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Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

Objective Muscle regeneration is a hallmark of the idiopathic inflammatory myopathies (IIMs), a group of autoimmune disorders that are characterized by leukocyte infiltration and dysfunction of the skeletal muscle. Despite detailed studies describing the clinical and histopathologic features of IIMs, the immunopathogenesis of these disorders remains undefined. The aim of this study was to investigate the immunopathologic processes of autoimmune myositis in experimental murine models. Methods Expression of the autoantigen histidyl–transfer RNA synthetase (HisRS) was analyzed in mice with acutely injured or dystrophic muscles, in inflammatory leukocytes, and in purified satellite cells. Anti-HisRS antibodies and myositis induction were assessed in mice after muscle injury and immunization with apoptotic satellite cells or C2C12 myoblasts, in the presence or absence of the Toll-like receptor 7 (TLR-7) agonist R848. Results Muscle necrosis, leukocyte infiltration, and myofiber regeneration induced by toxic agents (cardiotoxin or glycerol) or promoted by genetic disruption of the α-sarcoglycan/dystrophin complex in mice were uniformly associated with up-regulated expression of HisRS. Although regenerating myofibers and purified satellite cells are known to show increased expression of HisRS in these settings, anti-HisRS antibodies were not detectable. However, intramuscular immunization with ultraviolet B–irradiated, HisRS-expressing apoptotic myoblasts in the presence of R848 triggered the production of anti-HisRS IgG antibodies as well as persistent lymphocyte infiltration and prolonged/delayed muscle regeneration. Conversely, intramuscular administration of R848 alone or in combination with living or postapoptotic/necrotic myoblasts failed to generate this myositis phenotype. Conclusion In the presence of TLR/adjuvant signals and underlying muscle injury, apoptotic myogenic precursors expressing high levels of autoantigen can provoke autoantibody formation and lymphocytic infiltration of muscle tissue, effectively replicating the features of IIM.