ENDOvascular Interventions With AngioMAX: The ENDOMAX Trial (ENDOMAX)

The primary objective of the study is to test whether anticoagulation with bivalirudin results in fewer major bleeding complications compared with unfractionated heparin (UFH) in participants undergoing peripheral endovascular interventions (PEI). The secondary objective is to test whether there were potential benefits from bivalirudin therapy on other clinically important events such as death, myocardial infarction (MI), stroke and/or transient ischemic attack (TIA), amputation, unplanned repeat revascularization (URV), and minor bleeding, as well as potential economic benefits that may result from improved clinical outcomes.

Study Overview

• Status: Terminated
• Conditions: Bleeding; Peripheral Endovascular Interventions
• Intervention / Treatment: Drug: Bivalirudin; Drug: Unfractionated Heparin

• Study Type: Interventional
• Enrollment (Actual): 732
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Hot Springs, Arkansas, United States, 71901
      • Tri-Lakes Research
  • California
    • Stanford, California, United States, 94305-5407
      • Stanford Hospital and Clinics
  • Florida
    • Clearwater, Florida, United States, 33756
      • Clearwater Cardiovascular and Interventional Consultants
    • Gainesville, Florida, United States, 32605
      • Florida Research Network
    • Gainesville, Florida, United States, 32605
      • The Cardiac and Vascular Institute
    • Miami, Florida, United States, 33176
      • Baptist Cardiac & Vascular Institute
    • Orlando, Florida, United States, 32803
      • Florida Hospital
  • Illinois
    • Peoria, Illinois, United States, 61637
      • Peoria Radiology Research & Education Foundation
  • Iowa
    • Davenport, Iowa, United States, 52803
      • Midwest Cardiovascular Research Foundation
  • Kentucky
    • Ashland, Kentucky, United States, 41101
      • Kentucky Heart Foundation - King's Daughters Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02132
      • VA Boston Healthcare System
    • Hyannis, Massachusetts, United States, 02601
      • Cape Cod Research Institute
  • Michigan
    • Ypsilanti, Michigan, United States, 48197
      • Michigan Heart
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Browns Mills, New Jersey, United States, 08015
      • Deborah Heart and Lung Center
    • Teaneck, New Jersey, United States, 07666
      • Holy Name Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • New Mexico Heart Institute
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • Stony Brook, New York, United States, 11794
      • Stony Brook Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Heart and Vascular Institute
    • Greensboro, North Carolina, United States, 27401
      • LeBauer Cardiovascular Research Foundation
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Toledo, Ohio, United States, 43606
      • Jobst Vascular Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris - Baptist Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Lubbock, Texas, United States, 79430
      • Texas Tech University Health Science Center
    • Temple, Texas, United States, 76508
      • Scott and White Hospital
  • Utah
    • Ogden, Utah, United States, 84403
      • Alpine Research
  • Virginia
    • Alexandria, Virginia, United States, 22304
      • Inova Alexandria Hospital
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College Of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants ≥ 18 years of age

• Must be undergoing one of the following PEI procedures:

  • Carotid artery stenting
  • Lower Extremity Interventions (LEI) for Critical Limb Ischemia
  • LEI for claudication
• Provide written informed consent prior to any study-specific procedure being performed

Exclusion Criteria:

• Any known contra-indication to the use of bivalirudin or UFH
• Acute limb ischemia
• Planned amputation regardless of the outcome of the PEI
• Dialysis dependent
• Weight less than 38 kg or more than 202 kg
• History of any bleeding diathesis or severe hematological disease
• History of intra-cranial: mass, aneurysm, arteriovenous malformation or hemorrhage
• Gastrointestinal or genitourinary bleeding within the 30 days prior to randomization
• Any surgery (excluding punch or shave skin biopsy) within the 30 days prior to randomization
• Concomitant percutaneous coronary intervention
• Any percutaneous coronary, endovascular, or structural heart disease procedure within 30 days prior to randomization
• International normalized ratio >1.7 within 24 h prior to the index procedure
• Administration of therapeutic doses of UFH within 30 min prior to the index procedure (a low dose [≤2000 U] of heparin is permitted during the diagnostic angiogram prior to the intervention)
• Administration of enoxaparin within 8 h; other low molecular weight heparins or fondaparinux within 24 h; any oral anti-Xa or antithrombin agent within 48 h; or thrombolytics, glycoprotein inhibitors, or warfarin within 72 h prior to the index procedure
• Severe contrast allergy that cannot be pre-medicated
• Procedures performed by radial access when they are intended as the primary access site for the index procedure
• Known or suspected pregnant women or nursing mothers
• Previous enrollment in this study (MDCO-BIV-12-03)
• Participation in other investigational drug or device trials within 30 days prior to randomization
• Participants who, for any reason, are deemed by the investigator to be inappropriate for this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bivalirudin; Bivalirudin was administered as an intravenous (IV) bolus and infusion for the duration of the procedure (mean duration of 48.6 minutes). The bolus (0.75 milligrams (mg)/kilogram [kg]) was administered via systemic IV administration. Immediately after the bolus, an IV infusion of bivalirudin was initiated at a dose of 1.75 mg/kg/hour (h) (or 1 mg/kg/h for participants with an estimated glomerular filtration rate [eGFR] <30 milliliters/minute [mL/min]).	Drug: Bivalirudin; Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.; Other Names: Angiox; AngioMAX
Active Comparator: Unfractionated Heparin; UFH was administered as an IV bolus for the duration of the procedure (mean duration of 48.6 minutes). UFH was administered via weight-based IV bolus at a dose of 50 units (U)/kg to 70 U/kg. Additional bolus doses were administered per standard-of-care use.	Drug: Unfractionated Heparin; Unfractionated heparin is an anticoagulant.; Other Names: Heparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Bleeding Academic Research Consortium Type 3 or Greater (BARC ≥3) Events Up to 48 h or at Hospital Discharge, As Adjudicated by the Independent Clinical Events Committee (CEC)	BARC ≥3 includes: Type 3a-3c: clinical, laboratory, and/or imaging evidence of bleeding, which includes any transfusion with overt bleeding, bleeds that result in surgical intervention or administration of IV vasoactive drugs, overt bleeds with a hemoglobin drop greater than or equal to 3 grams (g)/deciliters (dL) to greater than or equal to 5 g/dL, cardiac tamponade caused by bleeding, intracranial hemorrhage, and intraocular bleeds that compromise vision. Type 4: (Coronary Artery Bypass Grafting-related Bleeding) includes perioperative intracranial bleeding within 48 h, bleeds that result in reoperation following closure of sternotomy for the purpose of controlling bleeding, bleeds that result in treatment with transfusion of ≥5 U of whole blood or packed red blood cells within a 48-h period; and chest tube output ≥2 liters within a 24-h period. Type 5: fatal bleeding that directly results in death that is either clinically suspicious or is confirmed as the cause of death.	Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Myocardial Infarction (MI), Stroke/Transient Ischemic Attack (TIA), Unplanned Repeat Revascularization (URV), Death, and Minor Bleeding Up to 48 h Post Study Drug Administration	Outcome assessments at 48 h post study drug initiation include bleeding events defined as BARC Type 2 or greater (BARC ≥2), bleeding events defined as thrombolysis in myocardial infarction (TIMI) major and TIMI minor, and net adverse clinical events (NACE) as adjudicated by the CEC (NACE=death, MI, stroke/TIA, amputations, URV, or bleeding events defined as BARC ≥3). In addition to Type 3(a-c), 4, and 5, BARC ≥2 also includes Type 2 bleeding, which is any overt, actionable sign of hemorrhage (more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for Type 3, 4, or 5, but does meet at least one of the following criteria of: requiring nonsurgical, medical intervention by a health-care professional; leading to hospitalization or increased level of care; prompting evaluation.	Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first
Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30	Outcome assessments at Day 30 include NACE, Major Adverse Clinical Events (MACE=death, MI, stroke/TIA, amputation, or URV), and bleeding defined as BARC ≥2, as adjudicated by the CEC. In addition to Type 3(a-c), 4, and 5, BARC ≥2 also includes Type 2 bleeding, which is any overt, actionable sign of hemorrhage (more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for Type 3, 4, or 5, but does meet at least one of the following criteria of: requiring nonsurgical, medical intervention by a health-care professional; leading to hospitalization or increased level of care; prompting evaluation.	Study drug initiation (Day 1) up to 30 days

Collaborators and Investigators

• Sponsor: The Medicines Company

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2013
• Primary Completion (Actual): March 16, 2016
• Study Completion (Actual): March 16, 2016

Study Registration Dates

• First Submitted: July 30, 2013
• First Submitted That Met QC Criteria: July 30, 2013
• First Posted (Estimate): August 1, 2013

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 21, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Heparin; Bivalirudin; Calcium heparin
• Other Study ID Numbers: MDCO-BIV-12-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No