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 100 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.
Bibliographical noteFunding Information:
PJD reports grants from Boehringer Ingelheim and Canadian Health Research Institutes of Canada during the conduct of the study, and grants from Abbott Diagnostics, Boehringer Ingelheim, Covidien, Octopharma, Philips Healthcare, Roche Diagnostics, and Stryker, all outside the submitted work. DX reports grants from Cadila Pharmaceuticals, Boehringer Ingelheim, Sanofi-Aventis, Pfizer, Bristol Myers Squibb, and United Health, all outside the submitted work. CSM reports grants from Ferring Pharmaceuticals and Merck, Sharp and Dohme outside the submitted work. OB reports grants and personal fees from AstraZeneca and Amgen; grants, personal fees, and non-financial support from Bayer; personal fees from Novo Nordisk and Sanofi; and grants from Ethicon, all outside the submitted work. JWE reports honoraria and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Glaxo Smith Kline, Janssen, Sanofi-Aventis, and Eli Lilly; and a personal award from the Heart and Stroke Foundation, all outside the submitted work. CK reports grants from Bayer and personal fees from Bayer and Bristol-Myers Squibb, outside the submitted work. MS reports grants and personal fees from Bayer, Bristol-Myers Squibb, and Daiichi Sankyo, and grants from Boehringer Ingelheim, all outside the submitted work. SJC reports grants and consulting fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Abbott, Portola, Daiichi Sankyo, Medtronic, and Sanofi Aventis, all during the conduct of the study; grants and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Abbott, Portola, Daiichi Sankyo, Medtronic, and Sanofi-Aventis, all outside the submitted work. SY reports grants from Boehringer Ingelheim during the conduct of the study, and grants from Boehringer Ingelheim outside the submitted work. All other authors declare no competing interests.
The Population Health Research Institute (PHRI) in Hamilton, ON, Canada sponsored the trial. The PHRI obtained a grant from Boehringer Ingelheim to fund MANAGE, and Boehringer Ingelheim provided the dabigatran and placebo study drugs. A Canadian Institutes of Health Research Foundation Grant also supported the trial. The PHRI coordinated MANAGE and was responsible for the randomisation, database, data validation, analyses, and trial coordination. The trial committees and their members, participating centres, and investigators are listed in the appendix . The International Operations Committee designed the trial, and representatives from Boehringer Ingelheim provided input. No MANAGE funding source had a role in the data collection, analyses, or manuscript write-up. The International Operations Committee prespecified the statistical analysis plan before any investigator was unblinded to the trial results. PJD wrote the initial draft of the paper, and the Writing Committee made critical revisions and decided to submit the paper for publication. PJD and SY vouch for the completeness and accuracy of the data.