Thomas Raphael Meinel, MD
Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y, Johnston SC, on behalf of the THALES Steering Committee and Investigators. Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin. Stroke. 2020.
Short-term dual antiplatelet therapy (DAPT) has emerged as a powerful treatment option in patients with non-severe ischemic stroke or high-risk TIA.1 However, the efficacy of antithrombotic therapy might vary according to etiology of the ischemic event.2 Amarenco et al. aimed to investigate whether the efficacy and safety of DAPT with Aspirin plus Ticagrelor as compared to Aspirin differed in the subgroup of patients with minor stroke or TIA due to atherosclerotic vascular disease.
For this purpose, the authors conducted a substudy of the THALES trial including patients aged 40 years or older with non-severe non-cardioembolic ischemic stroke (NIHSS ≤5) or high-risk TIA (ABCD2-Score ≥6 or vascular stenosis ≥50% in the suspected vascular territory). Main exclusion criteria were atrial fibrillation, suspicion of cardioembolic cause, high bleeding risk and — importantly — planned carotid revascularization that required halting study medication within 3 days of randomization. or the main prespecified analysis, atherosclerotic ipsilateral stenosis was defined as presence of narrowing of the lumen of ≥30% ipsilateral to the ischemic event as assessed by CT- or MR-angiography or neurovascular ultrasound. The primary efficacy endpoint was time from randomization to the first subsequent event of stroke or death. The primary safety endpoint was occurrence of a severe bleeding event according to the GUSTO definition. 11,016 patients underwent randomization (roughly 50% representing a European and 40% Asian population).
The authors found that 21% of patients had an ipsilateral stenosis ≥30% with a majority of 87% in the European population showing an extracranial stenosis and 70% of the Asian population showing an intracranial stenosis. DAPT with Ticagrelor resulted in fewer primary efficacy outcome events (8.1%) than placebo (10.9%), HR 0.73 (95% CI, 0.56-0.96) in this subgroup with a number needed to treat of 34. In the subgroup without ipsilateral stenosis, the numerical reduction in the Ticagrelor group (4.8%) did not reach significance as compared to placebo (5.4%), HR = 0.89 [95%CI, 0.74-1.08], and the test for interaction was non-significant (P= 0.245). The results were consistent when analyzing only ischemic stroke, disabling stroke/death, and after adjustment for geographical region. The potential downside of DAPT with more bleeding events seen in the main trial seemed to be less pronounced in the subgroup of patients with atherosclerotic vascular disease with a number needed to harm of 951 patients.
This substudy is consistent with the results of the SOCRATES subgroup analysis, arguing for a larger treatment effect of Ticagrelor (alone or in combination with Aspirin) in stroke and TIA patients with documented ipsilateral atherosclerosis. However, given the negative interaction analysis and evidence from the POINT trial, short-term DAPT should not be withheld in patients without ipsilateral atherosclerosis otherwise qualifying for this effective treatment option. Nevertheless, this analysis provides important insights into the effectiveness of different antithrombotic regimes in differing pathophysiologies of ischemic cerebrovascular events.
Furthermore, this study shows that also lesser degrees of vascular stenosis carry a high risk of recurrent events as compared to patients without atherosclerotic disease. Unfortunately, the authors did not dig into efficacy according to stenosis severity. Similar to other trials of DAPT, the main benefit was seen within the first two weeks. Hence, also in patients with atherosclerotic disease, most physicians will choose this duration in clinical practice.3 When applying those results in clinical practice, we should also keep in mind that the positive DAPT trials used loading doses of both Aspirin and Ticagrelor, early treatment within 24 hours after onset of symptoms, and included only clear-cut TIAs and patients not undergoing intravenous or endovascular recanalization.
1. Wang Y, Johnston SC, Bath PM, Grotta JC, Pan Y, Amarenco P, Wang Y, Simon T, Kim JS, Jeng JS, et al. Acute dual antiplatelet therapy for minor ischaemic stroke or transient ischaemic attack. BMJ. 2019;364.
2. Diener HC. The cause of stroke matters for secondary prevention. Lancet Neurol. 2017;16:256–257.
3. Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ, 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 Neurol. 2019;76:1466–1473.