Mechanism Of Action
Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anionbinding
exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a
central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate
Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which
stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin
generation, and activates platelets, stimulating aggregation and granule release. The binding of
bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond,
resulting in recovery of thrombin active site functions.
In in vitro studies, bivalirudin inhibited both soluble (free) and clot-bound thrombin, was not neutralized
by products of the platelet release reaction, and prolonged the activated partial thromboplastin time
(aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentrationdependent
manner. The clinical relevance of these findings is unknown.
In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine PTCA), bivalirudin
exhibited dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the
ACT, aPTT, PT, and TT. Intravenous administration of bivalirudin produces an immediate anticoagulant
effect. Coagulation times return to baseline approximately 1 hour following cessation of bivalirudin
In 291 patients with ≥70% vessel occlusion undergoing routine PTCA, a positive correlation was
observed between the dose of bivalirudin and the proportion of patients achieving ACT values of 300
sec or 350 sec. At a bivalirudin dose of 1 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours,
followed by 0.2 mg/kg/h, all patients reached maximal ACT values >300 sec.
Bivalirudin exhibits linear pharmacokinetics following IV administration to patients undergoing PTCA.
In these patients, a mean steady state bivalirudin concentration of 12.3 ± 1.7 mcg/mL is achieved
following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. Bivalirudin does not bind to
plasma proteins (other than thrombin) or to red blood cells. Bivalirudin is cleared from plasma by a
combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal
function of 25 min.
The disposition of bivalirudin was studied in PTCA patients with mild, moderate, and severe renal
impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was
similar for patients with normal renal function and with mild renal impairment (60 to 89 mL/min).
Clearance was reduced in patients with moderate and severe renal impairment and in dialysis-dependent
patients (see Table 6 for pharmacokinetic parameters).
Bivalirudin is hemodialyzable, with approximately 25% cleared by hemodialysis.
Table 6: PK Parameters in Patients with Renal Impairment*
|Normal renal function (≥90 mL/min)
|Mild renal impairment (60 to 89 mL/min)
|Moderate renal impairment (30 to 59 mL/min)
|Severe renal impairment (10 to 29 mL/min)
|Dialysis-dependent patients (off dialysis)
|*The ACT should be monitored in renally-impaired patients.
Bivalirudin has been evaluated in five randomized, controlled interventional cardiology trials reporting
11,422 patients. Stents were deployed in 6,062 of the patients in these trials – mainly in trials performed
since 1995. Percutaneous transluminal coronary angioplasty, atherectomy or other procedures were
performed in the remaining patients.
This was a randomized, double-blind, multicenter study reporting 6,002 (intent-to-treat) patients
undergoing PCI. Patients were randomized to treatment with bivalirudin with the “provisional” use of
platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a
“provisional” basis to patients who were randomized to bivalirudin in the following circumstances:
- decreased TIMI flow (0 to 2) or slow reflow;
- dissection with decreased flow;
- new or suspected thrombus;
- persistent residual stenosis;
- distal embolization;
- unplanned stent;
- suboptimal stenting;
- side branch closure;
- abrupt closure; clinical instability; and
- prolonged ischemia.
During the study, one or more of these circumstances occurred in 10.9% of patients in the bivalirudin
with provisional GPI arm. GPIs were administered to 7.2% of patients in the bivalirudin with
provisional GPI arm (66.8% of eligible patients).
Patients ranged in age from 25 to 95 years (median, 63); weight ranged from 35 to 199 kg (median 85.5);
74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of
patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%),
positive ischemic stress test (24%), and other not specified indications (8%). Stents were deployed in
85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines
prior to study treatment.
Bivalirudin was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration
of the procedure. The activated clotting time (ACT – measured by a Hemochron® device) was
measured 5 min after the first bolus of study medication. If the ACT was < 225 seconds, an additional
bolus of 0.3 mg/kg was given. At investigator discretion, the infusion could be continued following the
procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a
65 U/kg bolus. The activated clotting time (ACT – measured by a Hemochron® device) was measured
5 min after the first bolus of study medication. If the ACT was < 225 seconds, an additional bolus of 20
units/kg was given. GPIs (either abciximab or eptifibatide) were given according to manufacturers’
instructions. Both randomized groups could be given “provisional” treatments during the PCI at
investigator discretion, but under double-blind conditions. “Provisional” treatment with GPI was
requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2%
patients randomized to bivalirudin with provisional GPI (they were given abciximab or eptifibatide
according to pre-randomization investigator choice and patient stratification).
The percent of patients reaching protocol-specified levels of anticoagulation was greater in the
bivalirudin with provisional GPI group than in the heparin plus GPI group. For patients randomized to
bivalirudin with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320 to 400
sec) and the ACT was < 225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min
ACT was 317 sec (interquartile range 263 to 373 sec) and the ACT was < 225 sec in 12%. At the end of
the procedure, median ACT values were 334 sec (bivalirudin group) and 276 sec (heparin plus GPI
For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind
conditions, the frequency was higher (7.6%) (95% confidence interval 6.7% to 8.6%) in the bivalirudin
with “provisional” GPI arm when compared to the heparin plus GPI arm (7.1%) (95% confidence
interval 6.1% to 8.0%). However, major hemorrhage was reported significantly less frequently in the
bivalirudin with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study
outcomes are shown in Table 7.
Table 7: Incidences of Clinical Endpoints at 30 Days for REPLACE-2, a Randomized Doubleblind
||Bivalirudin with “Provisional” GPI
|Heparin + GPI
| Death, MI, or urgent revascularization
| Urgent revascularization
| Major hemorrhage1,2
|1Defined as intracranial bleeding, retroperitoneal bleeding, a transfusion of >2 units of blood/blood
products, a fall in Hgb >4 g/dL, whether or not bleeding site is identified, spontaneous or nonspontaneous
blood loss with a decrease in Hgb >3 g/dL.
2p-value <0.001 between groups.
At 12 months’ follow-up, mortality was 1.9% among patients randomized to bivalirudin with
“provisional” GPIs and 2.5% among patients randomized to heparin plus GPI.
Bivalirudin Angioplasty Trial (BAT)
Bivalirudin was evaluated in patients with unstable angina undergoing PTCA in two randomized, doubleblind,
multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1)
a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2)
angina or ischemic rest pain which developed between four hours and two weeks after an acute
myocardial infarction (MI). Overall, 4,312 patients with unstable angina, including 741 (17%) patients
with post-MI angina, were treated in a 1:1 randomized fashion with bivalirudin or heparin. Patients
ranged in age from 29 to 90 (median 63) years, their weight was a median of 80 kg (39 to 120 kg), 68%
were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within
one hour prior to randomization. All patients were administered aspirin 300 to 325 mg prior to PTCA
and daily thereafter. Patients randomized to bivalirudin were started on an intravenous infusion of
bivalirudin (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading
dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the
infusion was changed under double-blinded conditions to bivalirudin (0.2 mg/kg/h) for up to an
additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked
at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an
additional double-blinded bolus of placebo was administered. The bivalirudin dose was not titrated to
ACT. Median ACT values were: ACT in sec (5th percentile to 95th percentile): 345 sec (240 to 595
sec) at 5 min and 346 sec (range 269 to 583 sec) at 45 min after initiation of dosing. Patients randomized
to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned
procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was
continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under doubleblinded
conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min
and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional
double-blind bolus of heparin (60 IU/kg) was administered. Once the target ACT was achieved for
heparin patients, no further ACT measurements were performed. All ACTs were determined with the
Hemochron® device. The protocol allowed use of open-label heparin at the discretion of the
investigator after discontinuation of blinded study medication, whether or not an endpoint event
(procedural failure) had occurred. The use of open-label heparin was similar between bivalirudin and
heparin treatment groups (about 20% in both groups).
The studies were designed to demonstrate the safety and efficacy of bivalirudin in patients undergoing
PTCA as a treatment for unstable angina as compared with a control group of similar patients receiving
heparin during and up to 24 hours after initiation of PTCA. The primary protocol endpoint was a
composite endpoint called procedural failure, which included both clinical and angiographic elements
measured during hospitalization. The clinical elements were: the occurrence of death, MI, or urgent
revascularization, adjudicated under double-blind conditions. The angiographic elements were:
impending or abrupt vessel closure. The protocol-specified safety endpoint was major hemorrhage.
The median duration of hospitalization was 4 days for both the bivalirudin and the heparin treatment
groups. The rates of procedural failure were similar in the bivalirudin and heparin treatment groups.
Study outcomes are shown in Table 8.
Table 8: Incidences of In-hospital Clinical Endpoints in BAT Trial Occurring within 7 Days
| Procedural failure1
| Death, MI, revascularization
| Major hemorrhage4
|1The protocol-specified primary endpoint (a composite of death or MI or clinical deterioration of
cardiac origin requiring revascularization or placement of an aortic balloon pump or angiographic
evidence of abrupt vessel closure).
2Defined as: Q-wave MI; CK-MB elevation ≥2 x ULN, new ST- or T-wave abnormality, and chest pain
≥30 min; OR new LBBB with chest pain ≥30 min and/or elevated CK-MB enzymes; OR elevated CKMB
and new ST- or T-wave abnormality without chest pain; OR elevated CK-MB.
3Defined as: any revascularization procedure, including angioplasty, CABG, stenting, or placement of
an intra-aortic balloon pump.
4Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding,
clinically overt bleeding with a decrease in Hgb ≥3 g/dL or leading to a transfusion of ≥2 units of
This was a single-group open-label study which enrolled 51 patients with heparin-induced
thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS)
undergoing PCI. Evidence for the diagnosis of HIT/HITTS was based on a clinical history of a
decrease of platelets in patients after heparin administration [new diagnosis or history of clinically
suspected or objectively documented HIT/HITTS defined as either: 1) HIT: positive heparin-induced
platelet aggregation (HIPA) or other functional assay where the platelet count has decreased to
<100,000/mL (minimum 30% from prior to heparin), or has decreased to <150,000/mL (minimum 40%
from prior to heparin), or has decreased as above within hours of receiving heparin in a patient with a
recent, previous exposure to heparin; 2) HITTS: thrombocytopenia as above plus arterial or venous
thrombosis diagnosed by physician examination/laboratory and/or appropriate imaging studies]. Patients
ranged in age from 48 to 89 years (median 70); weight ranged from 42 to 123 kg (median 76); 50% were
male and 50% were female. Bivalirudin was administered as either 1 mg/kg bolus followed by 2.5
mg/kg/h (high dose in 28 patients) or 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion (lower dose
in 25 patients) for up to 4 hours. Ninety-eight percent of patients received aspirin, 86% received
clopidogrel and 19% received GPIs.
The median ACT values at the time of device activation were 379 sec (high dose) and 317 sec (lower
dose). Following the procedure, 48 of the 51 patients (94%) had TIMI grade 3 flow and stenosis
<50%. One patient died during a bradycardic episode 46 hours after successful PCI, another patient
required surgical revascularization, and one patient experienced no flow requiring a temporary intraaortic
Two of the fifty-one patients with the diagnosis of HIT/HITTS developed thrombocytopenia after
receiving bivalirudin and GPIs.