A total of 16,782 patients were treated in the Phase III clinical trials (PURSUIT, ESPRIT and IMPACT II). These 16,782 patients had a mean age of 62 years (range 20 to 94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUIT, IMPACT II and ESPRIT, data from the three studies were not pooled.

Bleeding The incidences of bleeding events and transfusions in the PURSUIT, IMPACT II and ESPRIT studies are shown in Table 8. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding events consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding events 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 period of the method of Landefeld et al.

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

In the PURSUIT study, the greatest increase in major bleeding in eptifibatide-treated patients compared to placebo was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genito-urinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in eptifibatide-treated patients compared to placebo-treated patients. Among patients experiencing a major bleed in the IMPACT II study, an increase in bleeding on eptifibatide versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).

Table 9 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUIT study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRIT is not presented as every patient underwent PCI in the ESPRIT study and only 11 patients underwent CABG.

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

Bleeding adverse events resulting in discontinuation of study drug were more frequent among patients receiving eptifibatide than placebo (4.6% versus 0.9% in ESPRIT, 8% versus 1% in PURSUIT, 3.5% versus 1.9% in IMPACT II).

Intracranial Hemorrhage and Stroke

Intracranial hemorrhage was rare in the PURSUIT, IMPACT II and ESPRIT clinical studies. In the PURSUIT study, 3 patients in the placebo group, 1 patient in the group treated with eptifibatide 180/1.3 and 5 patients in the group treated with eptifibatide 180/2.0 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving eptifibatide 180/1.3, 0.7% in patients receiving eptifibatide 180/2.0, and 0.8% in placebo patients.

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

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

Thrombocytopenia

In the PURSUIT and IMPACT II studies, the incidence of thrombocytopenia (<100,000/mm³ or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with eptifibatide and placebo. In the ESPRIT study, the incidence was 0.6% in the placebo group and 1.2% in the eptifibatide group.

Allergic REACTIONS

In the PURSUIT study, anaphylaxis was reported in 7 patients receiving placebo (0.15%) and 7 patients receiving eptifibatide 180/2.0 (0.16%). In the IMPACT II study, anaphylaxis was reported in 1 patient (0.08%) on placebo and in no patients on eptifibatide. In the IMPACT II study, 2 patients (1 patient (0.04%) receiving eptifibatide and 1 patient (0.08%) receiving placebo) discontinued study drug because of allergic reactions. In the ESPRIT study, there were no cases of anaphylaxis reported. There were 3 patients who suffered an allergic reaction, 1 on placebo and 2 on eptifibatide. In addition, 1 patient in the placebo group was diagnosed with urticaria.

The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was non-antigenic in 412 patients receiving a single administration of eptifibatide (135 µg/kg bolus followed by a continuous infusion of either 0.5 µg/kg/min or 0.75 µg/kg/min), and in 21 subjects to whom eptifibatide (135 µg/kg bolus followed by a continuous infusion of 0.75 µg/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.

Other Adverse REACTIONS

In the PURSUIT and ESPRIT studies, the incidence of serious non-bleeding adverse events was similar in patients receiving placebo or eptifibatide (19% and 19%, respectively in PURSUIT; 6% and 7%, respectively in ESPRIT). In PURSUIT, the only serious non-bleeding adverse event that occurred at a rate of at least 1% and was more common with eptifibatide than placebo (7% versus 6%) was hypotension. Most of the serious non-bleeding events consisted of cardiovascular events typical of an unstable angina population. In the IMPACT II study, serious non-bleeding events that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and eptifibatide-treated patients.

Discontinuation of study drug due to adverse events other than bleeding was uncommon in the PURSUIT, IMPACT II and ESPRIT studies, with no single event occurring in >0.5% of the study population (except for "other" in the ESPRIT study). In the PURSUIT study, non-bleeding adverse events leading to discontinuation occurred in the eptifibatide and placebo groups in the following body systems with an incidence of ≥0.1%: cardiovascular system (0.3% and 0.3%), digestive system (0.1% and 0.1%), hemic/lymphatic system (0.1% and 0.1%), nervous system (0.3% and 0.4%), urogenital system (0.1% and 0.1%), and whole body system (0.2% and 0.2%). In the ESPRIT study, the following non-bleeding adverse events leading to discontinuation occurred in the eptifibatide and placebo groups with an incidence of ≥0.1%: "other" (1.2% and 1.1%). In the IMPACT II study, non-bleeding adverse events leading to discontinuation occurred in the 135/0.5 eptifibatide and placebo groups in the following body systems with an incidence of ≥0.1%: whole body (0.3% and 0.1%), cardiovascular system (1.4% and 1.4%), digestive system (0.2% and 0%), hemic/lymphatic system (0.2% and 0%), nervous system (0.3% and 0.2%), and respiratory system (0.1% and 0.1%).

Post-Marketing Experience

The following adverse events have been reported in post-marketing experience, primarily with eptifibatide in combination with heparin and aspirin: cerebral, GI and pulmonary hemorrhage. Fatal bleeding events have been reported.

Enoxaparin dosed as a 1.0 mg/kg subcutaneous injection q12h for four doses did not alter the pharmacokinetics of eptifibatide or the level of platelet aggregation in healthy adults.

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