ENDOvascular Interventions With AngioMAX: The ENDOMAX Trial | NCT01913483

Label	Type	Description	Intervention Names
Bivalirudin	Experimental	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
Unfractionated Heparin	Active Comparator	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

Name	Type	Description	Arm Group Labels	Other Names
Bivalirudin	Drug	Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.	Bivalirudin

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Eligibility Module

Eligibility Criteria

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

Facility	Status	City	State	ZIP	Country	Contacts
Tri-Lakes Research		Hot Springs	Arkansas	71901	United States
Stanford Hospital and Clinics

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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 per minute [mL/min]).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

mITT Population: Participants who were randomized into the trial, received at least one dose of study drug, and underwent the index PEI procedure.

Posted

Number

percentage of participants

Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first

ID	Title	Description
OG000	Bivalirudin	Bivalirudin was administered as an IV bolus and infusion for the duration of the procedure (mean duration of 48.6 minutes). The bolus (0.75 mg/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/h (or 1 mg/kg/h for participants with an eGFR <30 mL/min).
OG001	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 U/kg to 70 U/kg. Additional bolus doses were administered per standard-of-care use.

Units	Counts
Participants	OG000335 OG001321

Title

Denominators

Categories

Title	Measurements
	OG0001.5 OG0011.6

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Assuming a bleeding event rate of 5.0% in the heparin control treatment group and 3.2% in the bivalirudin group (36% relative risk reduction, a sample size of 3900 participants was to provide more than 80% power with a two-tailed alpha level of 0.05). This estimate took into consideration that the interim efficacy analysis was to be performed when approximately 70% of participants were enrolled using the O'Brien-Fleming alpha spending function.	Chi-squared		0.9458	The primary endpoint analysis was to assess the superiority of bivalirudin versus UFH in BARC ≥3 bleeds within the 48 hours post study drug initiation or at hospital discharge, whichever occurred first.

Secondary

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.

mITT Population: Participants who were randomized into the trial, received at least one dose of study drug, and underwent the index PEI procedure.

Posted

Number

participants

Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first

ID	Title	Description
OG000	Bivalirudin	Bivalirudin was administered as an IV bolus and infusion for the duration of the procedure (mean duration of 48.6 minutes). The bolus (0.75 mg/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/h (or 1 mg/kg/h for participants with an eGFR <30 mL/min).

Secondary

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.

mITT Population: Participants who were randomized into the trial, received at least one dose of study drug, and underwent the index PEI procedure.

Posted

Number

participants

Study drug initiation (Day 1) up to 30 days

ID	Title	Description
OG000	Bivalirudin	Bivalirudin was administered as an IV bolus and infusion for the duration of the procedure (mean duration of 48.6 minutes). The bolus (0.75 mg/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/h (or 1 mg/kg/h for participants with an eGFR <30 mL/min).
OG001	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 U/kg to 70 U/kg. Additional bolus doses were administered per standard-of-care use.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cellulitis	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0002 affected335 at risk EG0012 affected321 at risk
Urinary tract infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0013 affected321 at risk
Postoperative wound infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0012 affected321 at risk
Sepsis	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0002 affected335 at risk EG0010 affected321 at risk
Groin infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Lobar pneumonia	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Localised infection	Infections and infestations	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Femoral artery dissection	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Femoral artery embolism	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Femoral artery occlusion	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Hypotension	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Peripheral artery dissection	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Peripheral artery stenosis	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Peripheral artery thrombosis	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Peripheral vascular disorder	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0012 affected321 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Compartment syndrome	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Tendon necrosis	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 16.1	Systematic Assessment	EG0002 affected335 at risk EG0011 affected321 at risk
Acute coronary syndrome	Cardiac disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Bradycardia	Cardiac disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Cardiac arrest	Cardiac disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Asthenia	General disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Ischaemic ulcer	General disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Local swelling	General disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Thrombosis in device	General disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Vessel puncture site pain	General disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Renal failure acute	Renal and urinary disorders	MedDRA 16.1	Systematic Assessment	EG0002 affected335 at risk EG0012 affected321 at risk
Urinary retention	Renal and urinary disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Vascular graft thrombosis	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Vascular pseudoaneurysm	Injury, poisoning and procedural complications	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0011 affected321 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Wheezing	Respiratory, thoracic and mediastinal disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Aortic aneurysm	Surgical and medical procedures	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Peripheral artery bypass	Surgical and medical procedures	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Vertigo	Ear and labyrinth disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Retroperitoneal haemorrhage	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Failure to thrive	Metabolism and nutrition disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Invasive ductal breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk
Syncope	Nervous system disorders	MedDRA 16.1	Systematic Assessment	EG0001 affected335 at risk EG0010 affected321 at risk
Mental status change	Psychiatric disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0011 affected321 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Hypertension	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG00015 affected335 at risk EG00113 affected321 at risk
Hypotension	Vascular disorders	MedDRA 16.1	Systematic Assessment	EG00010 affected335 at risk EG00115 affected321 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG00012 affected335 at risk EG00115 affected321 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG00011 affected335 at risk EG0018 affected321 at risk
Groin pain	Musculoskeletal and connective tissue disorders	MedDRA 16.1	Systematic Assessment	EG0006 affected335 at risk EG0011 affected321 at risk
Vessel puncture site pain	General disorders	MedDRA 16.1	Systematic Assessment	EG0009 affected335 at risk EG0015 affected321 at risk
Pain	General disorders	MedDRA 16.1	Systematic Assessment	EG0007 affected335 at risk EG0013 affected321 at risk
Nausea	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0008 affected335 at risk EG0015 affected321 at risk
Vomiting	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0005 affected335 at risk EG0012 affected321 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 16.1	Systematic Assessment	EG0000 affected335 at risk EG0014 affected321 at risk

ID	Term
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D006025	Glycosaminoglycans
D011134	Polysaccharides
D002241	Carbohydrates

ID	Title	Description
BG000	Bivalirudin	Bivalirudin was administered as an IV bolus and infusion for the duration of the procedure (mean duration of 48.6 minutes). The bolus (0.75 mg/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/h (or 1 mg/kg/h for participants with an eGFR <30 mL/min).
BG001	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 U/kg to 70 U/kg. Additional bolus doses were administered per standard-of-care use.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Bivalirudin	Bivalirudin was administered as an IV bolus and infusion for the duration of the procedure (mean duration of 48.6 minutes). The bolus (0.75 mg/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/h (or 1 mg/kg/h for participants with an eGFR <30 mL/min).	13	335	25	335	81	335
EG001	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.	16	321	27	321	70	321