A Large, International, Randomized, Placebo-controlled Trial to Assess the Impact of Dabigatran (a Direct Thrombin Inhibitor) and Omeprazole (a Proton-pump Inhibitor) in Patients Suffering Myocardial Injury After Noncardiac Surgery
Myocardial injury is the most common major vascular complication after noncardiac surgery.
Worldwide approximately 10 million adults annually suffer a perioperative myocardial injury.
This figure for perioperative myocardial injury represents 15-20% of all cases of
myocardial infarction in all settings. Myocardial injury after noncardiac surgery carries a
poor prognosis and is an independent predictor of 30-day and 1-year mortality.
Myocardial injury after noncardiac surgery (MINS) differs from non-operative myocardial
infarction in two ways; it has a poorer prognosis (patients suffering MINS are 2 times more
likely to die within 30 days compared to non-operative myocardial infarction in the
emergency room) and paradoxically its treatment is less intensive. This difference in the
intensity of treatment is likely influenced by several factors including: (1) a majority of
patients suffering MINS do not experience ischemic symptoms, potentially influencing
physicians' perception of the severity of the event; (2) there is debate as to the
pathophysiology of MINS (although emerging evidence does suggest that coronary arterial
thrombosis is an important mechanism of MINS); and (3) no randomized controlled trial (RCT)
has evaluated an intervention to manage MINS, and hence physicians are uncertain about the
risk-benefit ratio of potential interventions (e.g., interventions that are effective in the
management of non-operative myocardial infarction). From a human and economic perspective,
it is a tragedy that some patients undergoing noncardiac surgery for important reasons
(e.g., to obtain a cure of their cancer or to become mobile after a new prosthetic joint)
fail to obtain these benefits, because they suffer MINS that ultimately takes their life.
There is an urgent need for clinical trials to identify effective therapies to improve the
outcomes of patients suffering MINS.
There exists promising laboratory, autopsy, imaging, operative, and non-operative data
suggesting that patients suffering MINS will benefit from anticoagulant therapy. Dabigatran
(a direct thrombin inhibitor) warrants evaluation in the management of MINS. The major
limitation of anticoagulation therapy is bleeding, and gastrointestinal bleeding represents
a substantial proportion of these complications. Gastrointestinal bleeding is important in
its own right, but also because it leads to cessation of anticoagulant therapy which may
lead to breakthrough myocardial infarction. Omeprazole (a proton pump inhibitor) is
efficacious in preventing upper gastrointestinal bleeding in patients with coronary artery
disease who are taking dual antiplatelet therapy, and may benefit patients receiving
anticoagulation therapy after suffering MINS.
We will undertake a large international RCT to determine the impact of dabigatran in
patients who have suffered MINS. We will use a partial factorial design (for patients not
taking a proton pump inhibitor) to determine the impact of omeprazole in this setting. We
call this RCT the Management of myocardial injury After NoncArdiac surGEry (MANAGE) Trial.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Major vascular complication (for Dabigatran)
A composite of the number of patients suffering vascular mortality, nonfatal myocardial infarction, nonfatal stroke, nonfatal peripheral arterial thrombosis, and nonfatal symptomatic pulmonary embolism.
Average of 1 year follow-up
P.J. Devereaux, MD, PhD
Population Health Research Institute
Argentina: Ministry of Health