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

P J Devereaux; Emmanuelle Duceppe; Gordon Guyatt; Vikas Tandon; Reitze Rodseth; Bruce M Biccard; Denis Xavier; Wojciech Szczeklik; Christian S Meyhoff; Jessica Vincent; Maria Grazia Franzosi; Sadeesh K Srinathan; Jason Erb; Patrick Magloire; John Neary; Mangala Rao; Prashant V Rahate; Navneet K Chaudhry; Bongani Mayosi; Miriam de Nadal; Pilar Paniagua Iglesias; Otavio Berwanger; Juan Carlos Villar; Fernando Botto; John W Eikelboom; Daniel I Sessler; Clive Kearon; Shirley Pettit; Mukul Sharma; Stuart J Connolly; Shrikant I Bangdiwala; Purnima Rao-Melacini; Andreas Hoeft; Salim Yusuf; MANAGE Investigators

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

P J Devereaux, Emmanuelle Duceppe, Gordon Guyatt, Vikas Tandon, Reitze Rodseth, Bruce M Biccard, Denis Xavier, Wojciech Szczeklik, Christian S Meyhoff, Jessica Vincent, Maria Grazia Franzosi, Sadeesh K Srinathan, Jason Erb, Patrick Magloire, John Neary, Mangala Rao, Prashant V Rahate, Navneet K Chaudhry, Bongani Mayosi, Miriam de NadalPilar Paniagua Iglesias, Otavio Berwanger, Juan Carlos Villar, Fernando Botto, John W Eikelboom, Daniel I Sessler, Clive Kearon, Shirley Pettit, Mukul Sharma, Stuart J Connolly, Shrikant I Bangdiwala, Purnima Rao-Melacini, Andreas Hoeft, Salim Yusuf, MANAGE Investigators

Department of Clinical Medicine

110 Citations (Scopus)

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 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.

Original language	English
Journal	Lancet
Volume	391
Issue number	10137
Pages (from-to)	2325-2334
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(18)30832-8
Publication status	Published - 9 Jun 2018

Keywords

Aged
Aged, 80 and over
Antithrombins/pharmacology
Dabigatran/administration & dosage
Female
Hemorrhage/complications
Humans
Male
Myocardial Infarction/drug therapy
Omeprazole/administration & dosage
Perioperative Period/mortality
Peripheral Arterial Disease/complications
Placebo Effect
Proton Pump Inhibitors/therapeutic use
Stroke/complications
Thrombosis/pathology
Treatment Outcome
Troponin/drug effects
Venous Thromboembolism/drug therapy

Access to Document

10.1016/S0140-6736(18)30832-8

Cite this

Devereaux, P. J., Duceppe, E., Guyatt, G., Tandon, V., Rodseth, R., Biccard, B. M., Xavier, D., Szczeklik, W., Meyhoff, C. S., Vincent, J., Franzosi, M. G., Srinathan, S. K., Erb, J., Magloire, P., Neary, J., Rao, M., Rahate, P. V., Chaudhry, N. K., Mayosi, B., ... MANAGE Investigators (2018). Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet, 391(10137), 2325-2334. https://doi.org/10.1016/S0140-6736(18)30832-8

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, PV, Chaudhry, NK, Mayosi, B, de Nadal, M, Iglesias, PP, Berwanger, O, Villar, JC, Botto, F, Eikelboom, JW, Sessler, DI, Kearon, C, Pettit, S, Sharma, M, Connolly, SJ, Bangdiwala, SI, Rao-Melacini, P, Hoeft, A, Yusuf, S & MANAGE Investigators 2018, 'Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial', Lancet, vol. 391, no. 10137, pp. 2325-2334. https://doi.org/10.1016/S0140-6736(18)30832-8

@article{83365dc738db4a6399299373cf9122ba,

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

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 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.",

keywords = "Aged, Aged, 80 and over, Antithrombins/pharmacology, Dabigatran/administration & dosage, Female, Hemorrhage/complications, Humans, Male, Myocardial Infarction/drug therapy, Omeprazole/administration & dosage, Perioperative Period/mortality, Peripheral Arterial Disease/complications, Placebo Effect, Proton Pump Inhibitors/therapeutic use, Stroke/complications, Thrombosis/pathology, Treatment Outcome, Troponin/drug effects, Venous Thromboembolism/drug therapy",

author = "Devereaux, {P J} and Emmanuelle Duceppe and Gordon Guyatt and Vikas Tandon and Reitze Rodseth and Biccard, {Bruce M} and Denis Xavier and Wojciech Szczeklik and Meyhoff, {Christian S} and Jessica Vincent and Franzosi, {Maria Grazia} and Srinathan, {Sadeesh K} and Jason Erb and Patrick Magloire and John Neary and Mangala Rao and Rahate, {Prashant V} and Chaudhry, {Navneet K} and Bongani Mayosi and {de Nadal}, Miriam and Iglesias, {Pilar Paniagua} and Otavio Berwanger and Villar, {Juan Carlos} and Fernando Botto and Eikelboom, {John W} and Sessler, {Daniel I} and Clive Kearon and Shirley Pettit and Mukul Sharma and Connolly, {Stuart J} and Bangdiwala, {Shrikant I} and Purnima Rao-Melacini and Andreas Hoeft and Salim Yusuf and {MANAGE Investigators}",

year = "2018",

month = jun,

day = "9",

doi = "10.1016/S0140-6736(18)30832-8",

language = "English",

volume = "391",

pages = "2325--2334",

journal = "Lancet",

issn = "0140-6736",

publisher = "TheLancet Publishing Group",

number = "10137",

}

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

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 -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this