ENDOvascular Interventions With AngioMAX: The ENDOMAX Trial

Study Overview
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Brief Summary
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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.

Official Title
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ENDOvascular Interventions With AngioMAX: The ENDOMAX Trial

Conditions
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Peripheral Endovascular Interventions, Bleeding

Intervention / Treatment
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* Drug: Bivalirudin
* Drug: Unfractionated Heparin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bivalirudin<br>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<br>* Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.<br>* Other names: Angiox;|
| Active Comparator: Unfractionated Heparin<br>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<br>* Unfractionated heparin is an anticoagulant.<br>* Other names: Heparin;|

What is the study measuring?
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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 |