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

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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.

authors

  • Devereaux, Philip
  • Duceppe, Emmanuelle
  • Guyatt, Gordon
  • Tandon, Vikas
  • Rodseth, Reitze
  • Biccard, Bruce M
  • Xavier, Denis
  • Szczeklik, Wojciech
  • Meyhoff, Christian S
  • Vincent, Jessica
  • Franzosi, Maria Grazia
  • Srinathan, Sadeesh K
  • Erb, Jason
  • Magloire, Patrick
  • Neary, John
  • Rao, Mangala
  • Rahate, Prashant V
  • Chaudhry, Navneet K
  • Mayosi, Bongani
  • de Nadal, Miriam
  • Iglesias, Pilar Paniagua
  • Berwanger, Otavio
  • Villar, Juan Carlos
  • Botto, Fernando
  • Eikelboom, John W
  • Sessler, Daniel I
  • Kearon, Clive
  • Pettit, Shirley
  • Sharma, Mukul
  • Connolly, Stuart J
  • Bangdiwala, Shrikant
  • Rao-Melacini, Purnima
  • Hoeft, Andreas
  • Yusuf, Salim
  • Devereaux, PJ
  • Duceppe, Emmanuelle
  • Bangdiwala, Shrikant I
  • Connolly, Stuart
  • Eikelboom, John
  • Guyatt, Gordon
  • Kearon, Clive
  • Pettit, Shirley
  • Pogue, Janice
  • Rodseth, Reitze
  • Sessler, Daniel I
  • Vincent, Jessica
  • Yusuf, Salim
  • Vincent, Jessica
  • Di Diodato, Sara
  • Gasic, Zora
  • Mastrangelo, Louise J
  • Molnar, Sarah H
  • Pettit, Shirley
  • Swanson, Jennifer L
  • Tosh, Makayla L
  • Wells, Jennifer R
  • Botto, Fernando
  • Diaz, Rafael
  • Chow, Clara K
  • Berwanger, Otavio
  • Gonzales, Beatriz
  • Devereaux, PJ
  • Tandon, Vikas
  • Villar, Juan Carlos
  • Vásquez, Skarlet
  • Jansky, Petr
  • Dušek, Radovan
  • Meyhoff, Christian S
  • Coriat, Pierre
  • Hoeft, Andreas
  • Wittmann, Maria
  • Yonga, Gerald
  • Xavier, Denis
  • Rao, Mangala
  • Mathur, Nandini
  • Franzosi, Maria Grazia
  • Seletti, Elena
  • Malaga, German
  • Tumanan-Mendoza, Bernadette A
  • Tagle, Maria Pamela A
  • Szczeklik, Wojciech
  • Biccard, Bruce M
  • Alonso-Coello, Pablo
  • Popova, Ekaterine
  • Shields, Martin
  • Sessler, Daniel I
  • Devereaux, PJ
  • Biccard, Bruce M
  • Connolly, Stuart
  • Duceppe, Emmanuelle
  • Eikelboom, John
  • Guyatt, Gordon
  • Hoeft, Andreas
  • Jansky, Petr
  • Kearon, Clive
  • Le Manach, Yannick
  • Moayyedi, Paul
  • Pettit, Shirley
  • Pogue, Janice
  • Rodseth, Reitze
  • Sessler, Daniel I
  • van Zanten, Sander
  • Villar, Juan Carlos
  • Vincent, Jessica
  • Yusuf, Salim
  • Devereaux, PJ
  • Alonso-Coello, Pablo
  • Berwanger, Otavio
  • Biccard, Bruce M
  • Botto, Fernando
  • Chow, Clara K
  • Connolly, Stuart
  • Coriat, Pierre
  • Diaz, Rafael
  • Duceppe, Emmanuelle
  • Eikelboom, John
  • Fleischmann, Edith
  • Franzosi, Maria Grazia
  • Garg, Amit
  • Guyatt, Gordon
  • Hoeft, Andreas
  • Jansky, Petr
  • Karaye, Kamilu
  • Kearon, Clive
  • Le Manach, Yannick
  • Malaga, German
  • McFalls, Edward
  • Meyhoff, Christian S
  • Moayyedi, Paul
  • Pettit, Shirley
  • Pogue, Janice
  • Rodseth, Reitze
  • Sessler, Daniel I
  • Sigamani, Alben
  • Shields, Martin
  • Szczeklik, Wojciech
  • Tumanan-Mendoza, Bernadette A
  • van Zanten, Sander
  • Villar, Juan Carlos
  • Vincent, Jessica
  • Xavier, Denis
  • Yonga, Gerald
  • Yusuf, Salim
  • Connolly, Stuart
  • Belley-Côté, Emilie
  • Biedroń, Grzegorz
  • Borges, Flavia
  • Frosi Stella, Steffan
  • Haarmark Nielsen, Christian
  • Leong, Darryl P
  • Meyhoff, Christian S
  • Spence, Jessica
  • Tran, Allen
  • Wawrzycka-Adamczyk, Katarzyna
  • Yang, Stephen S
  • Yung, Terence
  • Wyse, D George
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  • Johnstone, David E
  • Wells, George A
  • Joseph, Philip
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  • Leong, Darryl P
  • Gregus, Krysten
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  • Conen, David
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  • Rapanos, Theodore
  • Van Helder, Tomas
  • Shroff, Anjali
  • Hare, Jacqueline
  • Kidane, Biniam
  • Nguyen, Thang
  • Leydier, Larissa
  • Bayaraa, Vanessa
  • Parlow, Joel
  • DuMerton, Deborah A
  • Thakrar, Amar
  • Shelley, Jessica
  • Deligne, Benoit
  • Carling, Roberta Daila
  • Mrkobrada, Marko
  • Dresser, George K
  • Jacka, Michael J
  • Garg, Amit
  • Hornstein, David
  • Winkelaar, Gerrit B
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  • Sharma, Ambika
  • Bhatt, Keyur Sureshchandra
  • Mangukiya, Dhaval Odhavajibhai
  • Nandaniya, Karshan Vira
  • Parekh, Viral Vasantrai
  • Pillai, Ashok Bhaskaran
  • Menon, Vidya P
  • Desai, Sanjay Channappa
  • Sidhu, Ravinder Singh
  • Gupta, Sandeep Kumar
  • George, Robbie K
  • Gurunath, TR
  • Drummond, Leanne W
  • Torborg, Alexandra M
  • Küsel, Belinda S
  • Naidoo, Prebashini
  • Naidoo, Datshana P
  • Rajah, Chantal
  • Farina, Zane
  • von Rahden, Richard Peter
  • Gumede, Simphiwe
  • Chishala, Chishala
  • Coetzee, Ettienne
  • Dyer, Robert A
  • Diedericks, Johan
  • Bielański, Piotr
  • Kaczmarek, Bogusz
  • Studzińska, Dorota
  • Zaniewski, Maciej
  • Libura, Marek Józef
  • Zacharias-Nalichowski, Tomasz Mikołaj
  • Sega, Aurelia AS
  • Salwa, Jakub
  • Kózka, Mateusz
  • Górka, Jacek
  • Wludarczyk, Anna
  • Nowak-Kózka, Ilona
  • Grudzień, Paweł Szczepan
  • Gucwa, Jaroslaw W
  • Słowiaczek, Michał Piotr
  • Dobosz, Paweł PD
  • Gögenur, Ismail
  • Eriksen, Jens Ravn
  • Borup, Tine
  • Kirkegaard, Tove
  • Isbye, Dan
  • Sonne, Asger
  • Rasmussen, Lars S
  • Pedersen, Sofie
  • Troensegaard, Hannibal
  • Duus, Camilla L
  • Halle, Benedikte M
  • Gundel, Ossian N
  • Bernholm, Katrine F
  • Martinsen, Kristian Rønsholt
  • Pedersen, Søren
  • Itenov, Theis S
  • Camio, Elena
  • Vázquez, Carles
  • Matarin, Silvia
  • Cano, Esther
  • Álvarez-García, Jesús
  • India, Inmaculada
  • González-Osuna, Aránzazu
  • Vives, Marc
  • Rosselló, Elena
  • Serrano, Ana B
  • Turiel, Maurizio
  • Drago, Lorenzo
  • Colombo, Chiara
  • Marra, Federica
  • Mos, Lucio
  • Arteni, Franco
  • Lembo, Rosalba
  • Ortalda, Alessandro
  • Passarani, Simonetta
  • Mokini, Zhirajr
  • Figueiredo, Estevao Lanna
  • Werner, Gustavo Fonseca
  • Petriz, Joao Luiz
  • Maia, Lilia Nigro
  • Bergo, Ricardo R
  • Precoma, Dalton Bertolim
  • Saraiva, José Francisco Kerr
  • Vilamajo, Oscar Gomez
  • Allegrini, Eduardo
  • Benzadón, Mariano
  • Parody, Maria Leonor
  • Duronto, Ernesto A
  • Ingaramo, Adrián C
  • Parra, Gustavo Adolfo
  • Novoa, Danny
  • Miller, Scott A
  • Thomas, Sabu
  • Karlapudi, Sudhakar P
  • Bourji, Mohamad H
  • Banerjee, Subhash
  • Gupta, Anita
  • Opole, Isaac O
  • Fischer, Michal
  • Jansky, Petr
  • Mendoza, Victor Lecaros
  • Reyes, Eugenio Borja
  • Pierson, Richard J
  • Shields, Martin O
  • Chow, Clara K
  • Coriat, Pierre
  • Piriou, Vincent
  • Wittmann, Maria
  • Zacharowski, Kai
  • Yonga, Gerald
  • Rotta-Rotta, Aida
  • Paper, Main
  • Devereaux, PJ
  • Duceppe, Emmanuelle
  • Guyatt, Gordon
  • Tandon, Vikas
  • Rodseth, Reitze
  • Biccard, Bruce M
  • Xavier, Denis
  • Szczeklik, Wojciech
  • Meyhoff, Christian S
  • Vincent, Jessica
  • Franzosi, Maria Grazia
  • Srinathan, Sadeesh K
  • Erb, Jason
  • Magloire, Patrick
  • Neary, John
  • Rao, Mangala
  • Rahate, Prashant
  • Chaudhry, Navneet
  • Mayosi, Bogani
  • de Nadal, Miriam
  • Paniagua Iglesias, Pilar
  • Berwanger, Otavio
  • Villar, Juan Carlos
  • Botto, Fernando
  • Eikelboom, John
  • Sessler, Daniel I
  • Kearon, Michael Clive
  • Pettit, Shirley
  • Sharma, Mukul
  • Connolly, Stuart
  • Bangdiwala, Shrikant I
  • Rao-Melacini, Purnima
  • Hoeft, Andreas
  • Yusuf, Salim

publication date

  • June 2018