Management of Myocardial Injury After Noncardiac Surgery Trial



Status:Completed
Conditions:Hospital
Therapuetic Areas:Other
Healthy:No
Age Range:45 - Any
Updated:4/17/2018
Start Date:January 2013
End Date:March 1, 2018

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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

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.

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 within 35 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. known hepatic impairment or liver disease expected to have an impact on survival;

5. condition that requires therapeutic dose anticoagulation (e.g., prosthetic heart
valve, venous thromboembolism, atrial fibrillation);

6. currently using or plan to initiate rifampicin, cyclosporine, itraconazole,
tacrolimus, ketoconazole, or dronedarone;

7. women who are pregnant, breastfeeding, or of childbearing potential who refuse to use
a medically acceptable form of contraception throughout the study;

8. investigator considers the patient unreliable regarding requirement for study
follow-up or study drug compliance; OR

9. 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:

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.

Exclusion Criteria Specific to Patients in the Omeprazole Factorial Component of the Trial:

Patients meeting any of the following criteria:

1. hypersensitivity or known allergy to omeprazole;

2. requirement for a proton pump inhibitor, an H2-receptor antagonist, sucralfate,
atazanavir, clopidogrel, or misoprostol;

3. esophageal or gastric variceal disease; OR

4. patient declines participation in the omeprazole arm of MANAGE.
We found this trial at
8
sites
3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
503 494-8311
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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Portland, OR
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601 Elmwood Avenue
Rochester, New York 14642
(585) 275-2100
Principal Investigator: Sabu Thomas, MD
Univ of Rochester Medical Center One of the nation's top academic medical centers, the University...
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Rochester, NY
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Buffalo, New York 14215
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Buffalo, NY
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Caba,
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4500 South Lancaster Road
Dallas, Texas 75216
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Dallas, TX
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Kansas City, Kansas
Principal Investigator: Isaac Opole, MD
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Kansas City, KS
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2900 W Queen Ln
Philadelphia, Pennsylvania 19129
(215) 991-8100
Drexel University College of Medicine Drexel University College of Medicine represents the consolidation of two...
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Philadelphia, PA
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Winston-Salem, North Carolina 27157
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Winston-Salem, NC
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