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
45 Years
N/A
Both
Myocardial Injury After Noncardiac Surgery (MINS)
Trial Information
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.
Inclusion Criteria:
Patients are eligible if they:
1. have undergone noncardiac surgery;
2. are ≥45 years of age;
3. 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
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 meeting any of the following criteria will be excluded:
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, venous thromboembolism, atrial fibrillation);
5. currently using or plan to initiate 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. investigator considers the patient unreliable regarding requirement for study
follow-up or study drug compliance; OR
8. previously enrolled in the MANAGE Trial.
Also excluded will be 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, or elastic
stockings are not sufficient for venous thromboembolism (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, or
the first dose of dabigatran will occur within 4 hours of epidural catheter removal;
OR
4. estimated glomerular filtration rate (eGFR) <35 ml/min as estimated by calculated
creatinine clearance.
5. it is expected that the patient will undergo cardiac catheterization for MINS.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Outcome Measure:
Major vascular complication (for Dabigatran)
Outcome Description:
A composite of the number of patients suffering vascular mortality, nonfatal myocardial infarction, nonfatal stroke, nonfatal peripheral arterial thrombosis, and nonfatal symptomatic pulmonary embolism.
Outcome Time Frame:
Average of 1 year follow-up
Safety Issue:
No
Principal Investigator
P.J. Devereaux, MD, PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Population Health Research Institute
Authority:
Argentina: Ministry of Health
Study ID:
1160.143
NCT ID:
NCT01661101
Start Date:
January 2013
Completion Date:
November 2015
Related Keywords:
- Myocardial Injury After Noncardiac Surgery (MINS)
- Perioperative myocardial infarction
- Myocardial injury
- noncardiac surgery
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