Comparative Pharmacodynamic Evaluation of Eptifibatide and Abciximab in Patients with Non-ST-Segment Elevation Acute Coronary Syndromes: The TAM2 Study
Background: The importance of the relationship between clinical outcome and degree of platelet aggregation inhibition (PAI) achieved with the dosing regimens of GPIIb-IIIa inhibitors used in large trials in patients with non-ST segment elevation (NSTE) acute coronary syndromes (ACS) is increasingly appreciated. In the PURSUIT trial, eptifibatide treatment that consistently provided >80% PAI was associated with clinical benefit at 30 days and 6 months. The GUSTO IV ACS trial, however, did not show any effect of abciximab on 30-day outcomes. This difference might be due to variability of antiplatelet effects of these drugs. As previous studies found, a 12 hr abciximab infusion had <80% PAI, particularly at 6 and 12 hr. These studies did not evaluate PAI with a longer, 24-hour infusion as used in GUSTO IV ACS. Methods: We conducted a prospective study in 40 patients with NSTE ACS prior to catheterization or coronary intervention at 3 centers using the PURSUIT dose of eptifibatide (180/0.2) and the GUSTO IV dose of abciximab (0.25, 0.125). Blood samples were collected at baseline, and during the infusion at 10 min, 1 hr, 6 hr, 8 hr, 12 hr, 18 hr, and 24 hr. Measurements of ex vivo light transmission aggregometry (LTA) were performed using PPACK anticoagulant and 20 μM ADP agonist. Receptor Occupancy (RO) was also determined in a subset of patients. Results: Eptifibatide achieves higher PAI during the entire infusion period than abciximab (p < 0.01). At 10 min, average PAI with eptifibatide and abciximab was 88% and 80%, respectively, 95% and 79% at 6 hr, and 97% and 79% at 24 hr. There was also more variability in individual patient response to abciximab. Although average RO for eptifibatide was similar to that of abciximab at 10 min, 67% versus 69%, respectively, average RO was higher in the eptifibatide cohort at all subsequent timepoints. By 24 hr, average RO for eptifibatide was 86%, whereas abciximab averaged 67%. Conclusion: These data support the hypothesis that differences in clinical outcomes of large GPIIb-IIIa trials in patients with NSTE ACS may be related to the consistency and potency of antiplatelet effects of the dosing regimens used. Abbreviated abstract. We compared platelet aggregation inhibition (PAI) with the glycoprotein IIb-IIIa inhibitors eptifibatide and abciximab in patients with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS), using light transmission aggregometry assays with D-phenylalanyl-L-propyl-L-arginine chloromethylketone (PPACK) as the anticoagulant and 20 μmol adenosine diphosphate (ADP) as the platelet agonist. Mean PAI with eptifibatide during the entire 24-hour infusion period was >80%, and it was significantly higher than the mean PAI achieved with abciximab (p < 0.0001). Mean PAI with abciximab was <80% at 6, 8, 12, 18, and 24 hr. Most patients in the eptifibatide arm had >80% PAI at all time points, whereas many patients treated with abciximab had <80% PAI throughout the infusion period, particularly at later times (6 hr and beyond). Mean GPIIb-IIIa receptor occupancy with eptifibatide was also higher than with abciximab. These pharmacodynamic differences may have contributed to differing clinical effects of eptifibatide and abciximab in large clinical trials in patients with NSTE ACS.