Management of Myocardial Injury After Noncardiac Surgery Trial

Myocardial Injury After Noncardiac Surgery (MINS) Clinical Trial

— MANAGE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01661101
• Other study ID #: 1160.143
• Secondary ID: 2011-006056-37
• Status: Completed
• Phase: Phase 3
• First received: August 7, 2012
• Last updated: March 22, 2018
• Start date: January 2013
• Est. completion date: March 1, 2018

Study information

• Verified date: March 2018
• Source: Population Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 1754
• Est. completion date: March 1, 2018
• Est. primary completion date: March 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myocardial Injury After Noncardiac Surgery (MINS)
• Wounds and Injuries

Intervention

Drug:
• Dabigatran
Dabigatran 110 mg taken twice daily
• Placebo (for Dabigatran)
Dabigatran placebo taken twice daily
• Omeprazole
Omeprazole 20 mg capsule taken once daily
• Placebo (for Omeprazole)
Omeprazole placebo taken once daily

Locations

Country	Name	City	State
Argentina	Favaloro Foundation	Buenos Aires
Argentina	Instituto Cardiovascular de Buenos Aires	Caba	Buenos Aires
Argentina	Hospital San Roque	Cordoba
Argentina	Clinica Parra - Centro de Investigaciones	Rafaela	Santa Fe
Argentina	Sanatorio San Martin	Venado Tuerto	Santa Fe
Australia	Westmead Hospital	Westmead
Brazil	Hospital Lifecenter	Belo Horizonte
Brazil	Sociendade Hospitalar Angelina Caron	Campina Grande do Sul	Paraná
Brazil	Hospital e Maternidade Celso Pierro - PUCCAMP	Campinas
Brazil	Hospital Maternidade	Poços de Caldas	Minas Gerais
Brazil	Hospital Barra D'Or	Rio de Janeiro
Brazil	Hospital de Base	São José do Rio Preto
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Grey Nuns Hospital	Edmonton,	Alberta
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	Juravinski Hospital and Cancer Centre	Hamilton	Ontario
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Canada	Queens University - Kingston General Hospital	Kingston	Ontario
Canada	University Hospital, London Health Sciences Centre	London	Ontario
Canada	Victoria Hospital, London Health Sciences Centre	London	Ontario
Canada	Centre Hospitalier Universitaire de Montreal - St. Luc Hospital	Montreal	Quebec
Canada	Montreal General Hospital - McGill University Health Centre	Montreal	Quebec
Canada	Health Sciences Centre Winnipeg	Winnipeg	Manitoba
Colombia	Fundacion Cardioinfantil - Instituto de Cardiologia	Bogota
Colombia	Clinica Foscal	Floridablanca	Santander
Czechia	Liberec Regional Hospital	Liberec
Czechia	University Hospital Motol	Motol
Denmark	Bispebjerg Hospital, University of Copenhagen	Copenhagen
Denmark	Copenhagen University Hospital, Rigshospitalet	Copenhagen
Denmark	Herlev Hospital	Herlev
Denmark	Nordsjaellands Hospital	Hillerød
Denmark	Koege-Roskilde Hospital	Køge
Denmark	Vejle Hospital	Vejle
France	Hospitalier Pitie Salpetriere	Paris
France	Hospice Civils de Lyon	Pierre Benite	Lyon
Germany	Universitätsklinikum Bonn	Bonn
Germany	Klinikum der J. W. Goethe-Universität Frankfurt	Frankfurt	Hesse
India	M.S. Ramaiah Medical College & Hospitals	Bangalore
India	Narayana Hrudayalaya	Bengaluru
India	Sidhu Hospital	Doraha	Distt- Ludhiana
India	Amrita Institute of Medical Sciences and Research Institute	Kochi	Kerala
India	M.V. Hospital & Research Centre	Lucknow
India	Christian Medical College	Ludhiana
India	Rahate Surgical Hospital	Nagpur
India	Surat Institute of Digestive Sciences	Surat	Gujarat,
India	Ramana Maharishi Rangammal Hospital	Tiruvannamalai
Italy	Azienda Ospedaliera Niguarda Ca'Granda	Milano
Italy	IRCCS Istituto Ortopedico Galeazzi Milan	Milano
Italy	IRCCS San Raffaele Scientific Institute	Milano
Italy	Ospedale San Gerardo	Monza
Italy	Sant'Antonio Hospital	San Daniele Del Friuli	Udine
Kenya	Aga Khan University Hospital - Nairobi	Nairobi
Peru	Hospital Nacional Cayetano Heredia	Lima
Philippines	De La Salle University Medical Center	Dasmariñas
Philippines	Philippines General Hospital	Manila
Poland	SPZOZ Szpital Powiatowy w Bochni	Bochnia
Poland	Spzoz w Brzesku	Brzesko
Poland	Malopolskie Centrum Medyczne	Krakow
Poland	OrtoMed sp. Z.o.o.	Kraków
Poland	Samodzielny Publiczny Zaklad Opieki	Kraków
Poland	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie	Kraków
Poland	Szpital sw. Anny w Miechowie	Miechów
Poland	Spzoz w Myslenicach	Myslenice
Poland	Specjalistyczny Szpital im. E. Szczeklika	Tarnow
Poland	Zaklad Opieki Zdrowotnej im. Jana Pawla II	Wloszczowa
South Africa	University of the Free State	Bloemfontein
South Africa	University of Cape Town	Cape Town
South Africa	University of Kwazulu-Natal	Congella	Kwazulu-Natal
South Africa	Grey's Hospital	Pietermaritzburg	Kwazulu-Natal
Spain	Bellvitge University Hospital	Barcelona
Spain	Hospital de la Santa Creu I Sant Pau	Barcelona
Spain	Hospital Universatario Valle Hebron	Barcelona
Spain	Hospital Universitario Ramon y Cajal	Madrid
United Kingdom	Belfast Health and Social Care Trust, Royal Victoria Hospital	Belfast	North Ireland
United Kingdom	Russell Halls Hospital, Dudley Group NHS	Dudley
United States	VA Western New York Healthcare System	Buffalo	New York
United States	VA North Texas Health Care System Dallas VA Medical Center	Dallas	Texas
United States	Kansas University Medical Center	Kansas City	Kansas
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	University of Rochester Medical Center	Rochester	New York
United States	Wake Forest School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Population Health Research Institute

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Colombia,  Czechia,  Denmark,  France,  Germany,  India,  Italy,  Kenya,  Peru,  Philippines,  Poland,  South Africa,  Spain,  United Kingdom, 

References & Publications (1)

Duceppe E, Yusuf S, Tandon V, Rodseth R, Biccard BM, Xavier D, Szczeklik W, Meyhoff CS, Franzosi MG, Vincent J, Srinathan SK, Parlow J, Magloire P, Neary J, Rao M, Chaudhry NK, Mayosi B, de Nadal M, Popova E, Villar JC, Botto F, Berwanger O, Guyatt G, Eikelboom JW, Sessler DI, Kearon C, Pettit S, Connolly SJ, Sharma M, Bangdiwala SI, Devereaux PJ. Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE). Can J Cardiol. 2018 Mar;34(3):295-302. doi: 10.1016/j.cjca.2018.01.020. Epub 2018 Feb 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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