Mechanism Of Action
Eptifibatide reversibly inhibits platelet aggregation by
preventing the binding of fibrinogen, von Willebrand factor and other adhesive
ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex
vivo platelet aggregation in a dose- and concentration-dependent manner.
Platelet aggregation inhibition is reversible following cessation of the
eptifibatide infusion; this is thought to result from dissociation of
eptifibatide from the platelet.
Infusion of eptifibatide into baboons caused a
dose-dependent inhibition of ex vivo platelet aggregation, with complete
inhibition of aggregation achieved at infusion rates greater than 5 mcg/kg/min.
In a baboon model that is refractory to aspirin and heparin, doses of
eptifibatide that inhibit aggregation prevented acute thrombosis with only a
modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation
in dogs was also inhibited by infusions of eptifibatide, with complete
inhibition at 2 mcg/kg/min. This infusion dose completely inhibited canine
coronary thrombosis induced by coronary artery injury (Folts model).
Human pharmacodynamic data were obtained in healthy
subjects and in patients presenting with UA or NSTEMI and/or undergoing
percutaneous coronary intervention. Studies in healthy subjects enrolled only
males; patient studies enrolled approximately one-third women. In these
studies, eptifibatide inhibited ex vivo platelet aggregation induced by
adenosine diphosphate (ADP) and other agonists in a dose- and
concentration-dependent manner. The effect of eptifibatide was observed
immediately after administration of a 180-mcg/kg intravenous bolus. Table 4
shows the effects of dosing regimens of eptifibatide used in the IMPACT II and
PURSUIT studies on ex vivo platelet aggregation induced by 20 μM ADP in
PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of
the dosing regimen used in ESPRIT on platelet aggregation have not been
Table 4: Platelet Inhibition and Bleeding Time
|Inhibition of platelet aggregation 15 min after bolus
|Inhibition of platelet aggregation at steady-state
|| > 90%
|Bleeding-time prolongation at steady-state
|| < 5x
|Inhibition of platelet aggregation 4h after infusion discontinuation
|| < 50%
|Bleeding-time prolongation 6h after infusion discontinuation
|* 180-mcg/kg bolus followed by a continuous infusion of 2
The eptifibatide dosing regimen used in the ESPRIT study
included two 180-mcg/kg bolus doses given 10 minutes apart combined with a
continuous 2-mcg/kg/min infusion.
When administered alone, eptifibatide has no measurable
effect on PT or aPTT.
There were no important differences between men and women
or between age groups in the pharmacodynamic properties of eptifibatide.
Differences among ethnic groups have not been assessed.
The pharmacokinetics of eptifibatide are linear and
dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion
rates from 0.5 to 3 mcg/kg/min. Plasma elimination half-life is approximately 2.5
hours. Administration of a single 180-mcg/kg bolus combined with an infusion
produces an early peak level, followed by a small decline prior to attaining
steady-state (within 4 to 6 hours). This decline can be prevented by
administering a second 180-mcg/kg bolus 10 minutes after the first. The extent
of eptifibatide binding to human plasma protein is about 25%. Clearance in
patients with coronary artery disease is about 55 mL/kg/h. In healthy subjects,
renal clearance accounts for approximately 50% of total body clearance, with
the majority of the drug excreted in the urine as eptifibatide, deaminated eptifibatide
and other, more polar metabolites. No major metabolites have been detected in
Patients in clinical studies were older (range: 20 to 94
years) than those in the clinical pharmacology studies. Elderly patients with
coronary artery disease demonstrated higher plasma levels and lower total body
clearance of eptifibatide when given the same dose as younger patients. Limited
data are available on lighter weight ( < 50 kg) patients over 75 years of age.
In patients with moderate to severe renal insufficiency
(CrCl < 50 mL/min using the Cockcroft-Gault equation), the clearance of
eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately
doubled [see Use in Specific Populations and DOSAGE AND
No studies have been conducted in patients with hepatic
Males and females have not demonstrated any clinically
significant differences in the pharmacokinetics of eptifibatide.
Eptifibatide was studied in 3 placebo-controlled,
randomized studies. PURSUIT evaluated patients with acute coronary syndromes:
UA or NSTEMI. Two other studies, ESPRIT and IMPACT II, evaluated patients about
to undergo a PCI. Patients underwent primarily balloon angioplasty in IMPACT II
and intracoronary stent placement, with or without angioplasty, in ESPRIT.
Non-ST-Segment Elevation Acute Coronary Syndrome
Non-ST-segment elevation acute coronary syndrome is
defined as prolonged ( ≥ 10 minutes) symptoms of cardiac ischemia within
the previous 24 hours associated with either ST-segment changes (elevations
between 0.6 mm and 1 mm or depression > 0.5 mm), T-wave inversion ( > 1 mm),
or positive CK-MB. This definition includes “unstable angina” and
“NSTEMI” but excludes MI that is associated with Q waves or greater
degrees of ST-segment elevation.
PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable
Angina: Receptor Suppression Using Eptifibatide Therapy)
PURSUIT was a 726-center, 27-country, double-blind,
randomized, placebo-controlled study in 10,948 patients presenting with UA or
NSTEMI. Patients could be enrolled only if they had experienced cardiac
ischemia at rest ( ≥ 10 minutes) within the previous 24 hours and had
either ST-segment changes (elevations between 0.6 mm and 1 mm or depression
> 0.5 mm), T-wave inversion ( > 1 mm), or increased CK-MB. Important
exclusion criteria included a history of bleeding diathesis, evidence of
abnormal bleeding within the previous 30 days, uncontrolled hypertension, major
surgery within the previous 6 weeks, stroke within the previous 30 days, any
history of hemorrhagic stroke, serum creatinine > 2 mg/dL, dependency on
renal dialysis, or platelet count < 100,000/mm³.
Patients were randomized to placebo, to eptifibatide
180-mcg/kg bolus followed by a 2-mcg/kg/min infusion (180/2), or to eptifibatide
180-mcg/kg bolus followed by a 1.3-mcg/kg/min infusion (180/1.3). The infusion
was continued for 72 hours, until hospital discharge, or until the time of
CABG, whichever occurred first, except that if PCI was performed, the
eptifibatide infusion was continued for 24 hours after the procedure, allowing
for a duration of infusion up to 96 hours.
The lower-infusion-rate arm was stopped after the first
interim analysis when the 2 active-treatment arms appeared to have the same
incidence of bleeding.
Patient age ranged from 20 to 94 (mean 63) years, and 65%
were male. The patients were 89% Caucasian, 6% Hispanic and 5% Black, recruited
in the United States and Canada (40%), Western Europe (39%), Eastern Europe
(16%) and Latin America (5%).
This was a “real world” study; each patient was
managed according to the usual standards of the investigational site;
frequencies of angiography, PCI and CABG therefore differed widely from site to
site and from country to country. Of the patients in PURSUIT, 13% were managed
with PCI during drug infusion, of whom 50% received intracoronary stents; 87%
were managed medically (without PCI during drug infusion).
The majority of patients received aspirin (75 to 325 mg
once daily). Heparin was administered intravenously or subcutaneously, at the
physician“s discretion, most commonly as an intravenous bolus of 5000
units followed by a continuous infusion of 1000 units/h. For patients weighing
less than 70 kg, the recommended heparin bolus dose was 60 units/kg followed by
a continuous infusion of 12 units/kg/h. A target aPTT of 50 to 70 seconds was
recommended. A total of 1250 patients underwent PCI within 72 hours after
randomization, in which case they received intravenous heparin to maintain an ACT
of 300 to 350 seconds.
The primary endpoint of the study was the occurrence of
death from any cause or new MI (evaluated by a blinded Clinical Endpoints
Committee) within 30 days of randomization.
Compared to placebo, eptifibatide administered as a
180-mcg/kg bolus followed by a 2mcg/kg/min infusion significantly (p=0.042)
reduced the incidence of endpoint events (see Table 6). The reduction in the
incidence of endpoint events in patients receiving eptifibatide was evident
early during treatment, and this reduction was maintained through at least 30
days (see Figure 1). Table 5 also shows the incidence of the components of the
primary endpoint, death (whether or not preceded by an MI) and new MI in
surviving patients at 30 days.
Table 5: Clinical Events in the PURSUIT Study
|Death or MI
|Eptifibatide (180 mcg/kg bolus then 2 mcg/kg/min infusion)
|30 days Death or MI (primary endpoint)
Figure 1: Kaplan-Meier Plot of Time to Death or
Myocardial Infarction Within 30 Days of Randomization in the PURSUIT Study
Treatment with eptifibatide prior to determination of
patient management strategy reduced clinical events regardless of whether
patients ultimately underwent diagnostic catheterization, revascularization
(i.e., PCI or CABG surgery) or continued to receive medical management alone.
Table 6 shows the incidence of death or MI within 72 hours.
Table 6: Clinical Events (Death or MI) in the PURSUIT
Study Within 72 Hours of Randomization
||Eptifibatide (180 mcg/kg bolus then 2 mcg/kg/min infusion)
|Overall patient population
|- At 72 hours Patients undergoing early PCI
|- Preprocedure (nonfatal MI only)
|- At 72 hours Patients not undergoing early PCI
|- At 72 hours
All of the effect of eptifibatide was established within
72 hours (during the period of drug infusion), regardless of management
strategy. Moreover, for patients undergoing early PCI, a reduction in events was
evident prior to the procedure.
An analysis of the results by sex suggests that women who
would not routinely be expected to undergo PCI receive less benefit from
eptifibatide (95% confidence limits for relative risk of 0.94 to 1.28) than do
men (0.72 to 0.9). This difference may be a true treatment difference, the
effect of other differences in these subgroups, or a statistical anomaly. No
differential outcomes were seen between male and female patients undergoing PCI
(see results for ESPRIT).
Follow-up data were available through 165 days for 10,611
patients enrolled in the PURSUIT trial (96.9% of the initial enrollment). This
follow-up included 4566 patients who received eptifibatide at the 180/2 dose.
As reported by the investigators, the occurrence of death from any cause or new
MI for patients followed for at least 165 days was reduced from 13.6% with
placebo to 12.1% with eptifibatide 180/2.
Percutaneous Coronary Intervention (PCI)
IMPACT II (Eptifibatide to Minimize Platelet Aggregation
and Prevent Coronary Thrombosis II)
IMPACT II was a multicenter, double-blind, randomized,
placebo-controlled study conducted in the United States in 4010 patients
undergoing PCI. Major exclusion criteria included a history of bleeding diathesis,
major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30
days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT
> 1.2 times control, hematocrit < 30%, platelet count < 100,000/mm³ and
Patient age ranged from 24 to 89 (mean 60) years, and 75%
were male. The patients were 92% Caucasian, 5% Black and 3% Hispanic. Forty-one
percent of the patients underwent PCI for ongoing ACS. Patients were randomly
assigned to 1 of 3 treatment regimens, each incorporating a bolus dose initiated
immediately prior to PCI followed by a continuous infusion lasting 20 to 24
- 135-mcg/kg bolus followed by a continuous infusion of 0.5
mcg/kg/min of eptifibatide (135/0.5);
- 135-mcg/kg bolus followed by a continuous infusion of
0.75 mcg/kg/min of eptifibatide (135/0.75); or
- a matching placebo bolus followed by a matching placebo
Each patient received aspirin and an intravenous heparin
bolus of 100 units/kg, with additional bolus infusions of up to 2000 additional
units of heparin every 15 minutes to maintain an ACT of 300 to 350 seconds.
The primary endpoint was the composite of death, MI, or
urgent revascularization, analyzed at 30 days after randomization in all
patients who received at least 1 dose of study drug.
As shown in Table 7, each eptifibatide regimen reduced
the rate of death, MI, or urgent intervention, although at 30 days, this
finding was statistically significant only in the lower-dose eptifibatide
As in the PURSUIT study, the effects of eptifibatide were
seen early and persisted throughout the 30- day period.
Table 7: Clinical Events in the IMPACT II Study
|Eptifibatide (135 mcg/kg bolus then 0.5 mcg/kg/min infusion)
|Eptifibatide (135 mcg/kg bolus then 0.75 mcg/kg/min infusion)
|p-value versus placebo
|Death, MI, or Urgent Intervention
|p- value versus placebo
|p- value versus placebo
|30 days(primary end point)
|p- value versus placebo
|p- value versus placebo
||‘ 136 (10.6%)*
|p- value versus placebo
|* Kaplan-Meier estimate of event rate.
ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa
Receptor with Eptifibatide Therapy)
The ESPRIT study was a multicenter, double-blind,
randomized, placebo-controlled study conducted in the United States and Canada
that enrolled 2064 patients undergoing elective or urgent PCI with intended
intracoronary stent placement. Exclusion criteria included MI within the
previous 24 hours, ongoing chest pain, administration of any oral antiplatelet
or oral anticoagulant other than aspirin within 30 days of PCI (although
loading doses of thienopyridine on the day of PCI were encouraged), planned PCI
of a saphenous vein graft or subsequent “staged” PCI, prior stent placement in
the target lesion, PCI within the previous 90 days, a history of bleeding
diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding
within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension,
PT > 1.2 times control, hematocrit < 30%, platelet count < 100,000/mm and
Patient age ranged from 24 to 93 (mean 62) years, and 73%
of patients were male. The study enrolled 90% Caucasian, 5% African American,
2% Hispanic and 1% Asian patients. Patients received a wide variety of stents.
Patients were randomized either to placebo or eptifibatide administered as an intravenous
bolus of 180 mcg/kg followed immediately by a continuous infusion of 2
mcg/kg/min, and a second bolus of 180 mcg/kg administered 10 minutes later
(180/2/180). Eptifibatide infusion was continued for 18 to 24 hours after PCI
or until hospital discharge, whichever came first. Each patient received at
least 1 dose of aspirin (162 to 325 mg) and 60 units/kg of heparin as a bolus
(not to exceed 6000 units) if not already receiving a heparin infusion.
Additional boluses of heparin (10 to 40 units/kg) could be administered in
order to reach a target ACT between 200 and 300 seconds.
The primary endpoint of the ESPRIT study was the
composite of death, MI, urgent target vessel revascularization (UTVR) and
“bailout” to open-label eptifibatide due to a thrombotic complication of PCI
(TBO) (e.g., visible thrombus, “no reflow,” or abrupt closure) at 48 hours. MI,
UTVR and TBO were evaluated by a blinded Clinical Events Committee.
As shown in Table 8, the incidence of the primary
endpoint and selected secondary endpoints was significantly reduced in patients
who received eptifibatide. A treatment benefit in patients who received eptifibatide
was seen by 48 hours and at the end of the 30-day observation period.
Table 8: Clinical Events in the ESPRIT Study
|Relative Risk (95% CI)
|Death, MI, UTVR, or Thrombotic “Bailout”
|48 hours (primary endpoint)
||0.629 0.0015 (0.471, 0.84)
||0.64 0.0011 (0.488, 0.84)
|Death, MI, UTVR 48 hours
||0.643 0.0045 (0.472, 0.875)
|30 days (key secondary endpoint) Death or MI
||0.653 0.0034 (0.49, 0.871)
||0.597 (0.435, 0.0013 0.82)
||0.625 0.0016 (0.465,0.84)
|* Eptifibatide was administered as 180 mcg/kg boluses at
times 0 and 10 minutes and an infusion at 2 mcg/kg/min.
The need for thrombotic “bailout” was significantly
reduced with eptifibatide at 48 hours (2.1% for placebo, 1% for eptifibatide;
p=0.029). Consistent with previous studies of GP IIb/IIIa inhibitors, most of
the benefit achieved acutely with eptifibatide was in the reduction of MI.
Eptifibatide reduced the occurrence of MI at 48 hours from 9% for placebo to
5.4% (p=0.0015) and maintained that effect with significance at 30 days.
There was no treatment difference with respect to sex in
ESPRIT. Eptifibatide reduced the incidence of the primary endpoint in both men
(95% confidence limits for relative risk: 0.54, 1.07) and women (0.24, 0.72) at
Follow-up (12-month) mortality data were available for
2024 patients (1017 on eptifibatide) enrolled in the ESPRIT trial (98.1% of the
initial enrollment). Twelve-month clinical event data were available for 1964
patients (988 on eptifibatide), representing 95.2% of the initial enrollment.
As shown in Table 9, the treatment effect of eptifibatide seen at 48 hours and
30 days appeared preserved at 6 months and 1 year. Most of the benefit was in
reduction of MI.
Table 9: Clinical Events at 6 Months and 1 Year in the
|Hazard Ratio (95% CI)
|Death, MI, or Target Vessel Re vas cularization
| 6 months
||0.744 (0.599, 0.924)
| 1 year
||0.762 (0.626, 0.929)
| 6 months
||0.631 (0.473, 0.841)
| 1 year
||0.63 (0.478, 0.832)
|Percentages are Kaplan-Meier event rates.