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1.
  • Amarenco, Pierre, et al. (författare)
  • Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling Stroke : A Randomized Clinical Trial
  • 2020
  • Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 78:2, s. 177-185
  • Tidskriftsartikel (refereegranskat)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.
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2.
  • Amarenco, Pierre, et al. (författare)
  • Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin
  • 2020
  • Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 51:12, s. 3504-3513
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose:Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events.Methods:In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days.Results:Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P=0.001).Conclusions:In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171).
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3.
  • Johnston, S. Claiborne, et al. (författare)
  • Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack
  • 2021
  • Ingår i: Stroke. - : Wolters Kluwer. - 0039-2499 .- 1524-4628. ; 52:11, s. 3482-3489
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose: In patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit. Methods: In a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, patients were randomized within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin or matching placebo plus aspirin. For the present analyses, we defined the efficacy outcome, major ischemic events, as the composite of ischemic stroke or nonhemorrhagic death, and defined the safety outcome, major hemorrhage, as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these 2 end points. Results: In 11 016 patients (5523 ticagrelor-aspirin and 5493 aspirin), a major ischemic event occurred in 294 patients (5.3%) in the ticagrelor-aspirin group and in 359 patients (6.5%) in the aspirin group (absolute risk reduction 1.19% [95% CI, 0.31%-2.07%]). Major hemorrhage occurred in 22 patients (0.4%) in the ticagrelor-aspirin group and 6 patients (0.1%) in the aspirin group (absolute risk increase 0.29% [95% CI, 0.10%-0.48%]). Net clinical impact favored ticagrelor-aspirin (absolute risk reduction 0.97% [95% CI, 0.08%-1.87%]). Findings were similar when different thresholds for disability were applied and over a range of predefined subgroups. Conclusions: In patients with mild-moderate ischemic stroke or high-risk transient ischemic attack, ischemic benefits of 30-day treatment with ticagrelor-aspirin outweigh risks of hemorrhage. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.
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4.
  • Johnston, S. Claiborne, et al. (författare)
  • The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial : Rationale and design
  • 2019
  • Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 14:7, s. 745-751
  • Tidskriftsartikel (refereegranskat)abstract
    • RationaleIn patients with acute cerebral ischemia, the rate of stroke, myocardial infarction, or death during 90 days was reported to be non-significantly lower with ticagrelor compared with aspirin, with no increase in major hemorrhage. Dual antiplatelet therapy may be more effective in this setting.AimTo investigate whether ticagrelor combined with aspirin are superior to aspirin alone in preventing stroke or death in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack.DesignThe Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial is a randomized, placebo-controlled, double-blind, event-driven study. Patients will be randomized within 24 h of onset of acute ischemic symptoms. THALES is expected to randomize 13,000 at ∼450 sites worldwide, to collect 764 primary outcome events. Study treatments are ticagrelor 180 mg loading dose on day 1, then 90 mg twice daily on days 2–30, or matching placebo. All patients will also receive open-label aspirin 300–325 mg on day 1, then 75–100 mg once daily on days 2–30.Study outcomesThe primary efficacy outcome is time to the composite endpoint of stroke or death through 30-day follow-up. The primary safety outcome is time to first severe bleeding event.DiscussionThe THALES trial will provide important information about the benefits and risks of dual antiplatelet therapy with ticagrelor and aspirin in patients with acute cerebral ischemia in a global setting (funding: AstraZeneca)
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5.
  • Johnston, S. Claiborne, et al. (författare)
  • Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA
  • 2020
  • Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 383:3, s. 207-217
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundTrials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied.MethodsWe conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding.ResultsA total of 11,016 patients underwent randomization (5523 in the ticagrelor–aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor–aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor–aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P=0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor–aspirin group and in 7 patients (0.1%) in the aspirin group (P=0.001).ConclusionsAmong patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor–aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor.
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6.
  • Tank, Amarjeet, et al. (författare)
  • Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack : an economic evaluation of the THALES trial
  • 2023
  • Ingår i: BMJ NEUROLOGY OPEN. - : BMJ. - 2632-6140. ; 5:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective THALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS) or high-risk transient ischaemic attack (TIA). There are no cost-effectiveness analyses supporting this combination in Europe. To address this, a cost-effectiveness analysis was performed.Methods Cost-effectiveness was evaluated using a decision tree and Markov model with a short-term and long-term (30-year) horizon. Stroke, mortality, bleeding and EuroQol-5 Dimension (EQ-5D) data from THALES were used to estimate short-term outcomes. Model transitions were based on stroke severity (disabling stroke was defined as modified Rankin Scale >2). Healthcare resource utilisation and EQ-5D data beyond 30 days were based on SOCRATES, another trial in AIS/TIA that compared ticagrelor with aspirin. Long-term costs, survival and disutilities were based on published literature. Unit costs were derived from national databases and discounted at 3% annually from a Swedish healthcare perspective.Results One-month treatment with ticagrelor plus aspirin resulted in 12 fewer strokes, 4 additional major bleeds and cost savings of euro95 000 per 1000 patients versus aspirin from a Swedish healthcare perspective. This translated into increased quality-adjusted life-years (0.04) and reduced societal costs (-euro1358) per patient over a lifetime horizon. Key drivers of cost-effectiveness were number of patients experiencing subsequent disabling stroke and degree of disability. Findings were robust over a range of input assumptions.Conclusion One month of treatment with ticagrelor plus aspirin is likely to improve outcomes and reduce costs versus aspirin in mild-to-moderate AIS or high-risk TIA.Trial registration number NCT03354429.
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7.
  • Wang, Yongjun, et al. (författare)
  • Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke : An Exploratory Analysis of the THALES Randomized Clinical Trial.
  • 2021
  • Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 78:9, s. 1091-1098
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: Prior trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial, but results have not been reported separately, raising concerns about safety and efficacy in this subgroup.Objective: To evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 4 to 5).Design, Setting, and Participants: The THALES trial was a randomized trial conducted at 414 hospitals in 28 countries in January 2018 and December 2019. This exploratory analysis compared patients with moderate stroke (baseline NIHSS score of 4 to 5) with patients with less severe stroke (NIHSS score of 0 to 3). A total of 9983 patients with stroke were included in the present analysis, after excluding 2 patients with NIHSS scores greater than 5 and 1031 patients with transient ischemic attack. Data were analyzed from March to April 2021.Interventions: Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) or placebo within 24 hours after symptom onset. All patients received aspirin, 300 to 325 mg, on day 1 followed by aspirin, 75 to 100 mg, daily on days 2 to 30. Patients were observed for 30 additional days.Main Outcomes and Measures: The primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe bleeding.Results: In total, 3312 patients presented with moderate stroke and 6671 presented with less severe stroke. Of those in the moderate stroke group, 1293 (39.0%) were female, and the mean (SD) age was 64.5 (10.8) years; of those in the less severe stroke group, 2518 (37.7%) were female, and the mean (SD) age was 64.8 (11.2) years. The observed primary outcome event rate in patients with moderate stroke was 7.6% (129 of 1671) for those in the ticagrelor group and 9.1% (150 of 1641) for those in the placebo group (hazard ratio, 0.84; 95% CI, 0.66-1.06); the primary outcome event rate in patients with less severe stroke was 4.7% (158 of 3359) for those in the ticagrelor group and 5.7% (190 of 3312) for those in the placebo group (hazard ratio, 0.82; 95% CI, 0.66-1.01) (P for interaction = .88). Severe bleeding occurred in 8 patients (0.5%) in the ticagrelor group and in 4 patients (0.2%) in the placebo group in those with moderate stroke compared with 16 patients (0.5%) and 3 patients (0.1%), respectively, with less severe stroke (P for interaction = .26).Conclusions and Relevance: In this study, patients with a moderate ischemic stroke had consistent benefit from ticagrelor plus aspirin vs aspirin alone compared with patients with less severe ischemic stroke, with no further increase in the risk of intracranial bleeding or other severe bleeding events.Trial Registration: ClinicalTrials.gov Identifier: NCT03354429.
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8.
  • Wang, Yongjun, et al. (författare)
  • Time Course for Benefit and Risk of Ticagrelor and Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack
  • 2022
  • Ingår i: Neurology. - : Wolters Kluwer. - 0028-3878 .- 1526-632X. ; 99:1, s. E46-E54
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Objectives The goal of this work was to investigate the short-term time-course benefit and risk of ticagrelor with aspirin in acute mild-moderate ischemic stroke or high-risk TIA in The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial. Methods In an exploratory analysis of the THALES trial, we evaluated the cumulative incidence of irreversible efficacy and safety outcomes at different time points during the 30-day treatment period. The efficacy outcome was major ischemic events defined as a composite of ischemic stroke or nonhemorrhagic death. The safety outcome was major hemorrhage defined as a composite of intracranial hemorrhage and fatal bleedings. Net clinical impact was defined as the combination of these 2 endpoints. Results This analysis included a total of 11,016 patients (5,523 in the ticagrelor-aspirin group, 5,493 in the aspirin group) with a mean age of 65 years, and 39% were women. The reduction of major ischemic events by ticagrelor occurred in the first week (4.1% vs 5.3%; absolute risk reduction 1.15%, 95% CI 0.36%-1.94%) and remained throughout the 30-day treatment period. An increase in major hemorrhage was seen during the first week and remained relatively constant in the following weeks (absolute risk increase approximate to 0.3%). Cumulative analysis showed that the net clinical impact favored ticagrelor-aspirin in the first week (absolute risk reduction 0.97%, 95% CI, 0.17%-1.77%) and remained constant throughout the 30 days. Discussion In patients with mild-moderate ischemic stroke or high-risk TIA, the treatment effect of ticagrelor-aspirin was present from the first week. The ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the treatment period, which may support the use of 30-day treatment with ticagrelor and aspirin in these patients. Classification of Evidence This study provides Class II evidence that, for patients with mild-moderate ischemic stroke or high-risk TIA, the ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the 30-day treatment period.
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