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New approaches to eptifibatide administration
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Eptifibatide, an intravenous glycoprotein IIb/IIIa inhibitor, is approved for use in the treatment of patients with acute coronary syndromes. It is also indicated for use in patients undergoing percutaneous coronary intervention, including coronary stenting.
The American College of Cardiology and the American Heart Association recommend either an intravenous glycoprotein IIb/IIIa inhibitor or clopidogrel before diagnostic angiography for low-risk patients and both for high-risk, troponin-positive patients (Class I recommendation).
For ACS, eptifibatide (Integrilin, Schering) is given as an IV bolus of 180 mcg/kg followed by an infusion of 2 mcg/kg per minute until hospital discharge or CABG (up to 72 hours). The dose for PCI is two 180 mcg/kg boluses administered 10 minutes apart, followed by an infusion of 2 mcg/kg per minute for 18 to 24 hours post-procedure. Although eptifibatide has indicated efficacy in multiple trials, there is a risk for bleeding associated with its use. The results of two recent trials, BRIEF-PCI and EARLY-ACS, suggested new dosing strategies for eptifibatide therapy that retain the drugs’ efficacy but minimize bleeding risk and reduce cost.
BRIEF-PCI
The BRIEF-PCI trial was a randomized, double blind, controlled study conducted to compare abbreviated eptifibatide infusion (<2 hours) with a standard infusion (18 hours) in 624 patients with stable angina, ACS or STEMI (>48 hours). Included were patients scheduled for nonemergent PCI or referred for diagnostic catheterization and possible PCI. All patients received aspirin pretreatment and underwent successful PCI with stenting. Adequate clopidogrel pretreatment (defined as 75 mg/day >4 days; 300-mg loading >6 hours or 600-mg loading >2 hours) was administered in 71% of patients in the <2-hour infusion group and 66% in the standard infusion group. The remaining patients were assigned clopidogrel 600 mg before or immediately after PCI. Patients with recent STEMI (<48 hours); visible thrombus; bivalirudin (Angiomax, The Medicines Company) treatment; unprotected left main; use of ablative or thrombectomy devices; allergy or intolerance to aspirin, thienopyridines or eptifibatide; or unsatisfactory PCI results were excluded.
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The primary endpoint — incidence of ischemic myonecrosis within 24 hours of PCI and before hospital discharge — did not differ between the treatment groups (30.1% in the ≤2-hour group vs. 28.3% in the standard group; mean difference: 1.8%; upper bound of 95% CI: 7.8%; P<.012 for noninferiority). There was no difference in the 30-day incidence of MI, death and target revascularization between the two groups. However, there was less in-hospital major bleeding in the <2-hour group compared with the standard group (1.0% vs. 4.2%; P=.02) based on REPLACE-2 criteria.
EARLY ACS
The EARLY ACS study compared early, routine eptifibatide administration with delayed, provisional administration in 9,492 high-risk patients with ACS (excluding STEMI) presenting within four hours of symptoms who were assigned to an invasive strategy. Patients included were considered high risk based on meeting two or more of the following criteria: ischemic changes on electrocardiogram; a troponin or CK-MB above the upper limit of normal; and aged older than 60 years. Patients in the early arm were assigned eptifibatide in two 180 mcg/kg boluses, followed by a 2 mcg/kg per minute infusion at trial randomization that continued for 18 to 24 hours after PCI. The delayed group was assigned eptifibatide after coronary angiography but before PCI. The infusion was continued for 18 to 24 hours after PCI. More than 97% of patients in each group were assigned aspirin on enrollment and 75% of patients in each arm were assigned early clopidogrel therapy (300- to 600-mg loading dose).
EARLY ACS results demonstrated no difference in the primary composite outcome of death, MI, recurrent ischemia requiring urgent revascularization or the occurrence of thrombotic complications requiring bailout therapy at 96 hours (9.3% vs. 10.0%; OR=0.92; 95% CI, 0.80-1.06). There was also no difference in the composite secondary endpoint of death or MI at 30 days (P=.08). No difference in the incidence of severe bleeding between the two treatment groups based on GUSTO criteria was observed. However, there was a higher rate of GUSTO moderate bleeding (6.8% vs. 4.3%; P=.001) and an increased need for red blood cell transfusion (8.6% vs. 6.7%; P=.001) in the early-eptifibatide group. There was also an increased rate of TIMI major (2.6% vs. 1.8%; P=.015) and minor bleeding (3.6% vs. 1.7%; P=.001) in the early-eptifibatide group.
The researchers from these trials evaluated new strategies for the administration of eptifibatide. The BRIEF-PCI trial results suggested that the post-procedure infusion of eptifibatide can be decreased to two hours in low-risk patients undergoing successful and uncomplicated PCI. The EARLY-ACS trial results showed that there is no benefit from the routine use of early eptifibatide therapy in high-risk ACS patients managed with an invasive strategy, which also ups the bleeding risk.
Although these new approaches have yet to be validated in broader populations, implementing either of them in patients similar to those included in the studies may result in optimal outcomes and reduced bleeding — at a reduced cost.
Emily Young Breedlove, PharmD, BCPS, is a Clinical Pharmacy Specialist in Cardiology, University Hospital, and Adjunct Clinical Instructor, James L. Winkle College of Pharmacy, University of Cincinnati.
Rhonda Cooper DeHoff, PharmD, MS, Associate Professor, University of Florida College of Pharmacy, Gainesville, is Cardiology Today’s regular Pharmacology Consult columnist and a member of the CHD and Prevention section of the Cardiology Today Editorial Board.
For more information:
- Anderson JL. J Am Coll Cardiol. 2007;50:e1-e157.
- Fung AY. J Am Coll Cardiol. 2009;53:837-845.
- Giugliano RP. N Engl J Med. 2009;360:2176-2190.