Management of Myocardial Injury After Noncardiac Surgery Trial

Study Overview
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Brief Summary
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Patients who have myocardial injury after noncardiac surgery are at a higher risk of dying than those who do not. One in 10 patients with myocardial injury will die within 30 days of surgery. This risk of death exists up to one year after myocardial injury. There are currently no treatments or guidelines available for heart injury after surgery, but there is evidence that taking a blood-thinner can prevent some of the deaths, both in the short and long-term. The purpose of this trial is to test the effect of two drugs (dabigatran and omeprazole) that may prevent mortality, major cardiovascular complications and major upper gastrointestinal bleeding in patients who have had myocardial injury after noncardiac surgery.

Detailed Description
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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.

Official Title
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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

Conditions
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Myocardial Injury After Noncardiac Surgery (MINS)

Intervention / Treatment
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* Drug: Dabigatran
* Drug: Placebo (for Dabigatran)
* Drug: Omeprazole
* Drug: Placebo (for Omeprazole)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are eligible if they: have undergone noncardiac surgery; are ≥45 years of age; have suffered MINS based upon fulfilling one of the following criteria: A. Elevated troponin or CK-MB measurement with one or more of the following defining features i. ischemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; shortness of breath, pulmonary edema); ii. development of pathologic Q waves present in any two contiguous leads that are ≥30 milliseconds; iii. electrocardiogram (ECG) changes indicative of ischemia (i.e., ST segment elevation [≥2 mm in leads V1, V2, or V3 OR ≥1 mm in the other leads], ST segment depression [≥1 mm], OR symmetric inversion of T waves ≥1 mm) in at least two contiguous leads; 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, sepsis) to myocardial injury; AND provide written informed consent to participate within 35 days of suffering their MINS. Exclusion Criteria: Patients meeting any of the following criteria will be excluded: hypersensitivity or known allergy to dabigatran; history of intracranial, intraocular, or spinal bleeding; hemorrhagic disorder or bleeding diathesis; known hepatic impairment or liver disease expected to have an impact on survival; condition that requires therapeutic dose anticoagulation (e.g., prosthetic heart valve, venous thromboembolism, atrial fibrillation); currently using or plan to initiate rifampicin, cyclosporine, itraconazole, tacrolimus, ketoconazole, or dronedarone; women who are pregnant, breastfeeding, or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study; investigator considers the patient unreliable regarding requirement for study follow-up or study drug compliance; OR previously enrolled in the MANAGE Trial. Also excluded will be patients in whom any of the following criteria persist beyond 35 days of their suffering MINS: the attending surgeon believes it is not safe to initiate therapeutic dose anticoagulation therapy; the attending physician believes ASA, intermittent pneumatic compression, or elastic stockings are not sufficient for venous thromboembolism (VTE) prophylaxis and that the patient requires a prophylactic-dose anticoagulant; the patient has an indwelling epidural or spinal catheter that cannot be removed, or the first dose of dabigatran will occur within 4 hours of epidural catheter removal; OR estimated glomerular filtration rate (eGFR) <35 ml/min as estimated by calculated creatinine clearance. it is expected that the patient will undergo cardiac catheterization for MINS. Exclusion Criteria Specific to Patients in the Omeprazole Factorial Component of the Trial: Patients meeting any of the following criteria: hypersensitivity or known allergy to omeprazole; requirement for a proton pump inhibitor, an H2-receptor antagonist, sucralfate, atazanavir, clopidogrel, or misoprostol; esophageal or gastric variceal disease; OR patient declines participation in the omeprazole arm of MANAGE.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran<br>Dabigatran 110 mg capsule taken twice daily | Drug: Dabigatran<br>* Dabigatran 110 mg taken twice daily<br>* Other names: Pradaxa;|
| Experimental: Omeprazole<br>Omeprazole 20 mg capsule taken once daily | Drug: Omeprazole<br>* Omeprazole 20 mg capsule taken once daily<br>* Other names: Zegerid;|
| Placebo Comparator: Placebo (dabigatran)<br>Dabigatran placebo taken twice daily | Drug: Placebo (for Dabigatran)<br>* Dabigatran placebo taken twice daily<br>|
| Placebo Comparator: Placebo (omeprazole)<br>Omeprazole placebo taken once daily | Drug: Placebo (for Omeprazole)<br>* Omeprazole placebo taken once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major vascular complication (for Dabigatran) | A composite of the number of patients suffering vascular mortality, nonfatal myocardial infarction, nonfatal non-hemorrhagic stroke, nonfatal peripheral arterial thrombosis, nonfatal amputation, and nonfatal symptomatic venous thromboembolism (i.e., symptomatic pulmonary embolism or symptomatic proximal deep venous thrombosis). | Average of 1 year follow-up | 
| Major upper gastrointestinal complication (for Omeprazole) | A composite of the number of patients suffering overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation. | Average of 1 year follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual secondary outcomes for Dabigatran | The number of patients suffering all-cause mortality, vascular mortality, myocardial infarction, non-hemorrhagic stroke, cardiac revascularization procedure, symptomatic venous thromboembolism (i.e., symptomatic pulmonary embolism or symptomatic proximal deep venous thrombosis), amputation, peripheral arterial thrombosis, and rehospitalization for vascular reasons. | Average of 1 year follow-up | 
| Upper gastrointestinal complication for Omeprazole | 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. | Average of 1 year follow-up | 
| Major vascular complication for Omeprazole | A composite of the number of patients suffering vascular mortality, nonfatal myocardial infarction, nonfatal non-hemorrhagic stroke, nonfatal peripheral arterial thrombosis, nonfatal amputation, and nonfatal symptomatic venous thromboembolism (i.e., symptomatic pulmonary embolism or symptomatic proximal deep venous thrombosis). | Average of 1 year follow-up | 
| Individual secondary outcomes for Omeprazole | 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, bleeding of assumed occult gastrointestinal origin with a documented drop in hemoglobin of ≥ 3.0 g/dL, dyspepsia, and mortality. | Average of 1 year follow-up | 
| Safety outcomes for Dabigatran | A composite of the number of patients suffering life-threatening bleeding, major bleeding, and critical organ bleeding (i.e., intracranial, intraocular, intraspinal, pericardial, retroperitoneal). The number of patients suffering life-threatening bleeding, major bleeding, critical organ bleeding, intracranial bleeding, minor bleeding, hemorrhagic stroke, significant lower gastrointestinal bleeding, non-significant lower gastrointestinal bleeding, fracture, and dyspepsia. | Average of 1 year follow-up | 
| Safety outcomes for Omeprazole | The number of patients suffering Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures. | Average of 1 year follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Perioperative myocardial infarction, Myocardial injury, noncardiac surgery