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Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling StrokeA Randomized Clinical Trial

Educational Objective
To determine whether ticagrelor plus aspirin is superior to aspirin alone in reducing disabling recurrent stroke at 30 days.
1 Credit CME
Key Points

Question  Is ticagrelor plus aspirin superior to aspirin alone in reducing disabling recurrent stroke at 30 days?

Findings  In the THALES trial, compared with aspirin alone, ticagrelor plus aspirin significantly reduced the 30-day risk of disabling stroke or death (4.0% vs 4.7%), and the shift analysis of the distribution of modified Rankin scale following subsequent ischemic stroke showed a significant 23% reduction of the total disability burden.

Meaning  In patients with transient ischemic attack and minor ischemic stroke, ticagrelor added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days and reduced the total burden of disability owing to ischemic stroke recurrence.

Abstract

Importance  Reduction of subsequent disabling stroke is the main goal of preventive treatment in the acute setting after transient ischemic attack (TIA) or minor ischemic stroke.

Objective  To evaluate the superiority of ticagrelor added to aspirin in preventing disabling stroke and to understand the factors associated with recurrent disabling stroke.

Design, Setting, and Participants  The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) was a randomized clinical trial conducted between January 22, 2018, and December 13, 2019, with a 30-day follow-up, at 414 hospitals in 28 countries. The trial included 11 016 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk TIA, including 10 803 with modified Rankin Scale score (mRS) recorded at 30 days.

Interventions  Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo within 24 hours of symptom onset. All patients received aspirin, 300 to 325 mg on day 1 followed by 75 to 100 mg daily for days 2 to 30.

Main Outcomes and Measures  Time to the occurrence of disabling stroke (progression of index event or new stroke) or death within 30 days, as measured by mRS at day 30. Disabling stroke was defined by mRS greater than 1.

Results  Among participants with 30-day mRS greater than 1, mean age was 68.1 years, 1098 were female (42.6%), and 2670 had an ischemic stroke (95.8%) as a qualifying event. Among 11 016 patients, a primary end point with mRS greater than 1 at 30 days occurred in 221 of 5511 patients (4.0%) randomized to ticagrelor and in 260 of 5478 patients (4.7%) randomized to placebo (hazard ratio [HR], 0.83; 95% CI, 0.69-0.99, P = .04). A primary end point with mRS 0 or 1 at 30 days occurred in 70 of 5511 patients (1.3%) and 87 of 5478 patients (1.6%) (HR, 0.79; 95% CI, 0.57-1.08; P = .14). The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; 95% CI, 0.65-0.91; P = .002). Factors associated with disability were baseline National Institutes of Health Stroke Scale score 4 to 5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure, while treatment with ticagrelor was associated with less disability.

Conclusions and Relevance  In patients with TIA and minor ischemic stroke, ticagrelor added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days and reduced the total burden of disability owing to ischemic stroke recurrence.

Trial Registration  ClinicalTrials.gov Identifier: NCT03354429

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Article Information

Accepted for Publication: September 3, 2020.

Published Online: November 7, 2020. doi:10.1001/jamaneurol.2020.4396

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Amarenco P et al. JAMA Neurology.

Corresponding Author: Pierre Amarenco, MD, Department of Neurology and Stroke Center, Bichat Hospital, 46 rue Henri Huchard, 75018 Paris, France (pierre.amarenco@aphp.fr).

Correction: This article was corrected on December 21, 2020, to fix errors in Figure 1.

Author Contributions: Dr Amarenco had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Amarenco, Denison, Evans, Himmelmann, James, Ladenvall, Johnston.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Amarenco.

Critical revision of the manuscript for important intellectual content: Denison, Evans, Himmelmann, James, Knutsson, Ladenvall, Molina, Wang, Johnston.

Statistical analysis: Knutsson.

Obtained funding: Himmelmann.

Administrative, technical, or material support: Denison, Himmelmann, Ladenvall, Wang, Johnston.

Supervision: Amarenco, Denison, Evans, Himmelmann, James, Ladenvall, Molina, Wang.

Conflict of Interest Disclosures: Dr Amarenco reported grants and personal fees from AstraZeneca and BMS during the conduct of the study; personal fees from Sanofi and Janssen during the conduct of the study; grants and personal fees from Pfizer and Boston Scientific outside the submitted work; grants from AstraZeneca and Merck; and personal fees from GSK, FibroGen, Shinpoong, and Amgen outside the submitted work. Dr Evans reported personal fees from AstraZeneca during the conduct of the study. Dr Himmelmann reported personal fees from AstraZeneca during the conduct of the study and outside the submitted work. Dr James reported grants from AstraZeneca outside the submitted work. Drs Knutsson, Denison, and Ladenvall reported personal fees from AstraZeneca outside the submitted work and that ticagrelor is manufactured and commercialized by AstraZeneca. Dr Wang reported grants from AstraZeneca during the conduct of the study; grants and other support from Sanofi; and grants from Amgen outside the submitted work. Dr Johnston reported other support from Sanofi and AstraZeneca outside the submitted work. No other disclosures were reported.

Funding/Support: The study was funded by AstraZeneca.

Role of the Funder/Sponsor: The funding source had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The THALES Steering Committee and Investigators are listed in See Supplement 3.

Meeting Presentation: This paper was presented at the European Stroke Organization/World Stroke Organization Word Congress; November 7, 2020; virtual conference.

Data Sharing Statement: See Supplement 4.

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