Protocol No: ECCT/13/08/06 Date of Protocol: 30-11-2012

Study Title:

Management of myocardial injury After NoncArdiac surgGEry (MANAGE) Trial

Study Objectives:
Laymans Summary:
Abstract of Study:

Study Size 3200 patients

Study Design Multicentre, international, blinded, randomized placebo controlled trial of dabigatran and omeprazole (partial factorial design among patients not taking a proton pump inhibitor [PPI]).

Primary Objectives

To determine the impact of dabigatran versus placebo on the risk of a major vascular complication and omeprazole versus placebo on the risk of a major upper gastrointestinal complication in patients who are followed on average for 1 year.

Safety Objectives

To determine the impact of dabigatran on the following individual outcomes: life-threatening bleeding, major bleeding, minor bleeding, intracranial bleeding, significant lower gastrointestinal bleeding, non-significant lower gastrointestinal bleeding, or dyspepsia. To determine the impact of omeprazole on the following individual outcomes: Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures.

Inclusion Criteria

Patients are eligible if they fulfill all of the following criteria: 1. undergone noncardiac surgery; 2. ≥45 years of age; 3. have suffered myocardial injury after noncardiac surgery (MINS) based upon fulfilling one of the following criterions:

A. elevated troponin or CK-MB measurement with one or more of the following defining features: i. ischemic signs or symptoms; ii. development of pathologic Q waves; iii. electrocardiogram changes indicative of ischemia (i.e., ST segment elevation, ST segment depression, or inversion of T waves); iv. new LBBB, or v. new or presumed new cardiac wall motion abnormality on echocardiography or new or presumed new fixed defect on radionuclide imaging.

B. elevated troponin measurement after surgery with no alternative explanation (e.g., pulmonary embolism) to MINS. and 4. provide written informed consent to participate while still in hospital after their index surgery and within 5 days of suffering their MINS.

Exclusion Criteria

Patients are excluded if they fulfill any of the following criteria: 1. hypersensitivity or known allergy to dabigatran; 2. history of intracranial, intraocular, or spinal bleeding; 3. Hemorrhagic disorder or bleeding diathesis; 4. condition that requires therapeutic dose anticoagulation (e.g., prosthetic heart valve, VTE, atrial fibrillation); 5. currently using or plan rifampicin, ketoconazole, or dronedarone; 6. women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study; 7. patient is considered unreliable for study follow-up or study drug compliance; OR 8. previously enrolled in MANAGE. We will also exclude patients in whom any of the following criteria persist beyond 5 days of their suffering MINS: 1. the attending surgeon believes it is not safe to initiate therapeutic dose anticoagulation therapy; 2. the attending physician believes ASA, intermittent pneumatic compression, and/or elastic stockings are not sufficient for VTE prophylaxis and that the patient requires a prophylactic-dose anticoagulant; 3. the patient has an indwelling epidural or spinal catheter that cannot be removed; 4. estimated glomerular filtration rate <35 ml/min, OR 5. it is expected that the patient will undergo cardiac catheterization for MINS .

Exclusion criteria specific to patients in the omeprazole factorial component:

1. hypersensitivity or known allergy to omeprazole; 2. requirement for a PPI, an H2-receptor antagonist, sucralfate, or misoprostol; 3. esophageal or gastric variceal disease; OR 4. Patient declines participation in omeprazole arm.

Treatment Regimen

Dabigatran 110mg (BID) or placebo and omeprazole 20 mg (once daily) or placebo for participants eligible for the PPI factorial component.