Bleeding, Peripheral Endovascular Interventions
Conditions
Brief summary
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.
Interventions
DRUGBivalirudin
Bivalirudin is an anticoagulant that binds directly to thrombin in a bivalent and reversible fashion.
DRUGUnfractionated Heparin
Unfractionated heparin is an anticoagulant.
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first | 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. |
| Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Study drug initiation (Day 1) up to 30 days | 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. |
Countries
United States
Participant flow
Pre-assignment details
Participants who were randomized into the trial, who received at least one dose of study drug (Safety Population), and underwent the index peripheral endovascular interventions (PEI) procedure were included in the modified Intent-to-Treat (mITT) Population. This was the primary population for analyses of the primary and secondary endpoints.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 335 |
| 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. | 321 |
| Total | 656 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 14 | 17 |
| Overall Study | Lost to Follow-up | 6 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Bivalirudin | Total | Unfractionated Heparin |
|---|---|---|---|
| Age, Continuous | 69.3 Years STANDARD_DEVIATION 10.3 | 69.0 Years STANDARD_DEVIATION 10.3 | 68.8 Years STANDARD_DEVIATION 10.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 49 Participants | 89 Participants | 40 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 282 Participants | 560 Participants | 278 Participants |
| Region of Enrollment United States | 335 participants | 656 participants | 321 participants |
| Sex: Female, Male Female | 133 Participants | 256 Participants | 123 Participants |
| Sex: Female, Male Male | 202 Participants | 400 Participants | 198 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 335 | 16 / 321 |
| other Total, other adverse events | 81 / 335 | 70 / 321 |
| serious Total, serious adverse events | 25 / 335 | 27 / 321 |
Outcome results
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.
Time frame: Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first
Population: mITT Population: Participants who were randomized into the trial, received at least one dose of study drug, and underwent the index PEI procedure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bivalirudin | 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) | 1.5 percentage of participants |
| Unfractionated Heparin | 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) | 1.6 percentage of participants |
Comparison: 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.p-value: 0.9458Chi-squared
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. 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.
Time frame: Study drug initiation (Day 1) up to 30 days
Population: mITT Population: Participants who were randomized into the trial, received at least one dose of study drug, and underwent the index PEI procedure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Bleed (BARC ≥ Type 3) | 6 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Amputation | 8 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | MI | 0 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | URV | 9 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Death | 2 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | MACE (Death/MI/Stroke/Amputation/URV) | 18 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Stroke/TIA | 1 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | NACE | 22 participants |
| Bivalirudin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Bleed (BARC ≥ Type 2) | 53 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | NACE | 23 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Bleed (BARC ≥ Type 2) | 51 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Bleed (BARC ≥ Type 3) | 7 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Death | 3 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | MI | 1 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Stroke/TIA | 2 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | Amputation | 5 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | URV | 11 participants |
| Unfractionated Heparin | Participants With MI, Stroke/TIA, URV, Death, or Minor Bleeding Up to Day 30 | MACE (Death/MI/Stroke/Amputation/URV) | 19 participants |
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.
Time frame: Study drug administration (Day 1) up to 48 h post study drug initiation or at hospital discharge, whichever occurs first
Population: mITT Population: Participants who were randomized into the trial, received at least one dose of study drug, and underwent the index PEI procedure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bivalirudin | 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 | TIMI major | 0 participants |
| Bivalirudin | 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 | Stroke/TIA | 0 participants |
| Bivalirudin | 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 | Death | 0 participants |
| Bivalirudin | 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 | Amputation | 0 participants |
| Bivalirudin | 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 | TIMI minor | 4 participants |
| Bivalirudin | 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 | URV | 2 participants |
| Bivalirudin | 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 | MI | 0 participants |
| Bivalirudin | 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 | NACE | 7 participants |
| Bivalirudin | 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 | Bleed (BARC ≥ Type 2) | 47 participants |
| Unfractionated Heparin | 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 | NACE | 6 participants |
| Unfractionated Heparin | 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 | Bleed (BARC ≥ Type 2) | 42 participants |
| Unfractionated Heparin | 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 | TIMI major | 4 participants |
| Unfractionated Heparin | 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 | TIMI minor | 1 participants |
| Unfractionated Heparin | 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 | Death | 1 participants |
| Unfractionated Heparin | 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 | MI | 0 participants |
| Unfractionated Heparin | 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 | Stroke/TIA | 0 participants |
| Unfractionated Heparin | 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 | Amputation | 0 participants |
| Unfractionated Heparin | 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 | URV | 2 participants |