Bivalirudin Clinical Trials

This section of the website contains information about various clinical trials sponsored by The Medicines Company (MDCO).  This information may contain uses for bivalirudin that have not been approved by the FDA.  This site is not intended to promote such uses, but is offered to provide additional information about ongoing and completed studies for bivalirudin.  Please note that the safety and efficacy of bivalirudin for the uses discussed in these clinical trials have not been established.  We refer you to the product’s complete prescribing information for information regarding safety and efficacy, including proper dosing. Additionally, to learn more about the regulatory status on each of these clinical trials please review our annual report on Form 10-K.

The Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial

Bivalirudin in the Management of Patients with ST-Segment Elevation Acute Myocardial Infarction Undergoing Primary PCI (BIAMI)

Harmonizing Outcomes with RevascularIZatiON and Stents (HORIZONS)

Percutaneous Peripheral Intervention Angiomax Peripheral Procedure Registry of Vascular Events (APPROVE) trial

Cardiac Surgery

EVOLUTION-ON Pump Trial (Non-HIT/HITTS Patients)

CHOOSE-ON Pump Trial (In Patients with or at risk of HIT/HITTS)

EVOLUTION-OFF Pump Trial (Non-HIT/HITTS Patients)

CHOOSE-OFF Pump Trial (In Patients with or at risk of HIT/HITTS)

Acute Coronary Syndromes

The Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial1 studied the use of in patients with acute coronary syndromes (ACS) prior to PCI.1

ACUITY is powered to answer two separate questions:

1. Bivalirudin with routine glycoprotein (GP) IIb/IIIa (whether upstream or for percutaneous coronary intervention [PCI]), compared with a heparin (either unfractionated heparin [UFH] or enoxaparin) with routine GP IIb/IIIa, provides either noninferior or superior 30-day clinical outcomes (death, myocardial infarction [MI], unplanned revascularization for ischemia, plus major bleeding) and
2. Bivalirudin alone (with provisional GP IIb/IIIa) reduces major bleeding compared with heparin (either UFH or enoxaparin) with routine GP IIb/IIIa.

The ACUITY trial was performed at 450 centers in a total of 17 countries and enrolled 13,819 moderate- to high-risk ACS patients randomized to 1 of the following 3 treatment groups:

• Unfractionated heparin or low-molecular-weight heparin (LMWH) plus GP IIb/IIIa (Group A)
• Bivalirudin plus GP IIb/IIIa (Group B)
• Bivalirudin alone with “bailout” GP IIb/IIIa (Group C)

Clinical End Points

• Composite net clinical benefit end point: Occurrence of either death, MI, unplanned revascularization for ischemia or clinically significant bleeding (ACUITY scale)
• Clinically significant bleeding (ACUITY scale)

Clinical Outcomes

• The composite net clinical benefit (composite incidence of 30-day death, MI, unplanned revascularization for ischemia and non–coronary artery bypass graft [CABG] major bleeding) end point occurred in 10.1% of patients in the bivalirudin alone Group (C) compared to 11.7% of patients in the heparin plus GP IIb/IIIa Group (A) (PNI <.0001; Psup =.015). The composite net clinical benefit end point occurred in 11.8% of patients in group B, bivalirudin plus GP IIb/IIIa, (PNI <.0001; Psup =.93).1
• The incidence of ACUITY-scale major bleeding was 3.0% in the bivalirudin alone group (Group C), vs 5.7% in the heparin plus GP IIb/IIIa group (Group A) (PNI <.0001; Psup <.0001) and 5.3% in the bivalirudin plus GP IIb/IIIa group (Group B) (PNI <.0001; Psup =.38)1
• The incidence of the composite ischemic end point (death, MI, unplanned revascularization) for patients in the bivalirudin alone Group (C) was 7.8% versus 7.3% in the heparin plus GP IIb/IIIa Group (A) (PNI <.011; Psup =.32) and 7.7% in the bivalirudin plus GP IIb/IIIa group (Group B) (PNI <.007; Psup =.39)1
• Mortality at 12 months in patients treated with bivalirudin alone (Group C) was 3.8% compared to 4.4% in patients treated with heparin plus GP IIb/IIIa (Group A) (Psup =.66). Mortality at 12 months was 4.4% in the bivalirudin plus GP IIb/IIIa (Group B) (Psup =.93)2
• Composite ischemia at 12 months in patients treated with bivalirudin alone (Group C) was 16.4% compared to 16.3% in patients treated with heparin plus GP IIb/IIIa (Group A) (Psup =.31). Composite ischemia at 12 months was 16.5% in the bivalirudin plus GP IIb/IIIa Group (B) (Psup =.38)2

The safety and effectiveness of bivalirudin have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Acute Myocardial Infarction

The use of bivalirudin has been evaluated in approximately 300 patients with ST- segment elevation MI (STEMI) undergoing primary PCI (without thrombolytics). Bivalirudin in the Management of Patients with ST-Segment Elevation Acute Myocardial Infarction Undergoing Primary PCI (BIAMI) was a prospective, open-label, single-group, multicenter, pilot study evaluating ANGIOMAX in 201 patients with STEMI undergoing primary PCI.3,4

Clinical Outcomes

The primary composite efficacy end point of death, reinfarction, repeat revascularization, or disabling stroke occurred in 2.5% of patients at 7 days and 4.1% of patients at 30 days. At the 6-month follow up, the primary composite end point occurred in 8.9% of patients. Ten percent of patients were administered abciximab postprocedure due to Thrombolysis in Myocardial Infarction (TIMI) flow of less than 3. Sixty percent of these patients achieved TIMI-3 flow post-abciximab administration. Three percent of patients, all of whom had postprocedural anticoagulation, experienced a clinically significant bleed at 7 days and 5 patients (2.5%) received a blood product transfusion. Thrombocytopenia occurred in 3 patients (1.5%).2-4 This pilot study formed the basis for the ongoing HORIZONS trial.

Harmonizing Outcomes with RevascularIZatiON and Stents (HORIZONS): Patients with acute myocardial infarction (AMI) undergoing primary PCI are a high-risk patient population. Preliminary results provide support for the HORIZONS trial, which investigated the use of bivalirudin with bailout GP IIb/IIIa compared to heparin and routine GP IIb/IIIa in primary PCI. The trial evaluated a 30-day composite end point of death, MI, target vessel revascularization, stroke, and major bleeding. Approximately 3400 patients were enrolled.

Return to Top

Percutaneous Peripheral Intervention

The etiologies of coronary artery disease and peripheral vascular disease are similar, yet patients with peripheral artery disease tend to have a larger thrombus burden, be older, and be more likely to have diabetes, renal impairment, coronary artery disease, and extensive peripheral artery disease compared to patients undergoing PCI.

Preliminary work evaluating the safety of bivalirudin in the setting of percutaneous peripheral intervention (PPI) has been reported by Shammas et al and by Allie et al.5-6 These 2 studies provided support for the Angiomax Peripheral Procedure Registry of Vascular Events (APPROVE) trial, which evaluated 500 patients undergoing peripheral angioplasty of the renal, iliac, or femoral artery.7

Clinical Outcomes

In APPROVE, in-hospital procedural success was achieved in 95% of patients.7 At 30 days, the incidence of the composite of death/MI/unplanned revascularization/amputation was 1.4%. All ischemic events reported at 30 days occurred in patients undergoing PPI of the femoral artery. In-hospital protocol major bleeding occurred in 2.2% of patients.

Return to Top

Cardiac Surgery

The use of bivalirudin had been evaluated in approximately 400 patients in on- and off-pump cardiac surgery including two Phase 2 studies and four Phase 3 open-label studies. Safety and efficacy of bivalirudin during CABG surgery on cardiopulmonary bypass (CPB) was initially assessed in 30 patients2,8 receiving bivalirudin. Subsequently two Phase 3 trials were conducted: EVOLUTION-ON,9 which assessed the safety of bivalirudin in this setting in 150 patients receiving either bivalirudin (100 patients) or heparin with protamine reversal (50 patients); and CHOOSE-ON,10 conducted in patients with or at risk of HIT/HITTS undergoing cardiac surgery (50 patients) on CPB and compared to a historical control receiving an anticoagulant other than bivalirudin.

The safety and efficacy of bivalirudin in off-pump cardiac surgery was initially assessed in 100 patients receiving either bivalirudin or heparin with protamine reversal11. Subsequently, two Phase 3 trials were conducted: EVOLUTION-OFF,12 which assessed the safety of bivalirudin in this setting in 150 patients receiving either bivalirudin (100 patients) or heparin with protamine reversal (50 patients); and CHOOSE-OFF,2 conducted in patients with or at risk of HIT/HITTS undergoing off-pump cardiac surgery (50 patients) and compared to a historical control receiving an anticoagulant other than bivalirudin.

EVOLUTION-ON Pump Trial (Non-HIT/HITTS Patients)

Trial Design

EValuation of patients during coronary artery bypass graft Operation: Linking UTilization of bivalirudin to Improved Outcomes and New anticoagulant strategies: on pump (EVOLUTION-ON)9 was a multicenter, open-label, randomized clinical trial designed to assess the safety of bivalirudin compared to heparin plus protamine reversal (2:1 randomization) in patients undergoing elective CABG, CABG-valve or isolated cardiac valve surgery on CPB (collectively termed cardiac surgery).

For full discussion of outcomes please refer to Dyke CM, Smedira NG, Koster A et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006;131(3):533-539.

Clinical End Points

The primary end point of procedural success, defined as an absence of death, Q-wave MI, repeat coronary revascularization and stroke (hemorrhagic and ischemic) was evaluated at 7 days or hospital discharge, whichever occurred first.

Secondary end points included bleeding complications such as transfusions and major bleeding events evaluated at 7 days or hospital discharge.

Clinical Outcomes

Procedural success rates at 7 days/discharge were 94.9% in the bivalirudin group and 96.2% in the heparin group. Major bleeding events at day 7/discharge occurred in 6.1% of bivalirudin patients and 1.9% of patients who received heparin/protamine. The postoperative reexploration rate in the bivalirudin group contributed to the difference in bleeding events between groups. The rate of transfusions in the bivalirudin group was 58.2% vs 59.6% in the heparin/protamine group.

Return to Top

CHOOSE-ON Pump Trial (In Patients with or at risk of HIT/HITTS)

Trial Design

CABG HIT/TS On- and Off-pump Safety and Efficacy: on pump (CHOOSE-ON)10 was a Phase III multicenter, open-label trial designed to assess the safety and efficacy of bivalirudin in 50 patients compared to a historical control group of 50 patients with or at risk of HIT/HITTS undergoing on-pump cardiac surgery. The historical control group received an anticoagulant other than bivalirudin.

For full discussion of outcomes please refer to Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patient with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007;83:572-7.

Clinical End Points

The primary end point of procedural success (7 days), the secondary end points of procedural success (30 days, 12 weeks) and the safety profile were identical to the end points outlined in the EVOLUTION-ON study.

Clinical Outcomes

Procedural success rates at 7 days/hospital discharge was 94% for bivalirudin patients and 92% for historical control patients. There were two deaths in the bivalirudin intent to treat group by day 7/discharge. One death occurred before surgery or administration of bivalirudin and one death occurred at day 7/discharge. There were 4 deaths in the safety population by week 12. Non Q wave MIs were higher in the bivalirudin group compared to the historical group at all time frames. Major bleeding events were 4.1% in the bivalirudin patients and 8% in the historical control patients. The frequency of transfusions was similar in both groups. Post operative blood loss was a median of 880 mL in the bivalirudin group and median of 797.5 mL in the historical group.

Return to Top

EVOLUTION-OFF Pump Trial (Non HIT/HITTS Patients)

Trial Design

EValuation of patients during coronary artery bypass graft Operation: Linking UTilization of bivalirudin to Improved Outcomes and New anticoagulant strategies: off pump (EVOLUTION-OFF) was a multicenter, open-label, randomized clinical trial designed to assess the safety of bivalirudin compared to heparin plus protamine reversal (2:1 randomization) in patients undergoing elective off-pump coronary artery bypass surgery (OPCAB).12

Clinical End Points

The primary end point of procedural success, defined as an absence of death, Q-wave MI, repeat coronary revascularization, and stroke (hemorrhagic and ischemic) was evaluated at 7 days or hospital discharge, whichever occurred first. Secondary end points included bleeding complications such as transfusions and major bleeding events evaluated at 7 days or hospital discharge.

Clinical Outcomes

Procedural success rates at 7 days/hospital discharge were 96.0% and 94.6 % for patients randomized to the bivalirudin and heparin groups, respectively. Two of the three strokes occurred prior to discharge. Major bleeding events occurred in 8.9% and 5.4% in the bivalirudin and heparin groups, respectively. Eight patients (7.9%) in the bivalirudin group had persistent hemorrhage necessitating repeat exploratory operation vs 3 patients (5.4%) in the heparin group. Transfusion rates were 45.5% in the bivalirudin group and 58.9% in the heparin/protamine group.

For full discussion of outcomes please refer to Smedira NG, Dyke CM, Koster A, et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg. 2006;131:686-692.

Return to Top

CHOOSE-OFF Pump Trial (In Patients with or at risk of HIT/HITTS)

CABG HIT/TS On- and Off-pump Safety and Efficacy: off pump (CHOOSE-OFF)2 was a multicenter, open-label trial designed to assess the safety and efficacy of bivalirudin in 52 patients compared to a historical control group of 36 patients with or at risk of HIT/HITTS undergoing off-pump CABG surgery.4 The historical control group received an anticoagulant other than bivalirudin.

Clinical End Points

The primary end point of procedural success, defined as an absence of death, Q-wave MI, repeat coronary revascularization and stroke (hemorrhagic and ischemic) was evaluated at 7 days or hospital discharge, whichever occurred first. Secondary end points included bleeding complications such as transfusions and major bleeding events evaluated at 7 days or hospital discharge.

Clinical Outcomes

Procedural success rates were 96.1% in the bivalirudin group and 97.2% in the historical group. One patient who received bivalirudin had an ischemic stroke within 7 days of surgery. Major bleeding events were 2 cases (3.9%) of hemorrhage necessitating exploratory operations in the bivalirudin group and 3 cases (8.3%) in the historical control group. Transfusions were required in 52.9% of bivalirudin patients compared to 88.9% in the historical group at 7 days/discharge.

Return to Top

Safety Considerations

ANGIOMAX with provisional use of glycoprotein IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI. ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin. ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components. The most common (10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration. Please see complete prescribing information.

1Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203-16.
2Data on file. The Medicines Company.
3Stella J, Stella R, Stella D, et al. Bivalirudin in the management of patients with ST-segment elevation acute myocardial infarction undergoing primary PCI (BIAMI) trial: in-hospital,
30-day, and 6-month results. Presented at The Society for Cardiovascular Angiography and Interventions (SCAI). Chicago, IL. May 10-13, 2006. Poster
4Stella J, Stella R, Stella D, et al. The bivalirudin in the management of patients with
ST-segment elevation acute myocardial infarction undergoing primary PCI (BIAMI) trial:
in-hospital, 30-day, and 6-month results. Cathet Cardiovasc Interv. 2006;67:751.
(abstract A-34)
5Shammas NW, Lemke JH, Dippel EJ, et al. Bilvalirudin in peripheral vascular interventions: a single center experience. J Invasive Cardiol. 2003;15:401-404.
6Allie DE, Lirtzman MD, Wyatt CH, et al. Bivalirudin as a foundation anticoagulant in peripheral vascular disease: a safe and feasible alternative for renal and iliac interventions.
J Invasive Cardiol. 2003;15:334-342.
7Allie DE, Hall P, Shammas NW, et al. The Angiomax Peripheral Procedure Registry of Vascular Events Trial (APPROVE): in-hospital and 30-day results. J Invasive Cardiol. 2004;16:651-656.
8Koster A, Speiss B, Chew D et al. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting.
Am J Cardiol 2004;93:356-359.
9Dyke CM, Smedira NG, Koster A et al A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006;131(3):533-539.
10Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patient with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007;83:572-7.
11Merry AF, Raudkivi PJ, Middleton NG, et al. Bivalirudin versus heparin and protamine in off-pump coronary bypass surgery. Ann Thorac Surg. 2004;77:925-931.
12Smedira NG, Dyke CM, Koster A, et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study.
J Thorac Cardiovasc Surg. 2006;131:686-692.

Return to Top