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Lancet. 2018 Jun 9;391(10137):2325-2334. doi: 10.1016/S0140-6736(18)30832-8.

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

Collaborators (313)

Devereaux PJ, Duceppe E, Bangdiwala SI, Connolly S, Eikelboom J, Guyatt G, Kearon C, Pettit S, Pogue J, Rodseth R, Sessler DI, Vincent J, Yusuf S, Vincent J, Di Diodato S, Gasic Z, Mastrangelo LJ, Molnar SH, Pettit S, Swanson JL, Tosh ML, Wells JR, Botto F, Diaz R, Chow CK, Berwanger O, Gonzales B, Devereaux PJ, Tandon V, Villar JC, Vásquez S, Jansky P, Dušek R, Meyhoff CS, Coriat P, Hoeft A, Wittmann M, Yonga G, Xavier D, Rao M, Mathur N, Franzosi MG, Seletti E, Malaga G, Tumanan-Mendoza BA, Tagle MPA, Szczeklik W, Biccard BM, Alonso-Coello P, Popova E, Shields M, Sessler DI, Devereaux PJ, Biccard BM, Connolly S, Duceppe E, Eikelboom J, Guyatt G, Hoeft A, Jansky P, Kearon C, Le Manach Y, Moayyedi P, Pettit S, Pogue J, Rodseth R, Sessler DI, van Zanten S, Villar JC, Vincent J, Yusuf S, Devereaux PJ, Alonso-Coello P, Berwanger O, Biccard BM, Botto F, Chow CK, Connolly S, Coriat P, Diaz R, Duceppe E, Eikelboom J, Fleischmann E, Franzosi MG, Garg A, Guyatt G, Hoeft A, Jansky P, Karaye K, Kearon C, Le Manach Y, Malaga G, McFalls E, Meyhoff CS, Moayyedi P, Pettit S, Pogue J, Rodseth R, Sessler DI, Sigamani A, Shields M, Szczeklik W, Tumanan-Mendoza BA, van Zanten S, Villar JC, Vincent J, Xavier D, Yonga G, Yusuf S, Connolly S, Belley-Côté E, Biedroń G, Borges F, Frosi Stella S, Haarmark Nielsen C, Leong DP, Meyhoff CS, Spence J, Tran A, Wawrzycka-Adamczyk K, Yang SS, Yung T, Wyse DG, Cheng D, Johnstone DE, Wells GA, Joseph P, Patel A, Leong DP, Gregus K, Lawrence K, Doharris L, Conen D, Cheung J, Douketis J, Wright D, Wikkerink S, Dechert W, Panju M, Azzam K, Rapanos T, Van Helder T, Shroff A, Hare J, Kidane B, Nguyen T, Leydier L, Bayaraa V, Parlow J, DuMerton DA, Thakrar A, Shelley J, Deligne B, Carling RD, Mrkobrada M, Dresser GK, Jacka MJ, Garg A, Hornstein D, Winkelaar GB, Haider ZH, Lanjewar PP, Varughese V, Calton R, Ahuja H, George P, Sharma A, Bhatt KS, Mangukiya DO, Nandaniya KV, Parekh VV, Pillai AB, Menon VP, Desai SC, Sidhu RS, Gupta SK, George RK, Gurunath TR, Drummond LW, Torborg AM, Küsel BS, Naidoo P, Naidoo DP, Rajah C, Farina Z, von Rahden RP, Gumede S, Chishala C, Coetzee E, Dyer RA, Diedericks J, Bielański P, Kaczmarek B, Studzińska D, Zaniewski M, Libura MJ, Zacharias-Nalichowski TM, Sega AAS, Salwa J, Kózka M, Górka J, Wludarczyk A, Nowak-Kózka I, Grudzień PS, Gucwa JW, Słowiaczek MP, Dobosz PPD, Gögenur I, Eriksen JR, Borup T, Kirkegaard T, Isbye D, Sonne A, Rasmussen LS, Pedersen S, Troensegaard H, Duus CL, Halle BM, Gundel ON, Bernholm KF, Martinsen KR, Pedersen S, Itenov TS, Camio E, Vázquez C, Matarin S, Cano E, Álvarez-García J, India I, González-Osuna A, Vives M, Rosselló E, Serrano AB, Turiel M, Drago L, Colombo C, Marra F, Mos L, Arteni F, Lembo R, Ortalda A, Passarani S, Mokini Z, Figueiredo EL, Werner GF, Petriz JL, Maia LN, Bergo RR, Precoma DB, Saraiva JFK, Vilamajo OG, Allegrini E, Benzadón M, Parody ML, Duronto EA, Ingaramo AC, Parra GA, Novoa D, Miller SA, Thomas S, Karlapudi SP, Bourji MH, Banerjee S, Gupta A, Opole IO, Fischer M, Jansky P, Mendoza VL, Reyes EB, Pierson RJ, Shields MO, Chow CK, Coriat P, Piriou V, Wittmann M, Zacharowski K, Yonga G, Rotta-Rotta A, Paper M, Devereaux PJ, Duceppe E, Guyatt G, Tandon V, Rodseth R, Biccard BM, Xavier D, Szczeklik W, Meyhoff CS, Vincent J, Franzosi MG, Srinathan SK, Erb J, Magloire P, Neary J, Rao M, Rahate P, Chaudhry N, Mayosi B, de Nadal M, Paniagua Iglesias P, Berwanger O, Villar JC, Botto F, Eikelboom J, Sessler DI, Kearon C, Pettit S, Sharma M, Connolly S, Bangdiwala SI, Rao-Melacini P, Hoeft A, Yusuf S.

Author information

1
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada. Electronic address: philipj@mcmaster.ca.
2
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; Department of Medicine, University of Montreal, Montreal, QC, Canada.
3
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
4
Department of Medicine, McMaster University, Hamilton, ON, Canada.
5
Department of Anaesthesia, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
6
Department of Anaesthesia and Perioperative Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.
7
Department of Pharmacology, St John's Medical College and Research Institute, Bangalore, India.
8
Department of Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Krakow, Poland.
9
Department of Anaesthesia and Intensive Care, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark.
10
Population Health Research Institute, Hamilton, ON, Canada.
11
Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
12
Department of Surgery, University of Manitoba, Winnipeg, MB, Canada.
13
Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, ON, Canada.
14
Department of Surgery, Rahate Surgical Hospital, Nagpur, India.
15
Department of Surgery, Christian Medical College Hospital, Ludhiana, India.
16
Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.
17
Department of Anesthesiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
18
Department of Anesthesiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
19
Instituto de Ensino e Pesquisa do Hospital do Coração (IEP-HCor), São Paulo, Brazil.
20
Departamento de Investigaciones, Fundación Cardioinfantil-Instituto de Cardiología (Bogotá) and Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga, Colombia.
21
Estudios Clínicos Latinoamérica (ECLA), Rosario and Hospital Austral, Pilar, Argentina.
22
Department of Outcomes Research, Cleveland Clinic, Anesthesiology Institute, Cleveland, OH, United States.
23
Department of Medicine, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada.
24
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada.
25
Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany.
26
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada; Population Health Research Institute, Hamilton, ON, Canada.

Erratum in

Abstract

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 [corrected].

FUNDING:

Boehringer Ingelheim and Canadian Institutes of Health Research.

PMID:
29900874
DOI:
10.1016/S0140-6736(18)30832-8
[Indexed for MEDLINE]

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