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 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: 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
• Journal: Lancet (London, England) (Lancet) Vol. 391 Issue 10137 Pg. 2325-2334 (06 09 2018) ISSN: 1474-547X [Electronic] England
• PMID: 29900874 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antithrombins
• Proton Pump Inhibitors
• Troponin
• Dabigatran
• Omeprazole

Topics

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