Management of Myocardial Injury After Noncardiac Surgery Trial

NCT ID: NCT01661101

Last Updated: 2018-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1754 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2018-03-01

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.

Conditions

Myocardial Injury After Noncardiac Surgery (MINS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Dabigatran

Dabigatran 110 mg capsule taken twice daily

Group Type: EXPERIMENTAL

Dabigatran

Intervention Type: DRUG

Dabigatran 110 mg taken twice daily

Omeprazole

Omeprazole 20 mg capsule taken once daily

Group Type: EXPERIMENTAL

Omeprazole

Intervention Type: DRUG

Omeprazole 20 mg capsule taken once daily

Placebo (dabigatran)

Dabigatran placebo taken twice daily

Group Type: PLACEBO_COMPARATOR

Placebo (for Dabigatran)

Intervention Type: DRUG

Dabigatran placebo taken twice daily

Placebo (omeprazole)

Omeprazole placebo taken once daily

Group Type: PLACEBO_COMPARATOR

Placebo (for Omeprazole)

Intervention Type: DRUG

Omeprazole placebo taken once daily

Interventions

Dabigatran

Dabigatran 110 mg taken twice daily

Intervention Type: DRUG

Placebo (for Dabigatran)

Dabigatran placebo taken twice daily

Intervention Type: DRUG

Omeprazole

Omeprazole 20 mg capsule taken once daily

Intervention Type: DRUG

Placebo (for Omeprazole)

Omeprazole placebo taken once daily

Intervention Type: DRUG

Other Intervention Names

Pradaxa; Prilosec; Zegerid

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Population Health Research Institute

OTHER

Sponsor Role: lead

Responsible Party

P.J. Devereaux

Professor, Medicine (Cardiology) and Clinical Epidemiology and Biostatistics, McMaster University

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

P.J. Devereaux, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Population Health Research Institute

Locations

Kansas University Medical Center

Kansas City, Kansas, United States

VA Western New York Healthcare System

Buffalo, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Wake Forest School of Medicine

Winston-Salem, North Carolina, United States

Oregon Health and Science University

Portland, Oregon, 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

Instituto Cardiovascular de Buenos Aires

Caba, Buenos Aires, Argentina

Clinica Parra - Centro de Investigaciones

Rafaela, Santa Fe Province, Argentina

Sanatorio San Martin

Venado Tuerto, Santa Fe Province, Argentina

Favaloro Foundation

Buenos Aires, , Argentina

Hospital San Roque

Córdoba, , Argentina

Westmead Hospital

Westmead, , Australia

Hospital Maternidade

Poços de Caldas, Minas Gerais, Brazil

Sociendade Hospitalar Angelina Caron

Campina Grande do Sul, Paraná, Brazil

Hospital Lifecenter

Belo Horizonte, , Brazil

Hospital e Maternidade Celso Pierro - PUCCAMP

Campinas, , Brazil

Hospital Barra D'Or

Rio de Janeiro, , Brazil

Hospital de Base

São José do Rio Preto, , Brazil

University of Alberta Hospital

Edmonton, Alberta, Canada

Grey Nuns Hospital

Edmonton, Alberta, Canada

Health Sciences Centre Winnipeg

Winnipeg, Manitoba, Canada

Hamilton General Hospital

Hamilton, Ontario, Canada

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Juravinski Hospital and Cancer Centre

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

Clinica Foscal

Floridablanca, Santander Department, Colombia

Fundacion Cardioinfantil - Instituto de Cardiologia

Bogotá, , Colombia

Liberec Regional Hospital

Liberec, , Czechia

University Hospital Motol

Motol, , Czechia

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, , Denmark

Hospice Civils de Lyon

Pierre-Bénite, Lyon, France

Hospitalier Pitie Salpetriere

Paris, , France

Klinikum der J. W. Goethe-Universität Frankfurt

Frankfurt am Main, Hesse, Germany

Universitätsklinikum Bonn

Bonn, , Germany

Sidhu Hospital

Dorāha, Distt- Ludhiana, India

Surat Institute of Digestive Sciences

Surat, Gujarat, India

Amrita Institute of Medical Sciences and Research Institute

Kochi, Kerala, India

M.S. Ramaiah Medical College & Hospitals

Bangalore, , India

Narayana Hrudayalaya

Bengaluru, , India

M.V. Hospital & Research Centre

Lucknow, , India

Christian Medical College

Ludhiana, , India

Rahate Surgical Hospital

Nagpur, , India

Ramana Maharishi Rangammal Hospital

Tiruvannamalai, , India

Sant'Antonio Hospital

San Daniele del Friuli, Udine, Italy

Azienda Ospedaliera Niguarda Ca'Granda

Milan, , Italy

IRCCS Istituto Ortopedico Galeazzi Milan

Milan, , Italy

IRCCS San Raffaele Scientific Institute

Milan, , Italy

Ospedale San Gerardo

Monza, , Italy

Aga Khan University Hospital - Nairobi

Nairobi, , Kenya

Hospital Nacional Cayetano Heredia

Lima, , Peru

De La Salle University Medical Center

Dasmariñas, , Philippines

Philippines General Hospital

Manila, , Philippines

SPZOZ Szpital Powiatowy w Bochni

Bochnia, , Poland

Spzoz w Brzesku

Brzesko, , Poland

Malopolskie Centrum Medyczne

Krakow, , Poland

OrtoMed sp. Z.o.o.

Krakow, , Poland

Samodzielny Publiczny Zakład Opieki

Krakow, , Poland

Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie

Krakow, , Poland

Szpital św. Anny w Miechowie

Miechów, , Poland

Spzoz w Myslenicach

Myślenice, , Poland

Specjalistyczny Szpital im. E. Szczeklika

Tarnów, , Poland

Zakład Opieki Zdrowotnej im. Jana Pawła II

Włoszczowa, , Poland

University of Kwazulu-Natal

KwaKhangela, KwaZulu-Natal, South Africa

Grey's Hospital

Pietermaritzburg, KwaZulu-Natal, South Africa

University of the Free State

Bloemfontein, , South Africa

University of Cape Town

Cape Town, , South Africa

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, , Spain

Belfast Health and Social Care Trust, Royal Victoria Hospital

Belfast, North Ireland, United Kingdom

Russell Halls Hospital, Dudley Group NHS

Dudley, , United Kingdom

Countries

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

References

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.

Reference Type: BACKGROUND

PMID: 29398173 (View on PubMed)

Lamy A, Tong W, Mian R, Vincent J, Szczeklik W, Biccard BM, Duceppe E, Franzosi MG, Srinathan SK, Meyhoff CS, Parlow J, Xavier D, Devereaux PJ. The Cost Implications of Dabigatran in Patients with Myocardial Injury After Non-Cardiac Surgery. Am J Cardiovasc Drugs. 2022 Jan;22(1):83-91. doi: 10.1007/s40256-021-00489-3. Epub 2021 Jul 26.

Reference Type: DERIVED

PMID: 34308517 (View on PubMed)

Devereaux PJ, Duceppe E, Guyatt G, Tandon V, Rodseth R, Biccard BM, Xavier D, Szczeklik W, Meyhoff CS, Vincent J, Franzosi MG, Srinathan SK, Erb J, Magloire P, Neary J, Rao M, Rahate PV, Chaudhry NK, Mayosi B, de Nadal M, Iglesias PP, Berwanger O, Villar JC, Botto F, Eikelboom JW, Sessler DI, Kearon C, Pettit S, Sharma M, Connolly SJ, Bangdiwala SI, Rao-Melacini P, Hoeft A, Yusuf S; MANAGE Investigators. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet. 2018 Jun 9;391(10137):2325-2334. doi: 10.1016/S0140-6736(18)30832-8.

Reference Type: DERIVED

PMID: 29900874 (View on PubMed)

Other Identifiers

2011-006056-37

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1160.143

Identifier Type: -

Identifier Source: org_study_id