Clinical trial NCT01661101: Management of Myocardial Injury After Noncardiac Surgery Trial
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myocardial Injury After Noncardiac Surgery (MINS)
Keywords: Perioperative myocardial infarction
Myocardial injury
noncardiac surgery
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
First posted: 2012-08-09
Enrollment: 1754
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Major vascular complication (for Dabigatran)
timeFrame: Average of 1 year follow-up
measure: Major upper gastrointestinal complication (for Omeprazole)
timeFrame: Average of 1 year follow-up
Secondary outcomes:
measure: Individual secondary outcomes for Dabigatran
timeFrame: Average of 1 year follow-up
measure: Upper gastrointestinal complication for Omeprazole
timeFrame: Average of 1 year follow-up
measure: Major vascular complication for Omeprazole
timeFrame: Average of 1 year follow-up
measure: Individual secondary outcomes for Omeprazole
timeFrame: Average of 1 year follow-up
measure: Safety outcomes for Dabigatran
timeFrame: Average of 1 year follow-up
measure: Safety outcomes for Omeprazole
timeFrame: Average of 1 year follow-up
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Buffalo
country: United States
facility: VA Western New York Healthcare System
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest School of Medicine
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center
state: Texas
city: Caba
country: Argentina
facility: Instituto Cardiovascular de Buenos Aires
state: Buenos Aires
city: Rafaela
country: Argentina
facility: Clinica Parra - Centro de Investigaciones
state: Santa Fe
city: Venado Tuerto
country: Argentina
facility: Sanatorio San Martin
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Favaloro Foundation
city: Cordoba
country: Argentina
facility: Hospital San Roque
city: Westmead
country: Australia
facility: Westmead Hospital
city: Poços de Caldas
country: Brazil
facility: Hospital Maternidade
state: Minas Gerais
city: Campina Grande do Sul
country: Brazil
facility: Sociendade Hospitalar Angelina Caron
state: Paraná
city: Belo Horizonte
country: Brazil
facility: Hospital Lifecenter
city: Campinas
country: Brazil
facility: Hospital e Maternidade Celso Pierro - PUCCAMP
city: Rio de Janeiro
country: Brazil
facility: Hospital Barra D'Or
city: São José do Rio Preto
country: Brazil
facility: Hospital de Base
city: Edmonton,
country: Canada
facility: Grey Nuns Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Winnipeg
country: Canada
facility: Health Sciences Centre Winnipeg
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Hospital and Cancer Centre
state: Ontario
city: Kingston
country: Canada
facility: Queens University - Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: University Hospital, London Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: Victoria Hospital, London Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire de Montreal - St. Luc Hospital
state: Quebec
city: Montreal
country: Canada
facility: Montreal General Hospital - McGill University Health Centre
state: Quebec
city: Floridablanca
country: Colombia
facility: Clinica Foscal
state: Santander
city: Bogota
country: Colombia
facility: Fundacion Cardioinfantil - Instituto de Cardiologia
city: Liberec
country: Czechia
facility: Liberec Regional Hospital
city: Motol
country: Czechia
facility: University Hospital Motol
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital, University of Copenhagen
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital, Rigshospitalet
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Hillerød
country: Denmark
facility: Nordsjaellands Hospital
city: Køge
country: Denmark
facility: Koege-Roskilde Hospital
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Pierre Benite
country: France
facility: Hospice Civils de Lyon
state: Lyon
city: Paris
country: France
facility: Hospitalier Pitie Salpetriere
city: Frankfurt
country: Germany
facility: Klinikum der J. W. Goethe-Universität Frankfurt
state: Hesse
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Doraha
country: India
facility: Sidhu Hospital
state: Distt- Ludhiana
city: Surat
country: India
facility: Surat Institute of Digestive Sciences
state: Gujarat,
city: Kochi
country: India
facility: Amrita Institute of Medical Sciences and Research Institute
state: Kerala
city: Bangalore
country: India
facility: M.S. Ramaiah Medical College & Hospitals
city: Bengaluru
country: India
facility: Narayana Hrudayalaya
city: Lucknow
country: India
facility: M.V. Hospital & Research Centre
city: Ludhiana
country: India
facility: Christian Medical College
city: Nagpur
country: India
facility: Rahate Surgical Hospital
city: Tiruvannamalai
country: India
facility: Ramana Maharishi Rangammal Hospital
city: San Daniele Del Friuli
country: Italy
facility: Sant'Antonio Hospital
state: Udine
city: Milano
country: Italy
facility: Azienda Ospedaliera Niguarda Ca'Granda
city: Milano
country: Italy
facility: IRCCS Istituto Ortopedico Galeazzi Milan
city: Milano
country: Italy
facility: IRCCS San Raffaele Scientific Institute
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Nairobi
country: Kenya
facility: Aga Khan University Hospital - Nairobi
city: Lima
country: Peru
facility: Hospital Nacional Cayetano Heredia
city: Dasmariñas
country: Philippines
facility: De La Salle University Medical Center
city: Manila
country: Philippines
facility: Philippines General Hospital
city: Bochnia
country: Poland
facility: SPZOZ Szpital Powiatowy w Bochni
city: Brzesko
country: Poland
facility: Spzoz w Brzesku
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne
city: Kraków
country: Poland
facility: OrtoMed sp. Z.o.o.
city: Kraków
country: Poland
facility: Samodzielny Publiczny Zakład Opieki
city: Kraków
country: Poland
facility: Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie
city: Miechów
country: Poland
facility: Szpital św. Anny w Miechowie
city: Myslenice
country: Poland
facility: Spzoz w Myslenicach
city: Tarnow
country: Poland
facility: Specjalistyczny Szpital im. E. Szczeklika
city: Włoszczowa
country: Poland
facility: Zakład Opieki Zdrowotnej im. Jana Pawła II
city: Congella
country: South Africa
facility: University of Kwazulu-Natal
state: Kwazulu-Natal
city: Pietermaritzburg
country: South Africa
facility: Grey's Hospital
state: Kwazulu-Natal
city: Bloemfontein
country: South Africa
facility: University of the Free State
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Barcelona
country: Spain
facility: Bellvitge University Hospital
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universatario Valle Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust, Royal Victoria Hospital
state: North Ireland
city: Dudley
country: United Kingdom
facility: Russell Halls Hospital, Dudley Group NHS
Study officials:
affiliation: Population Health Research Institute
name: P.J. Devereaux, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.