Claiborne Johnston, Pierre Amarenco, et al. for the THALES investigators.Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.N Engl J Med 2020;383:207-17.
Reviewed by Sanjeev Sivakumar,MD
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Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been shown to prevent recurrent strokes. Clopidogrel requires hepatic conversion to its active form and may be ineffective in a substantial number of Caucasians and patients of Asian descent. Ticagrelor, by reversible inhibition of the P2Y12 receptor, is a direct-acting antiplatelet agent and does not require metabolic activation.
This study compared ticagrelor and aspirin to aspirin alone for reduction of recurrent stroke or death after incident event. The authors performed an international multicenter, randomized, double-blind placebo-controlled trial. Eligible patients were ≥40 years of age with one of the following (1) mild to moderate acute noncardioembolic ischemic stroke and NIHSS≤ 5, (2) high-risk TIA [ABCD2 score ≥ 6] or (3) symptomatic intracranial/extracranial stenosis defined as ≥ 50% vessel narrowing. Patients with atrial fibrillation, ventricular aneurysm, those planned for carotid endarterectomy requiring discontinuation of trial drugs within 3 days, known bleeding disorder, history of intracranial hemorrhage, GI bleeding in the last 6 months or major surgery in the past 30 days were excluded.
Primary outcome was composite of stroke (ischemic and hemorrhagic) and death in the first 30 days. Secondary outcomes included first subsequent ischemic stroke and an mRS>1 at the end of treatment visit. Safety outcomes included first severe bleeding event (intracranial or fatal), first moderate to severe bleeding event, trial discontinuation due to bleeding or adverse events leading to trial discontinuation.
A total of 11,073 patients were randomized within 24 hours of symptom onset to either ticagrelor (180 mg load followed by 90mg BID) plus aspirin (300-325 mg load followed by 75-100 mg daily) or placebo plus aspirin for 30 days, after which they received standard-of-care treatment. Baseline characteristics were similar between the groups. Mean age of participants was 65 years; 39% women. 13.7% of treatment patients and 12.4% of control group patients were already taking aspirin. 16.3% and 16.6% of treatment and control group patients respectively had already had strokes and TIAs (5% in treatment and 4.4% in control groups). Ischemic strokes were the eligibility in 91% and TIA in 9%. 13% were on aspirin prior to index event.
The primary outcome occurred in 5.5% of ticagrelor-aspirin group vs. 6.6% in the aspirin group (hazard ratio [HR] 0.83; 95% CI 0.71 to 0.96; p=0.02). This translated to a 17% risk reduction with ticagrelor-aspirin and number needed to treat (NNT) of 92. Among secondary outcomes, treatment with ticagrelor-aspirin resulted in lower risk for ischemic stroke (5% vs. 6.3%; HR, 0.79; 95% CI, 0.68 to 0.93; p=0.004) without significant between-group differences in disability scores defined as mRS >1 at 30 days. From a safety standpoint, DAPT was significantly associated with 3 to 4-fold higher rates of severe bleeding (composite of and individual measures of fatal bleeding, ICH or bleeding leading to hemodynamic compromise; number needed to harm 263). Premature permanent discontinuation of study drug was higher with DAPT (HR 4.8; p<0.001).
This randomized control included 11,000 patients with mild-to-moderate acute ischemic stroke (NIHSS ≤ 5) or high-risk TIA and found that combined treatment with ticagrelor and aspirin decreased risk of recurrent stroke or death. without reduction in incidence of overall disability (mRS >1), while having a higher risk of severe hemorrhage and ICH.
This is consistent with prior data found using DAPT with aspirin and clopidogrel in the CHANCE and POINT trials, although both of those trials had a lower NNT (66 for POINT and 29 for CHANCE) and a longer follow-up period of 90 days. The strength of the trial is in the large number of patients enrolled, with a diverse number of centers and geographic locations represented. It is interesting that there was no difference in disability between groups, however,treatment and follow-up only extended for 30-34 days so the long-term benefits and risks are challenging to assess, although risk of stroke is highest after incident event. Only patients with high-risk TIA (ABCD2 score≥6) were recruited in the THALES study, while more severe strokes (NIHSS >6), cardioembolic strokes, and initiation of treatment after 24 hours were excluded. The bleeding risk may exceed benefits conferred by the DAPT among low-risk patients.
It is imperative to exercise caution and not generalize the results from this trial. Another direct comparison of dual antiplatelet strategies in patients with TIA or minor stroke (Clopidogrel with Aspirin in High-risk Patients with Acute Non-disabling Cerebrovascular Events II [CHANCE-2] is currently ongoing.