Management of Myocardial Injury After Noncardiac Surgery Trial
- Conditions
- Myocardial Injury After Noncardiac Surgery (MINS)
- Interventions
- Registration Number
- NCT01661101
- Lead Sponsor
- Population Health Research Institute
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1754
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.
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Placebo (dabigatran) Placebo (for Dabigatran) Dabigatran placebo taken twice daily Placebo (omeprazole) Placebo (for Omeprazole) Omeprazole placebo taken once daily Dabigatran Dabigatran Dabigatran 110 mg capsule taken twice daily Omeprazole Omeprazole Omeprazole 20 mg capsule taken once daily
- Primary Outcome Measures
Name Time Method Major upper gastrointestinal complication (for Omeprazole) Average of 1 year follow-up A composite of the number of patients suffering overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation.
Major vascular complication (for Dabigatran) Average of 1 year follow-up 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).
- Secondary Outcome Measures
Name Time Method Individual secondary outcomes for Dabigatran Average of 1 year follow-up 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.
Major vascular complication for Omeprazole Average of 1 year follow-up 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).
Individual secondary outcomes for Omeprazole Average of 1 year follow-up 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.
Upper gastrointestinal complication for Omeprazole Average of 1 year follow-up 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.
Safety outcomes for Dabigatran Average of 1 year follow-up 1. A composite of the number of patients suffering life-threatening bleeding, major bleeding, and critical organ bleeding (i.e., intracranial, intraocular, intraspinal, pericardial, retroperitoneal).
2. 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.Safety outcomes for Omeprazole Average of 1 year follow-up The number of patients suffering Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures.
Trial Locations
- Locations (82)
Hospital Nacional Cayetano Heredia
🇵🇪Lima, Peru
Instituto Cardiovascular de Buenos Aires
🇦🇷Caba, Buenos Aires, Argentina
Clinica Parra - Centro de Investigaciones
🇦🇷Rafaela, Santa Fe, Argentina
Sanatorio San Martin
🇦🇷Venado Tuerto, Santa Fe, Argentina
Sociendade Hospitalar Angelina Caron
🇧🇷Campina Grande do Sul, Paraná, Brazil
Narayana Hrudayalaya
🇮🇳Bengaluru, India
De La Salle University Medical Center
🇵🇭Dasmariñas, Philippines
SPZOZ Szpital Powiatowy w Bochni
🇵🇱Bochnia, Poland
Malopolskie Centrum Medyczne
🇵🇱Krakow, Poland
Spzoz w Myslenicach
🇵🇱Myslenice, Poland
Specjalistyczny Szpital im. E. Szczeklika
🇵🇱Tarnow, Poland
Zakład Opieki Zdrowotnej im. Jana Pawła II
🇵🇱Włoszczowa, Poland
Hospital Lifecenter
🇧🇷Belo Horizonte, Brazil
Fundacion Cardioinfantil - Instituto de Cardiologia
🇨🇴Bogota, Colombia
Hospital de Base
🇧🇷São José do Rio Preto, Brazil
Queens University - Kingston General Hospital
🇨🇦Kingston, Ontario, Canada
Hospital e Maternidade Celso Pierro - PUCCAMP
🇧🇷Campinas, Brazil
Clinica Foscal
🇨🇴Floridablanca, Santander, Colombia
Montreal General Hospital - McGill University Health Centre
🇨🇦Montreal, Quebec, Canada
Aga Khan University Hospital - Nairobi
🇰🇪Nairobi, Kenya
Philippines General Hospital
🇵🇭Manila, Philippines
Samodzielny Publiczny Zakład Opieki
🇵🇱Kraków, Poland
University of the Free State
🇿🇦Bloemfontein, South Africa
IRCCS San Raffaele Scientific Institute
🇮🇹Milano, Italy
Bispebjerg Hospital, University of Copenhagen
🇩🇰Copenhagen, Denmark
Belfast Health and Social Care Trust, Royal Victoria Hospital
🇬🇧Belfast, North Ireland, United Kingdom
University Hospital Motol
🇨🇿Motol, Czechia
University Hospital, London Health Sciences Centre
🇨🇦London, Ontario, Canada
Rahate Surgical Hospital
🇮🇳Nagpur, India
Spzoz w Brzesku
🇵🇱Brzesko, Poland
Hamilton General Hospital
🇨🇦Hamilton, Ontario, Canada
Herlev Hospital
🇩🇰Herlev, Denmark
Russell Halls Hospital, Dudley Group NHS
🇬🇧Dudley, United Kingdom
Victoria Hospital, London Health Sciences Centre
🇨🇦London, Ontario, Canada
Copenhagen University Hospital, Rigshospitalet
🇩🇰Copenhagen, Denmark
Sidhu Hospital
🇮🇳Doraha, Distt- Ludhiana, India
M.S. Ramaiah Medical College & Hospitals
🇮🇳Bangalore, India
Sant'Antonio Hospital
🇮🇹San Daniele Del Friuli, Udine, Italy
OrtoMed sp. Z.o.o.
🇵🇱Kraków, Poland
Azienda Ospedaliera Niguarda Ca'Granda
🇮🇹Milano, Italy
Centre Hospitalier Universitaire de Montreal - St. Luc Hospital
🇨🇦Montreal, Quebec, Canada
Juravinski Hospital and Cancer Centre
🇨🇦Hamilton, Ontario, Canada
Vejle Hospital
🇩🇰Vejle, Denmark
Ospedale San Gerardo
🇮🇹Monza, Italy
Hospice Civils de Lyon
🇫🇷Pierre Benite, Lyon, France
University of Cape Town
🇿🇦Cape Town, South Africa
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Hospital de la Santa Creu I Sant Pau
🇪🇸Barcelona, Spain
Hospital Universatario Valle Hebron
🇪🇸Barcelona, Spain
Ramana Maharishi Rangammal Hospital
🇮🇳Tiruvannamalai, India
IRCCS Istituto Ortopedico Galeazzi Milan
🇮🇹Milano, Italy
Bellvitge University Hospital
🇪🇸Barcelona, Spain
Grey's Hospital
🇿🇦Pietermaritzburg, Kwazulu-Natal, South Africa
University of Kwazulu-Natal
🇿🇦Congella, Kwazulu-Natal, South Africa
Kansas University Medical Center
🇺🇸Kansas City, Kansas, United States
Hospital Maternidade
🇧🇷Poços de Caldas, Minas Gerais, Brazil
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Koege-Roskilde Hospital
🇩🇰Køge, Denmark
VA Western New York Healthcare System
🇺🇸Buffalo, New York, United States
Wake Forest School of Medicine
🇺🇸Winston-Salem, North Carolina, United States
Drexel University College of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
VA North Texas Health Care System Dallas VA Medical Center
🇺🇸Dallas, Texas, United States
Favaloro Foundation
🇦🇷Buenos Aires, Argentina
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Hospital San Roque
🇦🇷Cordoba, Argentina
Westmead Hospital
🇦🇺Westmead, Australia
Grey Nuns Hospital
🇨🇦Edmonton,, Alberta, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
Hospital Barra D'Or
🇧🇷Rio de Janeiro, Brazil
Health Sciences Centre Winnipeg
🇨🇦Winnipeg, Manitoba, Canada
Liberec Regional Hospital
🇨🇿Liberec, Czechia
Nordsjaellands Hospital
🇩🇰Hillerød, Denmark
Hospitalier Pitie Salpetriere
🇫🇷Paris, France
Klinikum der J. W. Goethe-Universität Frankfurt
🇩🇪Frankfurt, Hesse, Germany
Surat Institute of Digestive Sciences
🇮🇳Surat, Gujarat,, India
Universitätsklinikum Bonn
🇩🇪Bonn, Germany
Amrita Institute of Medical Sciences and Research Institute
🇮🇳Kochi, Kerala, India
M.V. Hospital & Research Centre
🇮🇳Lucknow, India
Christian Medical College
🇮🇳Ludhiana, India
Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie
🇵🇱Kraków, Poland
Szpital św. Anny w Miechowie
🇵🇱Miechów, Poland
St. Joseph's Healthcare Hamilton
🇨🇦Hamilton, Ontario, Canada