COMMENTARY: Alternative Safe, Effective and Cost-Efficient Dosing for Eptifibatide in Low-Risk Patients

Platelets play a central role in coronary atherothrombosis.¹ Local trauma to the coronary artery at the site of percutaneous coronary intervention (PCI) causes endothelial denudation and platelet activation. The level of ambient platelet activation prior to and during PCI has been shown to predict subsequent adverse clinical outcomes. The platelet glycoprotein receptor IIb/IIIa (GP IIb/IIIa) serves as the final common pathway of platelet aggregation by binding fibrinogen and other adhesive ligands that cross-link adjacent platelets.² Adjunctive use of GP IIb/IIIa antagonists has contributed significantly to the improvements of PCI success and safety over the last decade. In a meta-analysis of 19 trials involving 20,137 patients, 30-day and 6-month mortality rates were both significantly reduced for those receiving GP IIb/IIIa antagonists. An absolute reduction of 1.5% to 6.5% in the 30-day risk of death, myocardial infarction (MI) or repeat urgent revascularization can be anticipated with some variability among the agents tested.³ The clinical utility of eptifibatide, a short-acting cyclic heptapeptide that reversibly inhibits the GP IIb/IIIa receptor, was evaluated in two major prospective, randomized trials. The Integrilin to Minimize Platelet Aggregation to Prevent Coronary Thrombosis-II (IMPACT II) trial enrolled 4,010 patients undergoing coronary angioplasty. Two different low-dose regimens were used versus placebo. There was no statistically significant difference in the combined endpoint of death or myocardial infarction at 30 days between the placebo versus the 2 integrilin dosing regimens. The frequency of major bleeding was similar among the three groups.⁴ The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) study evaluated a larger double eptifibatide bolus (two 180 ug/kg boluses 10 minutes apart) and continuous infusion (2.0 ug/kg/minute for 18 to 24 hours), or a placebo in 2,064 patients undergoing nonemergency coronary stent implantation. The 48-hour primary combined endpoint of death, MI, urgent target vessel revascularization or thrombotic bailout was reduced by 37% with eptifibatide. At 30 days, the secondary composite endpoint of death, MI and urgent target vessel revascularization was also improved by 35%, and these benefits were maintained at 6 months and 1 year. Major bleeding was rare, but occurred more frequently in patients assigned to eptifibatide compared with placebo (1.3% versus 0.4%, respectively; p = 0.027).⁵ The limitations that contribute to the underutilization of GP IIb/IIIa antagonists in current interventional practice are mainly focused around bleeding risks and cost. Additionally, the recent demonstration of equivalent efficacy of eptifabitide and bivalirudin in the REPLACE-2 trial and pilot results from the ACUITY study, with diminished risk of bleeding with bivalirudin, provide an attractive evidence-based alternative to the use of GP IIb/IIIa inhibitors.⁶ In this issue of the Journal, Fischell et al evaluated the efficacy, safety and cost of single-bolus, high-dose eptifibatide as an alternative to the conventional double-bolus plus intravenous infusion dosing regimen for elective PCI. Toward that goal, they studied 401 patients with stable and unstable angina who were treated with a 20 mg single bolus of eptifibatide plus weight-adjusted heparin prior to the start of elective PCI. All patients received aspirin and clopidogrel or ticlopidine. Similar to the ESPRIT and REPLACE-2 trials, the primary endpoint of this study was major clinical adverse events (MACE) defined as in-hospital and 30-day mortality, MI, repeat urgent target vessel revascularization and/or major bleeding events. In-hospital MI occurred in 7 patients (1.75%) and major bleeding complications in 2 patients (0.49%). Four additional MACE events occurred in the 30-day follow up. The average per-patient anticoagulation cost was $66. Potent platelet inhibition was confirmed by point-of-care testing in the first 32 patients, and based upon known pharmacokinetics of eptifabitide, platelet inhibition was expected to last for at least 2 to 3 hours after the single high-dose bolus. The authors suggested that adoption of high-pressure stent deployment and use of high-dose thienopyridines are measures that attenuate the risks of acute closure and thrombotic complications, and as such, may obviate the need for postprocedural prolonged infusion of GP IIb/IIIa inhibitors. The clinical outcomes in this study compare favorably with those observed in both the ESPRIT and REPLACE-2 trials. The median cost of the eptifibatide regimen in the ESPRIT was $502. In the REPLACE-2 trial, the costs of eptifabitide and bivalirudin were $930 and $530, respectively.⁷ In contrast, the cost of a single-bolus vial of eptifibatide in this study was $59. When combined with the small cost for weight-adjusted heparin, the total average cost per patient was $66. The Fischell et al study is an observational registry that has several important limitations, including the lack of a control arm. Furthermore, no statistical analysis was used to compare the results of this study with outcomes from previous trials, despite relating current results to historical data. The study also excluded MI and coronary artery bypass graft patients, leaving the question of the effectiveness of this single-bolus regimen in a higher-risk population unanswered. This is an important point, given the recent data from Puma et al comparing the long-term outcomes of high- versus low-risk patients in the ESPRIT trial, as well as data from the ISAR-REACT II, showing that the greatest benefit of GP IIb/IIIa inhibitors is seen primarily in high-risk patients.^8,9 Clearly, there is a need for a large, prospective, controlled, randomized trial to confirm the outcomes of this novel approach and evaluate its efficacy and safety in various patient populations.

References 1. Fitzgerald DJ, Roy L, Castella F, et al. Platelet activation in unstable coronary artery disease. N Engl J Med 1986;315:983–989. 2. Coller BS. Blockade of GP IIb/IIIa receptors as an antithrombotic strategy. Circulation 1995;92:2373–2380. 3. Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein IIb/IIIA receptor antagonists reduce mortality after percutaneous coronary interventions. J Am Coll Cardiol 2003;41:26–32. 4. The IMPACT II Investigators. Integrilin to minimize platelet aggregation to prevent coronary thrombosis-II (IMPACT II). Lancet 1997;349:1422–1428. 5. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT). Lancet 2000;356:2037–2044. 6. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIA blockade compared with heparin and planned IIb/IIIA blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863. 7. Cohen DJ, Lincoff MA, Lavelle TA, et al. Economic evaluation of bivalirudin and provisional glycoprotein IIb/IIIA blockade compared with heparin and planned IIb/IIIA blockade during percutaneous coronary intervention: Results from the REPLACE-2 trial. J Am Coll Cardiol 2004;44:1792–1800. 8. Puma JA, Banko LT, Pieper KS, et al. Clinical characteristics predict benefits from eptifibatide therapy during coronary stenting: insights from the ESPRIT trial. J Am Coll Cardiol 2006;47:715–718. 9. Kastati A, Mehilli J, Neumann FJ, et al. Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. JAMA 2006;295:1531–1538.