Summary Background Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and ...cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial. Methods SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2–90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov , number NCT01994720. Findings Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 50% to ticagrelor and 6610 50% to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 95% CI 0·53–0·88; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 0·84–1·13; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group. Interpretation In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention. Funding AstraZeneca.
Summary Background The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial showed that apixaban is better than warfarin at prevention of stroke ...or systemic embolism, causes less bleeding, and results in lower mortality. We assessed in this trial's participants how results differed according to patients' CHADS2 , CHA2 DS2 VASc, and HAS-BLED scores, used to predict the risk of stroke and bleeding. Methods ARISTOTLE was a double-blind, randomised trial that enrolled 18 201 patients with atrial fibrillation in 39 countries. Patients were randomly assigned apixaban 5 mg twice daily (n=9120) or warfarin (target international normalised ratio 2·0–3·0; n=9081). The primary endpoint was stroke or systemic embolism. The primary safety outcome was major bleeding. We calculated CHADS2 , CHA2 DS2 VASc, and HAS-BLED scores of patients at randomisation. Efficacy analyses were by intention to treat, and safety analyses were of the population who received the study drug. ARISTOTLE is registered with ClinicalTrials.gov , number NCT00412984. Findings Apixaban significantly reduced stroke or systemic embolism with no evidence of a differential effect by risk of stroke (CHADS2 1, 2, or ≥3, p for interaction=0·4457; or CHA2 DS2 VASc 1, 2, or ≥3, p for interaction=0·1210) or bleeding (HAS-BLED 0–1, 2, or ≥3, p for interaction=0·9422). Patients who received apixaban had lower rates of major bleeding than did those who received warfarin, with no difference across all score categories (CHADS2 , p for interaction=0·4018; CHA2 DS2 VASc, p for interaction=0·2059; HAS-BLED, p for interaction=0·7127). The relative risk reduction in intracranial bleeding tended to be greater in patients with HAS-BLED scores of 3 or higher (hazard ratio HR 0·22, 95% CI 0·10–0·48) than in those with HAS-BLED scores of 0–1 (HR 0·66, 0·39–1·12; p for interaction=0·0604). Interpretation Because apixaban has benefits over warfarin that are consistent across patient risk of stroke and bleeding as assessed by the CHADS2 , CHA2 DS2 VASc, and HAS-BLED scores, these scores might be less relevant when used to tailor apixaban treatment to individual patients than they are for warfarin. Further improvement in risk stratification for both stroke and bleeding is needed, particularly for patients with atrial fibrillation at low risk for these events. Funding Bristol-Myers Squibb and Pfizer.
Summary Background Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether ...rimonabant would improve major vascular event-free survival. Methods This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18 695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00263042. Findings At a mean follow-up of 13·8 months (95% CI 13·6–14·0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3·9%) patients assigned to rimonabant and 375 (4·0%) assigned to placebo (hazard ratio 0·97, 95% CI 0·84–1·12, p=0·68). With rimonabant, gastrointestinal (3038 33% vs 2084 22%), neuropsychiatric (3028 32% vs 1989 21%), and serious psychiatric side-effects (232 2·5% vs 120 1·3%) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. Interpretation The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated. Funding Sanofi-Aventis.
