Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents

Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y 12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT [see Dosage and Administration (2)] .

Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI)

In patients undergoing PCI, treatment with Eptifibatide Injection is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, Eptifibatide infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while Eptifibatide Injection is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of <45 seconds or ACT <150 seconds be achieved. In any case, both heparin and eptifibatide should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of eptifibatide and heparin should be discontinued immediately.

Bleeding

The incidence of bleeding and transfusions in the PURSUET and ESPRET studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.

The majority of major bleeding reactions in the ESPRET study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and Eptifibatide Injection groups, respectively). Bleeding at "other" locations occurred in 0.2% and 0.4% of patients, respectively.

In the PURSUET study, the greatest increase in major bleeding in Eptifibatide Injection-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in Eptifibatide Injection-treated patients compared to placebo-treated patients.

Among patients experiencing a major bleed in the EMPACT II study, an increase in bleeding on Eptifibatide Injection versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).

Table 3 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUET study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRET is not presented, as every patient underwent PCI in the ESPRET study and only 11 patients underwent CABG.

In the PURSUET and ESPRET studies, the risk of major bleeding with Eptifibatide Injection increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg.

Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving Eptifibatide Injection than placebo (4.6% versus 0.9% in ESPRET, 8% versus 1% in PURSUET, 3.5% versus 1.9% in EMPACT II).

Intracranial Hemorrhage and Stroke

Intracranial hemorrhage was rare in the PURSUET, EMPACT II, and ESPRET clinical studies. In the PURSUET study, 3 patients in the placebo group, 1 patient in the group treated with Eptifibatide Injection 180/1.3, and 5 patients in the group treated with Eptifibatide Injection 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving Eptifibatide Injection 180/1.3, 0.7% in patients receiving Eptifibatide Injection 180/2, and 0.8% in placebo patients.

In the EMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with Eptifibatide Injection 135/0.5, 2 patients treated with Eptifibatide Injection 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 Eptifibatide Injection, 0.7% in patients receiving Eptifibatide Injection 135/0.75, and 0.7% in the placebo group.

In the ESPRET study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the Eptifibatide Injection group. In addition there was 1 case of cerebral infarction in the Eptifibatide Injection group.

Immunogenicity/Thrombocytopenia

The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide Injection was nonantigenic in 412 patients receiving a single administration of Eptifibatide Injection (135-mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom Eptifibatide Injection (135-mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated.

In patients with suspected Eptifibatide Injection-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in Eptifibatide Injection-naïve patients. These findings suggest acute thrombocytopenia after the administration of Eptifibatide Injection can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to Eptifibatide Injection. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with Eptifibatide Injection may be associated with hypotension and/or other signs of hypersensitivity.

In the PURSUET and EMPACT II studies, the incidence of thrombocytopenia (<100,000/mm 3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with Eptifibatide Injection and placebo. In the ESPRET study, the incidence was 0.6% in the placebo group and 1.2% in the Eptifibatide Injection group.

Other Adverse Reactions

In the PURSUET and ESPRET studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or Eptifibatide Injection (19% and 19%, respectively, in PURSUET; 6% and 7%, respectively, in ESPRET). In PURSUET, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with Eptifibatide Injection than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the EMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and Eptifibatide Injection-treated patients.

Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUET, EMPACT II, and ESPRET studies, with no single reaction occurring in >0.5% of the study population (except for "other" in the ESPRET study).

Risk Summary

Available data on eptifibatide use in pregnant women from published literature and the pharmacovigilance database are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Untreated myocardial infarction can be fatal to the pregnant woman and fetus (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental effects when eptifibatide was administered intravenously to pregnant rats and rabbits at approximately 4 times the recommended maximum daily human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Myocardial infarction is a medical emergency in pregnancy which can be fatal to the pregnant woman and fetus if left untreated. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of Eptifibatide Injection on the fetus.

Data

Animal Data

Embryo-fetal development studies have been performed by continuous intravenous infusion of eptifibatide in pregnant rats during the period of organogenesis at total daily doses of up to 72 mg/kg/day (about 4 times the recommended maximum daily human dose on a body surface area basis) and in pregnant rabbits during the period of organogenesis at total daily doses of up to 36 mg/kg/day (also about 4 times the recommended maximum daily human dose on a body surface area basis). These studies revealed no evidence of harm to the fetus due to eptifibatide.

Special Populations

PURSUET (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Eptifibatide Therapy)

PURSUET 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/mm 3.

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 PURSUET, 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 (75-325 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 2-mcg/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.

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.

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 - 1.28) than do men (0.72 - 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 ESPRET).

Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUET 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.

EMPACT II (Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)

EMPACT 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/mm 3, and pregnancy.

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 hours:

• 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 continuous infusion.

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 group. As in the PURSUET study, the effects of eptifibatide were seen early and persisted throughout the 30-day period.

ESPRET (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Eptifibatide Therapy)

The ESPRET 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 3, and pregnancy.

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 (162-325 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 (10-40 units/kg) could be administered in order to reach a target ACT between 200 and 300 seconds.

The primary endpoint of the ESPRET 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.

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 ESPRET. 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 48 hours.

Follow-up (12-month) mortality data were available for 2024 patients (1017 on eptifibatide) enrolled in the ESPRET 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.