critical care unit) and follow-up imaging (but refer to the study by Tabaac et al,4 which indicates that follow-up CT is not always necessary) to rule out hemorrhage. The cost of 90-day aspirin therapy is $3 to $5, and the cost of 90-day clopidogrel therapy is approximately $600. A pooled analysis of outcomes in participants from the CHANCE and POINT trials5 does indicate that clopidogrel plus aspirin up to 21 days after minor stroke is more effective than aspirin alone in reducing the risk of major ischemic events. However, there is no benefit to adding clopidogrel after 21 days. Therefore, the treatment of minor nondisabling stroke should consist of aspirin plus clopidogrel for 21 days (<$200) rather than alteplase (≥$5000). After 21 days, aspirin alone daily ($7–$8 per year) along with high-dose statin therapy, regular exercise, and a healthy diet serves as an optimal secondary stroke prevention strategy.
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Additional Info
- Palaiodimou L, Sarraj A, Safouris A, et al. Endovascular Treatment for Large-Core Ischaemic Stroke: A Meta-Analysis of Randomised Controlled Clinical Trials. J Neurol Neurosurg Psychiatry. 2023;94(10):781-785.
- Chen HS, Cui Y, Zhou ZH, et al. Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial. JAMA. 2023;329(24):2135-2144.
- Khatri P, Kleindorfer DO, Devlin T, et al. Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018;320(2):156-166.
- Tabaac B, Dickstein L, Gurnea K, et al. Follow-up Imaging After Thrombolysis: FIAT, A Randomized Trial. J Stroke Cerebrovasc Dis. 2023;32(6):107092.
- Pan Y, Elm JJ, Li H, et al. Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack: A Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials. JAMA Neurology. 2019;76(12):1466-1473.
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