Management of Myocardial Injury After Noncardiac Surgery Trial (MANAGE)

• Major vascular complication (for Dabigatran) [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: No ]
  A composite of the number of patients suffering vascular mortality, nonfatal myocardial infarction, nonfatal stroke, nonfatal peripheral arterial thrombosis, and nonfatal symptomatic pulmonary embolism.
  
  
• Major upper gastrointestinal complication (for Omeprazole) [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: No ]
  A composite of the number of patients suffering overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation.
  
  

• Individual secondary outcomes for Dabigatran [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: No ]
  The number of patients suffering all-cause mortality, vascular mortality, myocardial infarction, stroke, cardiac revascularization procedure, symptomatic venous thromboembolism (i.e., symptomatic pulmonary embolism or symptomatic deep venous thrombosis), amputation, peripheral arterial thrombosis, and rehospitalization for vascular reasons.
  
  
• Upper gastrointestinal complication for Omeprazole [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: No ]
  A composite of the number of patients suffering overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, symptomatic gastroduodenal ulcer, gastrointestinal pain with underlying multiple gastroduodenal erosions, or upper gastrointestinal perforation.
  
  
• Major vascular complication for Omeprazole [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: No ]
  A composite of the number of patients suffering vascular mortality, nonfatal myocardial infarction, nonfatal stroke, nonfatal peripheral arterial thrombosis and nonfatal symptomatic pulmonary embolism.
  
  
• Individual secondary outcomes for Omeprazole [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: No ]
  The number of patients suffering overt gastroduodenal bleeding, overt esophageal bleeding, overt upper gastrointestinal bleeding of unknown origin, symptomatic gastroduodenal ulcer, gastrointestinal pain with underlying multiple gastroduodenal erosions, upper gastrointestinal perforation, and bleeding of assumed occult gastrointestinal origin with a documented drop in hemoglobin of ≥ 3.0 g/dL.
  
  
• Safety outcomes for Dabigatran [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: Yes ]
  The number of patients suffering life-threatening bleeding, major bleeding, intracranial bleeding, minor bleeding, significant lower gastrointestinal bleeding, non-significant lower gastrointestinal bleeding, and dyspepsia.
  
  
• Safety outcomes for Omeprazole [ Time Frame: Average of 1 year follow-up ] [ Designated as safety issue: Yes ]
  The number of patients suffering Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures.
  
  

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.