Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial.

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\ub772, 95% CI 0\ub755-0\ub793; p=0\ub70115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0\ub792, 95% CI 0\ub755-1\ub753; p=0\ub776). 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 [corrected]

Preoperative N-Terminal Pro-B-Type Natriuretic Peptide and Cardiovascular Events After Noncardiac Surgery A Cohort Study

Background: Preliminary data suggest that preoperative N-terminal pro–B-type natriuretic peptide (NT-proBNP) may improve risk prediction in patients undergoing noncardiac surgery. Objective: To determine whether preoperative NT-proBNP has additional predictive value beyond a clinical risk score for the composite of vascular death and myocardial injury after noncardiac surgery (MINS) within 30 days after surgery. Design: Prospective cohort study. Setting: 16 hospitals in 9 countries. Patients: 10 402 patients aged 45 years or older having inpatient noncardiac surgery. Measurements: All patients had NT-proBNP levels measured before surgery and troponin T levels measured daily for up to 3 days after surgery. Results: In multivariable analyses, compared with preoperative NT-proBNP values less than 100 pg/mL (the reference group), those of 100 to less than 200 pg/mL, 200 to less than 1500 pg/mL, and 1500 pg/mL or greater were associated with adjusted hazard ratios of 2.27 (95% CI, 1.90 to 2.70), 3.63 (CI, 3.13 to 4.21), and 5.82 (CI, 4.81 to 7.05) and corresponding incidences of the primary outcome of 12.3% (226 of 1843), 20.8% (542 of 2608), and 37.5% (223 of 595), respectively. Adding NT-proBNP thresholds to clinical stratification (that is, the Revised Cardiac Risk Index [RCRI]) resulted in a net absolute reclassification improvement of 258 per 1000 patients. Preoperative NT-proBNP values were also statistically significantly associated with 30-day all-cause mortality (less than 100 pg/mL [incidence, 0.3%], 100 to less than 200 pg/mL [incidence, 0.7%], 200 to less than 1500 pg/mL [incidence, 1.4%], and 1500 pg/mL or greater [incidence, 4.0%]). Limitation: External validation of the identified NT-proBNP thresholds in other cohorts would reinforce our findings. Conclusion: Preoperative NT-proBNP is strongly associated with vascular death and MINS within 30 days after noncardiac surgery and improves cardiac risk prediction in addition to the RCRI

Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery

Non-commercial use only. Funding for this study came from more than 60 grants for VISION and its substudies. Canada: Canadian Institutes of Health Research (7 grants); Heart and Stroke Foundation of Ontario (2 grants); Academic Health Science Centres Alternative Funding Plan Innovation Fund Ontario; Population Health Research Institute; CLARITY Research Group; McMaster University Department of Surgery Surgical Associates; Hamilton Health Science New Investigator Fund; Hamilton Health Sciences; Ontario Ministry of Resource and Innovation; Stryker Canada; McMaster University, Department of Anesthesiology (2 grants); St Joseph’s Healthcare, Department of Medicine (2 grants); Father Sean O’Sullivan Research Centre (2 grants); McMaster University Department of Medicine (2 grants); Roche Diagnostics Global Office (5 grants); Hamilton Health Sciences Summer Studentships (6 grants); McMaster University Department of Clinical Epidemiology and Biostatistics; McMaster University, Division of Cardiology; Canadian Network and Centre for Trials Internationally; Winnipeg Health Sciences Foundation; University of Manitoba Department of Surgery (2 grants); Diagnostic Services of Manitoba Research; Manitoba Medical Services Foundation; Manitoba Health Research Council; University of Manitoba Faculty of Dentistry Operational Fund; University of Manitoba Department of Anesthesia; University Medical Group, Department of Surgery, University of Manitoba, Start-up Fund. Australia: National Health and Medical Research Council Program. Brazil: Projeto Hospitais de Excelência a Serviço do SUS (PROADI-SUS) grant from the Brazilian Ministry of Health in partnership with Hcor (Cardiac Hospital Sao Paulo–SP); National Council for Scientific and Technological Development (CNPq) grant from the Brazilian Ministry of Science and Technology. China: Public Policy Research Fund (grant CUHK-4002-PPR-3), Research Grant Council, Hong Kong SAR; General Research Fund (grant 461412), Research Grant Council, Hong Kong SAR; Australian and New Zealand College of Anaesthetists (grant 13/008). Colombia: School of Nursing, Universidad Industrial de Santander; Grupo de Cardiología Preventiva, Universidad Autónoma de Bucaramanga; Fundación Cardioinfantil–Instituto de Cardiología; Alianza Diagnóstica SA. France: Université Pierre et Marie Curie, Département d’anesthésie Réanimation, Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris. India: St John’s Medical College and Research Institute; Division of Clinical Research and Training. Malaysia: University of Malaya (grant RG302-14AFR); University of Malaya, Penyelidikan Jangka Pendek. Poland: Polish Ministry of Science and Higher Education (grant NN402083939). South Africa: University of KwaZulu-Natal. Spain: Instituto de Salud Carlos III; Fundació La Marató de TV3. United States: American Heart Association; Covidien. United Kingdom: National Institute for Health Researc