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

Pierre Amarenco, Hans Denison, Scott R Evans, Anders Himmelmann, Stefan James, Mikael Knutsson, Per Ladenvall, Carlos A Molina, Yongjun Wang, S Claiborne Johnston, THALES Steering Committee and Investigators

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.

Conflict of interest statement

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.

Figures

Figure 1.. Kaplan-Meier Event Curves for the…
Figure 1.. Kaplan-Meier Event Curves for the Primary Efficacy End Point (Stroke or Death) in Patients With a 30-Day Modified Rankin Scale Score (mRS) Greater Than 1 and With a 30-Day mRS 0 to 1
Figure 2.. Modified Rankin Scale Score (mRS)…
Figure 2.. Modified Rankin Scale Score (mRS) Distribution at 30 Days in Patients With an Ischemic Stroke
Figure 3.. Forest Plot Showing the Efficacy…
Figure 3.. Forest Plot Showing the Efficacy of Ticagrelor vs Placebo on the Primary End Point With Modified Rankin Scale Score (mRS) Greater Than 1 or Death at Day 30 According to Prespecified Subgroups
NIHSS indicates National Institutes of Health Stroke Scale; TIA, transient ischemic attack.

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