Pharmacy and Therapeutics - January 2008 - (Page 53) Meeting Highlights: American Heart Association, 2007 dose warfarin of 10 mg on days one and two, followed by 5 mg daily (i.e., 35 mg weekly, modified by INR results) as a comparator therapy to the PG-guided warfarin dosing. The follow-up period lasted as long as three months. For PGguided dosing, the investigators performed a genetics test using buccal swab samples and a rapid assay. Dosing was determined via a regression equation. Scores were categorized into 14 daily dose increments. The primary endpoint was the percentage of out-of-range INRs (below 1.8 and above 3.2), with a subset analysis by genotype. The enrolled patients included those with an indication for oral anticoagulation (mean age, 61 years; 53% male). The target INR was 2 to 3. The initial maintenance dose was scaled according to the number of variant alleles. Patients with the wild-type form (no variant alleles) received warfarin 44.7 mg/week; those with the maximum number of variants (four) received 8 mg/week. Dr. Anderson reported that although PG modeling was good at predicting the observed warfarin stable maintenance dose, the primary endpoint of percentage out-of-range INRs was not significantly reduced in the PG-guided group (30.7%), compared with the standard-dosing group (33.1%) (P = 0.47). For the prespecified groups, the difference in the percentage of out-of-range INRs was significant only when patients with multivariant alleles were added to those with the wild-type form: 29.3% for PG modeling and 39.1% for standard-dose warfarin (P = 0.03). Dr. Anderson called this analysis “exploratory” but suggested that although Couma-Gen demonstrated the feasibility of real-time genotyping, and PG-guidance was associated with a need for less INR monitoring and fewer dose adjustments, reduced percentages of out-of-range INRs were not achieved. 1. In the absence of eptifibatide, it took a loading dose of clopidogrel about six hours to achieve the level of reduced platelet aggregation observed in patients receiving the clopidogrel maintenance dose. 2. Inhibition of platelet aggregation (IPA) with eptifibatide was immediate and significantly greater than in the patients receiving bivalirudin alone, without variability in response. Cardiac marker release was also higher in the non-eptifibatide patients. Although the trial was not powered for clinical events, Dr. Gurbel noted lower rates of periprocedural myocardial infarction (MI) in the eptifibatide groups; however, there was some increase in major bleeding. He concluded that CLEAR PLATELETS 2 supported the link between platelet reactivity and post-stent MI. He speculated further: “Selection of patients for adjunctive GP IIb/IIIa blockade may be facilitated in future studies by individualized platelet function measurements.” EVA–AMI: Eptifibatide and Abciximab Presenter: Uwe Zeymer, MD, Herzzentrum Ludwigshafen, Germany EVA–AMI (Eptifibatide versus Abciximab in Primary PCI for Acute ST elevation Myocardial Infarction), another latebreaking trial, suggested that the antithrombin agent eptifibatide (Integrilin), given as a double bolus, might be an alternative to abciximab (ReoPro, Centocor/Lilly) in STEMI patients undergoing primary PCI. Both acquisition and hospitalization costs have been significantly lower with eptifibatide than with abciximab.1 Dr. Zeymer said that abciximab and eptifibatide, which are both GP IIb/IIIa inhibitors, reduce events in elective PCI patients, but they have not been compared directly. The objective of EVA–AMI was to show non-inferiority for eptifibatide in patients scheduled for primary PCI who were receiving an abciximab bolus plus a 12-hour infusion or a double bolus of eptifibatide plus a 24-hour infusion. The primary endpoint was complete ST resolution at one hour after PCI, a marker of myocardial reperfusion that is closely linked to mortality after STEMI. Among 429 patients (mean age, 61 years), complete reperfusion was similar between the groups (59.6% for abciximab, 63.1% for eptifibatide) (P = not significant), as were in-hospital events (death, re-infarction, heart failure, tricuspid valve replacement, and CABG). Dr. Zeymeyer concluded: “Eptifibatide given as a double bolus is equally effective as abciximab as adjunct to primary PCI with respect to myocardial reperfusion. Also, there were no differences in preliminary clinical events.” CLEAR PLATELETS: Clopidogrel, Eptifibatide, and Bivalirudin Presenter: Paul Gurbel, MD, Sinai Hospital, Baltimore, Md. Further promise toward highly individualized therapy was suggested in the setting of coronary artery disease for patients undergoing elective stenting. Dr. Gurbel presented the CLEAR PLATELETS 2 trial (Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets). This study enrolled 200 individuals receiving clopidogrel (a loading dose of 600 mg for clopidogrel-naive patients and 75 mg/day for those already on clopidogrel maintenance doses) plus the standard dose of bivalirudin (Angiomax, The Medicines Company) with or without the standard dose of the glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor eptifibatide (Integrilin, Millennium/Schering). All patients received 325 mg of aspirin per day. The investigators evaluated the relationship between platelet aggregation and biochemical markers of myocardial necrosis, namely troponin and the creatine kinase-MB (CK-MB) isoenzyme. For the evaluations, platelet aggregation was induced with adenosine diphosphate (ADP), collagen, and the thrombin receptor agonist peptide (TRAP). Dr. Gurbel pointed to two important findings from the platelet-aggregation study: REFERENCE 1. Coons JC. Outcomes and costs of abciximab versus eptifibatide for percutaneous coronary intervention. Ann Pharmacother 2005; 39(10):1621–1626. I Vol. 33 No. 1 • January 2008 • P&T® 53
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