<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01661101</url>
  </required_header>
  <id_info>
    <org_study_id>1160.143</org_study_id>
    <secondary_id>2011-006056-37</secondary_id>
    <nct_id>NCT01661101</nct_id>
  </id_info>
  <brief_title>Management of Myocardial Injury After Noncardiac Surgery Trial</brief_title>
  <acronym>MANAGE</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Population Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Population Health Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients who have myocardial injury after noncardiac surgery are at a higher risk of dying&#xD;
      than those who do not. One in 10 patients with myocardial injury will die within 30 days of&#xD;
      surgery. This risk of death exists up to one year after myocardial injury. There are&#xD;
      currently no treatments or guidelines available for heart injury after surgery, but there is&#xD;
      evidence that taking a blood-thinner can prevent some of the deaths, both in the short and&#xD;
      long-term. The purpose of this trial is to test the effect of two drugs (dabigatran and&#xD;
      omeprazole) that may prevent mortality, major cardiovascular complications and major upper&#xD;
      gastrointestinal bleeding in patients who have had myocardial injury after noncardiac&#xD;
      surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Myocardial injury is the most common major vascular complication after noncardiac surgery.&#xD;
      Worldwide approximately 10 million adults annually suffer a perioperative myocardial injury.&#xD;
      This figure for perioperative myocardial injury represents 15-20% of all cases of myocardial&#xD;
      infarction in all settings. Myocardial injury after noncardiac surgery carries a poor&#xD;
      prognosis and is an independent predictor of 30-day and 1-year mortality.&#xD;
&#xD;
      Myocardial injury after noncardiac surgery (MINS) differs from non-operative myocardial&#xD;
      infarction in two ways; it has a poorer prognosis (patients suffering MINS are 2 times more&#xD;
      likely to die within 30 days compared to non-operative myocardial infarction in the emergency&#xD;
      room) and paradoxically its treatment is less intensive. This difference in the intensity of&#xD;
      treatment is likely influenced by several factors including: (1) a majority of patients&#xD;
      suffering MINS do not experience ischemic symptoms, potentially influencing physicians'&#xD;
      perception of the severity of the event; (2) there is debate as to the pathophysiology of&#xD;
      MINS (although emerging evidence does suggest that coronary arterial thrombosis is an&#xD;
      important mechanism of MINS); and (3) no randomized controlled trial (RCT) has evaluated an&#xD;
      intervention to manage MINS, and hence physicians are uncertain about the risk-benefit ratio&#xD;
      of potential interventions (e.g., interventions that are effective in the management of&#xD;
      non-operative myocardial infarction). From a human and economic perspective, it is a tragedy&#xD;
      that some patients undergoing noncardiac surgery for important reasons (e.g., to obtain a&#xD;
      cure of their cancer or to become mobile after a new prosthetic joint) fail to obtain these&#xD;
      benefits, because they suffer MINS that ultimately takes their life. There is an urgent need&#xD;
      for clinical trials to identify effective therapies to improve the outcomes of patients&#xD;
      suffering MINS.&#xD;
&#xD;
      There exists promising laboratory, autopsy, imaging, operative, and non-operative data&#xD;
      suggesting that patients suffering MINS will benefit from anticoagulant therapy. Dabigatran&#xD;
      (a direct thrombin inhibitor) warrants evaluation in the management of MINS. The major&#xD;
      limitation of anticoagulation therapy is bleeding, and gastrointestinal bleeding represents a&#xD;
      substantial proportion of these complications. Gastrointestinal bleeding is important in its&#xD;
      own right, but also because it leads to cessation of anticoagulant therapy which may lead to&#xD;
      breakthrough myocardial infarction. Omeprazole (a proton pump inhibitor) is efficacious in&#xD;
      preventing upper gastrointestinal bleeding in patients with coronary artery disease who are&#xD;
      taking dual antiplatelet therapy, and may benefit patients receiving anticoagulation therapy&#xD;
      after suffering MINS.&#xD;
&#xD;
      We will undertake a large international RCT to determine the impact of dabigatran in patients&#xD;
      who have suffered MINS. We will use a partial factorial design (for patients not taking a&#xD;
      proton pump inhibitor) to determine the impact of omeprazole in this setting. We call this&#xD;
      RCT the Management of myocardial injury After NoncArdiac surGEry (MANAGE) Trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2013</start_date>
  <completion_date type="Actual">March 1, 2018</completion_date>
  <primary_completion_date type="Actual">March 1, 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Major vascular complication (for Dabigatran)</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>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).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Major upper gastrointestinal complication (for Omeprazole)</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>A composite of the number of patients suffering overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Individual secondary outcomes for Dabigatran</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Upper gastrointestinal complication for Omeprazole</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major vascular complication for Omeprazole</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Individual secondary outcomes for Omeprazole</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety outcomes for Dabigatran</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>A composite of the number of patients suffering life-threatening bleeding, major bleeding, and critical organ bleeding (i.e., intracranial, intraocular, intraspinal, pericardial, retroperitoneal).&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety outcomes for Omeprazole</measure>
    <time_frame>Average of 1 year follow-up</time_frame>
    <description>The number of patients suffering Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">1754</enrollment>
  <condition>Myocardial Injury After Noncardiac Surgery (MINS)</condition>
  <arm_group>
    <arm_group_label>Dabigatran</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dabigatran 110 mg capsule taken twice daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Omeprazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Omeprazole 20 mg capsule taken once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (dabigatran)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Dabigatran placebo taken twice daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (omeprazole)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Omeprazole placebo taken once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabigatran</intervention_name>
    <description>Dabigatran 110 mg taken twice daily</description>
    <arm_group_label>Dabigatran</arm_group_label>
    <other_name>Pradaxa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo (for Dabigatran)</intervention_name>
    <description>Dabigatran placebo taken twice daily</description>
    <arm_group_label>Placebo (dabigatran)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Omeprazole</intervention_name>
    <description>Omeprazole 20 mg capsule taken once daily</description>
    <arm_group_label>Omeprazole</arm_group_label>
    <other_name>Prilosec</other_name>
    <other_name>Zegerid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo (for Omeprazole)</intervention_name>
    <description>Omeprazole placebo taken once daily</description>
    <arm_group_label>Placebo (omeprazole)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients are eligible if they:&#xD;
&#xD;
          1. have undergone noncardiac surgery;&#xD;
&#xD;
          2. are ≥45 years of age;&#xD;
&#xD;
          3. have suffered MINS based upon fulfilling one of the following criteria: A. Elevated&#xD;
             troponin or CK-MB measurement with one or more of the following defining features i.&#xD;
             ischemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; shortness of&#xD;
             breath, pulmonary edema); ii. development of pathologic Q waves present in any two&#xD;
             contiguous leads that are ≥30 milliseconds; iii. electrocardiogram (ECG) changes&#xD;
             indicative of ischemia (i.e., ST segment elevation [≥2 mm in leads V1, V2, or V3 OR ≥1&#xD;
             mm in the other leads], ST segment depression [≥1 mm], OR symmetric inversion of T&#xD;
             waves ≥1 mm) in at least two contiguous leads; iv. new LBBB; or v. new or presumed new&#xD;
             cardiac wall motion abnormality on echocardiography or new or presumed new fixed&#xD;
             defect on radionuclide imaging B. Elevated troponin measurement after surgery with no&#xD;
             alternative explanation (e.g., pulmonary embolism, sepsis) to myocardial injury; AND&#xD;
&#xD;
          4. provide written informed consent to participate within 35 days of suffering their&#xD;
             MINS.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients meeting any of the following criteria will be excluded:&#xD;
&#xD;
          1. hypersensitivity or known allergy to dabigatran;&#xD;
&#xD;
          2. history of intracranial, intraocular, or spinal bleeding;&#xD;
&#xD;
          3. hemorrhagic disorder or bleeding diathesis;&#xD;
&#xD;
          4. known hepatic impairment or liver disease expected to have an impact on survival;&#xD;
&#xD;
          5. condition that requires therapeutic dose anticoagulation (e.g., prosthetic heart&#xD;
             valve, venous thromboembolism, atrial fibrillation);&#xD;
&#xD;
          6. currently using or plan to initiate rifampicin, cyclosporine, itraconazole,&#xD;
             tacrolimus, ketoconazole, or dronedarone;&#xD;
&#xD;
          7. women who are pregnant, breastfeeding, or of childbearing potential who refuse to use&#xD;
             a medically acceptable form of contraception throughout the study;&#xD;
&#xD;
          8. investigator considers the patient unreliable regarding requirement for study&#xD;
             follow-up or study drug compliance; OR&#xD;
&#xD;
          9. previously enrolled in the MANAGE Trial.&#xD;
&#xD;
        Also excluded will be patients in whom any of the following criteria persist beyond 35 days&#xD;
        of their suffering MINS:&#xD;
&#xD;
          1. the attending surgeon believes it is not safe to initiate therapeutic dose&#xD;
             anticoagulation therapy;&#xD;
&#xD;
          2. the attending physician believes ASA, intermittent pneumatic compression, or elastic&#xD;
             stockings are not sufficient for venous thromboembolism (VTE) prophylaxis and that the&#xD;
             patient requires a prophylactic-dose anticoagulant;&#xD;
&#xD;
          3. the patient has an indwelling epidural or spinal catheter that cannot be removed, or&#xD;
             the first dose of dabigatran will occur within 4 hours of epidural catheter removal;&#xD;
             OR&#xD;
&#xD;
          4. estimated glomerular filtration rate (eGFR) &lt;35 ml/min as estimated by calculated&#xD;
             creatinine clearance.&#xD;
&#xD;
          5. it is expected that the patient will undergo cardiac catheterization for MINS.&#xD;
&#xD;
        Exclusion Criteria Specific to Patients in the Omeprazole Factorial Component of the Trial:&#xD;
&#xD;
        Patients meeting any of the following criteria:&#xD;
&#xD;
          1. hypersensitivity or known allergy to omeprazole;&#xD;
&#xD;
          2. requirement for a proton pump inhibitor, an H2-receptor antagonist, sucralfate,&#xD;
             atazanavir, clopidogrel, or misoprostol;&#xD;
&#xD;
          3. esophageal or gastric variceal disease; OR&#xD;
&#xD;
          4. patient declines participation in the omeprazole arm of MANAGE.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>P.J. Devereaux, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Population Health Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kansas University Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Western New York Healthcare System</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester Medical Center</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wake Forest School of Medicine</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health and Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Drexel University College of Medicine</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA North Texas Health Care System Dallas VA Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Cardiovascular de Buenos Aires</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>1428</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica Parra - Centro de Investigaciones</name>
      <address>
        <city>Rafaela</city>
        <state>Santa Fe</state>
        <zip>S2300MMA</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sanatorio San Martin</name>
      <address>
        <city>Venado Tuerto</city>
        <state>Santa Fe</state>
        <zip>2600</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Favaloro Foundation</name>
      <address>
        <city>Buenos Aires</city>
        <zip>C1093AAS</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital San Roque</name>
      <address>
        <city>Cordoba</city>
        <zip>5000</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Westmead Hospital</name>
      <address>
        <city>Westmead</city>
        <zip>2145</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Maternidade</name>
      <address>
        <city>Poços de Caldas</city>
        <state>Minas Gerais</state>
        <zip>50761160</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sociendade Hospitalar Angelina Caron</name>
      <address>
        <city>Campina Grande do Sul</city>
        <state>Paraná</state>
        <zip>83430</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Lifecenter</name>
      <address>
        <city>Belo Horizonte</city>
        <zip>30110-921</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital e Maternidade Celso Pierro - PUCCAMP</name>
      <address>
        <city>Campinas</city>
        <zip>13060-904</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Barra D'Or</name>
      <address>
        <city>Rio de Janeiro</city>
        <zip>22775-002</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de Base</name>
      <address>
        <city>São José do Rio Preto</city>
        <zip>15090-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Grey Nuns Hospital</name>
      <address>
        <city>Edmonton,</city>
        <state>Alberta</state>
        <zip>T6R 3G8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Alberta Hospital</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2P4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Health Sciences Centre Winnipeg</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <zip>R3A1R9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hamilton General Hospital</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8L 2X2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph's Healthcare Hamilton</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8N 4A6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Juravinski Hospital and Cancer Centre</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8V 4X2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queens University - Kingston General Hospital</name>
      <address>
        <city>Kingston</city>
        <state>Ontario</state>
        <zip>K7K2V7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital, London Health Sciences Centre</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5A5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Victoria Hospital, London Health Sciences Centre</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6O 5R1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Montreal - St. Luc Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2X3J4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montreal General Hospital - McGill University Health Centre</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3G1A4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica Foscal</name>
      <address>
        <city>Floridablanca</city>
        <state>Santander</state>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fundacion Cardioinfantil - Instituto de Cardiologia</name>
      <address>
        <city>Bogota</city>
        <country>Colombia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Liberec Regional Hospital</name>
      <address>
        <city>Liberec</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Motol</name>
      <address>
        <city>Motol</city>
        <zip>150 06</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bispebjerg Hospital, University of Copenhagen</name>
      <address>
        <city>Copenhagen</city>
        <zip>2400</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Copenhagen University Hospital, Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Herlev Hospital</name>
      <address>
        <city>Herlev</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nordsjaellands Hospital</name>
      <address>
        <city>Hillerød</city>
        <zip>3400</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Koege-Roskilde Hospital</name>
      <address>
        <city>Køge</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vejle Hospital</name>
      <address>
        <city>Vejle</city>
        <zip>7100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospice Civils de Lyon</name>
      <address>
        <city>Pierre Benite</city>
        <state>Lyon</state>
        <zip>69495</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospitalier Pitie Salpetriere</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum der J. W. Goethe-Universität Frankfurt</name>
      <address>
        <city>Frankfurt</city>
        <state>Hesse</state>
        <zip>60596</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Bonn</name>
      <address>
        <city>Bonn</city>
        <zip>53105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sidhu Hospital</name>
      <address>
        <city>Doraha</city>
        <state>Distt- Ludhiana</state>
        <zip>141421</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Surat Institute of Digestive Sciences</name>
      <address>
        <city>Surat</city>
        <state>Gujarat,</state>
        <zip>395002</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amrita Institute of Medical Sciences and Research Institute</name>
      <address>
        <city>Kochi</city>
        <state>Kerala</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>M.S. Ramaiah Medical College &amp; Hospitals</name>
      <address>
        <city>Bangalore</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Narayana Hrudayalaya</name>
      <address>
        <city>Bengaluru</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>M.V. Hospital &amp; Research Centre</name>
      <address>
        <city>Lucknow</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Christian Medical College</name>
      <address>
        <city>Ludhiana</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rahate Surgical Hospital</name>
      <address>
        <city>Nagpur</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ramana Maharishi Rangammal Hospital</name>
      <address>
        <city>Tiruvannamalai</city>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sant'Antonio Hospital</name>
      <address>
        <city>San Daniele Del Friuli</city>
        <state>Udine</state>
        <zip>33038</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Niguarda Ca'Granda</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Istituto Ortopedico Galeazzi Milan</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS San Raffaele Scientific Institute</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale San Gerardo</name>
      <address>
        <city>Monza</city>
        <zip>20900</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Aga Khan University Hospital - Nairobi</name>
      <address>
        <city>Nairobi</city>
        <zip>00508</zip>
        <country>Kenya</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Nacional Cayetano Heredia</name>
      <address>
        <city>Lima</city>
        <country>Peru</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>De La Salle University Medical Center</name>
      <address>
        <city>Dasmariñas</city>
        <zip>4114</zip>
        <country>Philippines</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Philippines General Hospital</name>
      <address>
        <city>Manila</city>
        <zip>1000</zip>
        <country>Philippines</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SPZOZ Szpital Powiatowy w Bochni</name>
      <address>
        <city>Bochnia</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spzoz w Brzesku</name>
      <address>
        <city>Brzesko</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Malopolskie Centrum Medyczne</name>
      <address>
        <city>Krakow</city>
        <zip>30-510</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>OrtoMed sp. Z.o.o.</name>
      <address>
        <city>Kraków</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Samodzielny Publiczny Zakład Opieki</name>
      <address>
        <city>Kraków</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie</name>
      <address>
        <city>Kraków</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Szpital św. Anny w Miechowie</name>
      <address>
        <city>Miechów</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Spzoz w Myslenicach</name>
      <address>
        <city>Myslenice</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Specjalistyczny Szpital im. E. Szczeklika</name>
      <address>
        <city>Tarnow</city>
        <zip>33-100</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Zakład Opieki Zdrowotnej im. Jana Pawła II</name>
      <address>
        <city>Włoszczowa</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kwazulu-Natal</name>
      <address>
        <city>Congella</city>
        <state>Kwazulu-Natal</state>
        <zip>4013</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Grey's Hospital</name>
      <address>
        <city>Pietermaritzburg</city>
        <state>Kwazulu-Natal</state>
        <zip>3200</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of the Free State</name>
      <address>
        <city>Bloemfontein</city>
        <zip>9300</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Cape Town</name>
      <address>
        <city>Cape Town</city>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bellvitge University Hospital</name>
      <address>
        <city>Barcelona</city>
        <zip>08907</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de la Santa Creu I Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>8025</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universatario Valle Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>8035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramon y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Belfast Health and Social Care Trust, Royal Victoria Hospital</name>
      <address>
        <city>Belfast</city>
        <state>North Ireland</state>
        <zip>BT12 6BA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Russell Halls Hospital, Dudley Group NHS</name>
      <address>
        <city>Dudley</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Australia</country>
    <country>Brazil</country>
    <country>Canada</country>
    <country>Colombia</country>
    <country>Czechia</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Germany</country>
    <country>India</country>
    <country>Italy</country>
    <country>Kenya</country>
    <country>Peru</country>
    <country>Philippines</country>
    <country>Poland</country>
    <country>South Africa</country>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Austria</country>
    <country>Czech Republic</country>
    <country>Israel</country>
    <country>Nigeria</country>
  </removed_countries>
  <reference>
    <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>
    <PMID>29398173</PMID>
  </reference>
  <verification_date>March 2018</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <last_update_submitted>March 22, 2018</last_update_submitted>
  <last_update_submitted_qc>March 22, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 26, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Population Health Research Institute</investigator_affiliation>
    <investigator_full_name>P.J. Devereaux</investigator_full_name>
    <investigator_title>Professor, Medicine (Cardiology) and Clinical Epidemiology and Biostatistics, McMaster University</investigator_title>
  </responsible_party>
  <keyword>Perioperative myocardial infarction</keyword>
  <keyword>Myocardial injury</keyword>
  <keyword>noncardiac surgery</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Omeprazole</mesh_term>
    <mesh_term>Dabigatran</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01661101
org study id: 1160.143
secondary id: 2011-006056-37
nct id: NCT01661101
lead sponsor: 
has dmc: Yes
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.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Major vascular complication (for Dabigatran)
time frame: Average of 1 year follow-up
description: 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).
measure: Major upper gastrointestinal complication (for Omeprazole)
time frame: Average of 1 year follow-up
description: A composite of the number of patients suffering overt gastroduodenal bleeding, overt upper gastrointestinal bleeding of unknown origin, or upper gastrointestinal perforation.
measure: Individual secondary outcomes for Dabigatran
time frame: Average of 1 year follow-up
description: 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.
measure: Upper gastrointestinal complication for Omeprazole
time frame: Average of 1 year follow-up
description: 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.
measure: Major vascular complication for Omeprazole
time frame: Average of 1 year follow-up
description: 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).
measure: Individual secondary outcomes for Omeprazole
time frame: Average of 1 year follow-up
description: 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.
measure: Safety outcomes for Dabigatran
time frame: Average of 1 year follow-up
description: 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.
measure: Safety outcomes for Omeprazole
time frame: Average of 1 year follow-up
description: The number of patients suffering Clostridium difficile-associated diarrhea, diarrhea, community-acquired pneumonia, and fractures.
arm group label: Dabigatran
arm group type: Experimental
description: Dabigatran 110 mg capsule taken twice daily
arm group label: Omeprazole
arm group type: Experimental
description: Omeprazole 20 mg capsule taken once daily
arm group label: Placebo (dabigatran)
arm group type: Placebo Comparator
description: Dabigatran placebo taken twice daily
arm group label: Placebo (omeprazole)
arm group type: Placebo Comparator
description: Omeprazole placebo taken once daily
intervention type: Drug
intervention name: Dabigatran
description: Dabigatran 110 mg taken twice daily
arm group label: Dabigatran
other name: Pradaxa
intervention type: Drug
intervention name: Placebo (for Dabigatran)
description: Dabigatran placebo taken twice daily
arm group label: Placebo (dabigatran)
intervention type: Drug
intervention name: Omeprazole
description: Omeprazole 20 mg capsule taken once daily
arm group label: Omeprazole
other name: Prilosec
other name: Zegerid
intervention type: Drug
intervention name: Placebo (for Omeprazole)
description: Omeprazole placebo taken once daily
arm group label: Placebo (omeprazole)
criteria: 
gender: All
minimum age: 45 Years
maximum age: N/A
healthy volunteers: No
last name: P.J. Devereaux, MD, PhD
role: Principal Investigator
affiliation: Population Health Research Institute
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country: Argentina
country: Australia
country: Brazil
country: Canada
country: Colombia
country: Czechia
country: Denmark
country: France
country: Germany
country: India
country: Italy
country: Kenya
country: Peru
country: Philippines
country: Poland
country: South Africa
country: Spain
country: United Kingdom
country: United States
country: Austria
country: Czech Republic
country: Israel
country: Nigeria
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.
PMID: 29398173
responsible party type: Principal Investigator
investigator affiliation: Population Health Research Institute
investigator full name: P.J. Devereaux
investigator title: Professor, Medicine (Cardiology) and Clinical Epidemiology and Biostatistics, McMaster University
mesh term: Wounds and Injuries
mesh term: Omeprazole
mesh term: Dabigatran