THALES trial met primary endpoint: Ticagrelor plus aspirin effective in secondary stroke prevention
High disease burden of stroke
According to the Global Burden of Disease (GBD) study 2016, stroke was the second leading cause of death (5.5 million) and the cause of the second greatest number of disability-adjusted life years (DALYs) (116.4 million) globally. Ischaemic stroke accounted for 2.7 million deaths and 51.9 million DALYs worldwide. [Lancet Neurol 2019;18:459-480; Lancet 2018;392:1736-1788]
The highest age-standardized incidence of stroke was in East Asia, especially China (354 per 100,000 person-years), followed by Eastern Europe, whereas the lowest incidence was in Central Latin America. [Lancet Neurol 2019;18:459-480]
The global estimated lifetime risk of stroke for men and women from the age ≥25 years was 24.9 percent and 25.1 percent, respectively, with the lifetime risk of ischaemic stroke and haemorrhagic stroke being 18.3 percent and 8.2 percent, respectively. [N Engl J Med 2018;379:2429-2437]
With an expanding and ageing population worldwide, the disease burden of stroke will likely increase, resulting in a larger absolute pool of individuals at risk of acute stroke despite a declining incidence of stroke globally (-8.1 percent). [Lancet Neurol 2019;18:417-418; Semin Neurol 2018;38:208-211; Lancet Neurol 2019;18:459-480]
Most (88.8 percent) stroke DALYs were attributed to modifiable risk factors evaluated in the GBD study, which were grouped as metabolic risks (72.1 percent), behavioural factors (66.3 percent) and environmental risks (28.1 percent). Continuous efforts in stroke prevention and risk factor management are thus vital in addressing the high disease burden. [Lancet Neurol 2019;18:459-480; Lancet Neurol 2019;18:417-418; BMC Med 2019;17:191; Nat Rev Neurol 2019;15:371-372]
Current guidelines on acute ischaemic stroke management
Current international guidelines recommend antiplatelet therapy for secondary prevention in patients with ischaemic stroke or TIA. Aspirin is the only antiplatelet agent that has received a Class 1A recommendation. [Stroke 2019;50:3331-3332; Int J Stroke 2017;12:302-320; Cerebrovasc Dis 2008;25:457-507]
Ticagrelor is a reversibly binding, direct-acting, oral P2Y12 receptor antagonist with a faster onset and offset of action as well as greater and more consistent platelet inhibition than the irreversible inhibitor, clopidogrel. [Circulation 2009;120:2577-2585; Int J Stroke 2019;14:745-751] Ticagrelor, co-administered with aspirin, is currently indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndrome or a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event. [Ticagrelor prescribing information]
SOCRATES trial: Ticagrelor’s efficacy in acute stroke or TIA
The international, double-blind, controlled SOCRATES trial found a numerically lower rate of stroke, MI, or death within 90 days with ticagrelor vs aspirin (6.7 percent vs 7.5 percent; hazard ratio [HR], 0.89; 95 percent confidence interval [CI], 0.78 to 1.01; p=0.07), with no increase in major bleeding (0.5 percent vs 0.6 percent; HR, 0.83; 95 percent CI, 0.52 to 1.34; p=0.45) when initiated within 24 hours of symptom onset in patients with non-cardioembolic, non-severe ischaemic stroke or high-risk TIA. [N Engl J Med 2016;375:1395; Circulation 2017;136:907-916]
Ischaemic stroke constituted 87.9 percent of all patient cases in the study. Secondary analysis indicated benefit of ticagrelor vs aspirin in reducing recurrent ischaemic stroke events (5.8 percent vs 6.7 percent; HR, 0.87; 95 percent CI, 0.76 to 1.00, p=0.046). [N Engl J Med 2016;375:1395]
In addition, ticagrelor effectively reduced primary endpoint events of stroke, MI, or death among patients with ipsilateral atherosclerotic stenosis (6.7 percent vs 9.6 percent for aspirin; HR, 0.68; 95 percent CI, 0.53 to 0.88; p=0.003; pinteraction=0.017), demonstrating the importance of its rapid offset of action in patients who were likely to undergo surgical intervention. [Lancet Neurol 2017;16:301-310; Int J Stroke 2019;14:745-751]
Another subgroup analysis of the SOCRATES trial revealed that among patients who received any aspirin in the week prior their stroke, the primary end point occurred in 6.5 percent of patients on ticagrelor 8.3 percent of patients on aspirin (HR, 0.76; 95 percent CI, 0.61 to 0.95; p=0.02), suggesting a potential benefit of DAPT with ticagrelor plus aspirin since the antiplatelet effect of aspirin persisted into the first week of the trial. [Stroke 2018;49:1678-1685; Int J Stroke 2019;14:745-751]
These results led to the design and execution of the THALES trial, with data collection for primary outcome measures completed in December 2019. [Mo Med 2019;116:303-307; Int J Stroke 2019;14:220-222; Int J Stroke 2019;14:745-751; NCT03354429]
The THALES trial
The THALES trial, a randomized, placebo-controlled, double-blind, parallel-group, international, multicentre, phase III study, aimed to investigate whether ticagrelor combined with aspirin would be superior to aspirin alone in reducing stroke or death in patients ≥40 years of age with non-cardioembolic, non-severe ischaemic stroke (defined as National Institutes of Health Stroke Scale score ≤5) or high-risk TIA (defined as an ABCD2 [Age, Blood Pressure, Clinical Features of the TIA, Duration of Symptoms, History of diabetes] score ≥6 or ipsilateral atherosclerotic stenosis ≥50 percent in an extra-/intra-cranial artery) during 30 days of follow-up. (Figure) [Int J Stroke 2019;14:745-751]
Patients (n=11,018) from about 450 sites in 28 countries worldwide were randomized (1:1) within 24 hours of symptom onset to receive ticagrelor (180 mg loading dose on day 1, then 90 mg twice daily on days 2–30) or matching placebo, plus standard-of-care therapy with open-label aspirin (300–325 mg on day 1, then 75–100 mg once daily on days 2–30), and were followed up for 30 days for efficacy and 60 days for safety. The dose of ticagrelor was the same as that used in the SOCRATES trial, in which ticagrelor was well tolerated and demonstrated a similar safety profile as aspirin. [NCT03354429; Int J Stroke 2019;14:745-751; N Engl J Med 2016;375:1395]
Topline efficacy results of the THALES trial showed that ticagrelor 90 mg, used twice daily and taken with aspirin for 30 days, resulted in a statistically significant and clinically meaningful reduction in the risk of the primary composite endpoint of stroke and death, compared with aspirin alone. The preliminary safety findings of the THALES trial were consistent with the known safety profile of ticagrelor, with an increased bleeding rate in the DAPT vs aspirin alone arm. [https://www.astrazeneca.com/media-centre/press-releases/2020/brilinta-met-primary-endpoint-in-phase-iii-thales-trial-in-stroke-27012020.html]
“The risk of having a subsequent stroke is highest in the first few days and weeks after a minor acute ischaemic stroke or high-risk TIA. While an expected increase in bleeding was observed, the findings from THALES showed that ticagrelor, in combination with aspirin, reduced the risk of potentially devastating events in this crucial time,” said Dr Clay Johnston, lead investigator of the THALES trial and Dean of the Dell Medical School, The University of Texas, Austin, US.
The THALES investigators also evaluated time to first subsequent ischaemic stroke and modified Rankin Scale (mRS) score >1 at the end of treatment (visit 3) as secondary efficacy outcomes. The primary safety outcome was the time to severe bleeding, according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition.
Full results of the trial will be presented at a forthcoming medical meeting.