TY - JOUR
T1 - Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE)
T2 - an international, randomised, placebo-controlled trial
AU - Devereaux, P J
AU - Duceppe, Emmanuelle
AU - Guyatt, Gordon
AU - Tandon, Vikas
AU - Rodseth, Reitze
AU - Biccard, Bruce M
AU - Xavier, Denis
AU - Szczeklik, Wojciech
AU - Meyhoff, Christian S
AU - Vincent, Jessica
AU - Franzosi, Maria Grazia
AU - Srinathan, Sadeesh K
AU - Erb, Jason
AU - Magloire, Patrick
AU - Neary, John
AU - Rao, Mangala
AU - Rahate, Prashant V
AU - Chaudhry, Navneet K
AU - Mayosi, Bongani
AU - de Nadal, Miriam
AU - Iglesias, Pilar Paniagua
AU - Berwanger, Otavio
AU - Villar, Juan Carlos
AU - Botto, Fernando
AU - Eikelboom, John W
AU - Sessler, Daniel I
AU - Kearon, Clive
AU - Pettit, Shirley
AU - Sharma, Mukul
AU - Connolly, Stuart J
AU - Bangdiwala, Shrikant I
AU - Rao-Melacini, Purnima
AU - Hoeft, Andreas
AU - Yusuf, Salim
AU - MANAGE Investigators
N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.
PY - 2018/6/9
Y1 - 2018/6/9
N2 - 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.
AB - 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.
KW - Aged
KW - Aged, 80 and over
KW - Antithrombins/pharmacology
KW - Dabigatran/administration & dosage
KW - Female
KW - Hemorrhage/complications
KW - Humans
KW - Male
KW - Myocardial Infarction/drug therapy
KW - Omeprazole/administration & dosage
KW - Perioperative Period/mortality
KW - Peripheral Arterial Disease/complications
KW - Placebo Effect
KW - Proton Pump Inhibitors/therapeutic use
KW - Stroke/complications
KW - Thrombosis/pathology
KW - Treatment Outcome
KW - Troponin/drug effects
KW - Venous Thromboembolism/drug therapy
U2 - 10.1016/S0140-6736(18)30832-8
DO - 10.1016/S0140-6736(18)30832-8
M3 - Journal article
C2 - 29900874
SN - 0140-6736
VL - 391
SP - 2325
EP - 2334
JO - Lancet
JF - Lancet
IS - 10137
ER -