Brilinta significantly reduced the rate of the composite of stroke and death in patients who had an acute ischaemic stroke or transient ischaemic attack in the Phase III THALES trial
Detailed results from the positive Phase III THALES trial showed AstraZeneca’s Brilinta (ticagrelor) 90mg used twice daily and taken with daily aspirin for 30 days, reduced the rate of the primary composite endpoint of stroke and death by 17% (HR 0.83 [95% CI 0.71, 0.96], p=0.02), compared to aspirin alone in patients who had an acute ischemic stroke or transient ischemic attack (TIA).1
This was a statistically significant and clinically meaningful reduction. Furthermore, aspirin plus Brilinta significantly reduced the rate of the first secondary endpoint of ischaemic stroke by 21%, compared to aspirin alone up to day 30.1 The risk for severe bleeding events was 0.5% in the aspirin plus Brilinta group and 0.1% in the aspirin group. The results were in line with the known safety profile of Brilinta.1
Dr. Clay Johnston, lead investigator for the THALES trial and Dean of the Dell Medical School at The University of Texas in Austin, US, said: “About one in four stroke survivors go on to experience a second stroke, and the risk is particularly high within the first month after the initial event. Early treatment is important to prevent a subsequent stroke that may be disabling or fatal. It is also expected to improve long-term outcomes.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Patients who had an acute ischaemic stroke or transient ischemic attack may experience a subsequent, potentially avoidable stroke. Results from the Phase III THALES trial confirm that aspirin plus Brilinta has the potential to be a new effective treatment option for these high-risk patients and we look forward to continuing discussions with regulatory authorities.”
Key efficacy and safety data from the THALES trial
|Ticagrelor 90 mg bd (N=5523)||Placebo (N=5493)|
|Variable||Patients with events (%)||KM%||Patients with events (%)||KM%||Hazard ratio (95% CI) p-value|
|Composite of stroke/death||303 (5.5)||5.4||362 (6.6)||6.5||0.83 (0.71, 0.96) p= 0.02|
|Stroke||284 (5.1)||5.1||347 (6.3)||6.3||0.81 (0.69, 0.95)|
|Death||36 (0.7)||0.6||27 (0.5)||0.5||1.33 (0.81, 2.19)|
|Ischaemic stroke (secondary endpoint)||276 (5.0)||5.0||345 (6.3)||6.2||0.79 (0.68, 0.93) p=0.004|
|Severe bleeding*||28 (0.5)||0.5||7 (0.1)||0.1||3.99 (1.74, 9.14)|
|Intracranial haemorrhage or fatal bleeding||22 (0.4)||0.4||6 (0.1)||0.1||3.66 (1.48, 9.02)|
|Fatal bleeding||11 (0.2)||2 (0.0)|
|Intracranial haemorrhage||20 (0.4)||0.4||6 (0.1)||0.1||3.33 (1.34, 8.28)|
- et al. N Engl J Med 2020; DOI: 10.1056/NEJMoa1916870.*By GUSTO definition; CI=confidence interval; GUSTO=Global Utilization of Streptokinase and Tissue-type plasminogen activator for Occluded coronary arteries; KM=Kaplan–Meier
Results from the THALES trial were published in The New England Journal of Medicine.
This month, AstraZeneca announced that the US Food and Drug Administration (FDA) accepted a supplemental New Drug Application (sNDA) and granted Priority Review for Brilinta for the reduction of subsequent stroke in patients who experienced an acute ischemic stroke or TIA based on the Phase III THALES trial. The Prescription Drug User Fee Act date, the FDA action date for this supplemental application, is scheduled for the fourth quarter of 2020.
Brilinta is approved in more than 110 countries for the prevention of atherothrombotic events in adult patients with acute coronary syndrome (ACS) and in more than 70 countries for the secondary prevention of cardiovascular events among high-risk patients who have experienced a heart attack. In May 2020, the FDA approved a label update for Brilinta in the US to include the reduction of the risk of a first heart attack or stroke in high-risk patients with coronary artery disease.
Stroke is the second leading cause of death worldwide, with 6.2 million stroke-related deaths in 2017, from which 2.7 million were due to ischaemic stroke.2 Patients who experience an acute ischaemic stroke or TIA are at high risk of developing subsequent ischaemic events, with particularly high risk within 30 days after the initial event and the highest risk period being the first 24 hours after the initial event.3
THALES is an AstraZeneca-sponsored, randomised, placebo-controlled, double-blinded, international, multicentre, event-driven trial involving more than 11,000 patients from 28 countries. It tested the hypothesis whether aspirin plus Brilinta is superior to aspirin alone in preventing the composite of stroke and death in patients with non-cardioembolic acute ischaemic stroke or high-risk TIA. Patients were randomised within 24 hours of onset of acute ischaemic stroke or high-risk TIA symptoms and followed-up for 30 days of treatment. Study treatments were Brilinta 180mg loading dose on day 1 as soon as possible after randomisation, followed by 90mg twice daily on days 2–30, or matching placebo. All patients received open-label aspirin 300–325mg on day 1, followed by 75–100mg once daily on days 2–30. The primary efficacy outcome was the time to the composite endpoint of stroke and death at 30 days. The primary safety outcome is time to first severe bleeding event according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition, which includes fatal bleedings, intracranial haemorrhage; and bleeding causing hemodynamic compromise requiring intervention. Patients were followed for an additional 30 days on standard of care.
Brilinta is an oral, reversible, direct-acting P2Y12 receptor antagonist that works by inhibiting platelet activation. Brilinta, together with aspirin, has been shown to significantly reduce the risk of major adverse cardiovascular (CV) events (heart attack, stroke or CV death), in patients with ACS or a history of heart attack.
Brilinta, co-administered with aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, or for patients with a history of MI and a high risk of developing an atherothrombotic event.
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1. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med 2020; published on July 15, 2020, at NEJM.org. DOI: 10.1056/NEJMoa1916870.
2. GBD 2017. Causes of Death Collaborators 2018. Global, regional, and national age-sex specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736-88.
3. GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1859-922.