PCI with and without Abciximab after Upstream Eptifibatide Use: Outcomes in High-Risk Patients
- Volume 18 - Issue 12 - December, 2006
- Posted on: 8/1/08
- 1 Comments
- 6366 reads
Several clinical trials have demonstrated that platelet glycoprotein (GP) IIb/IIIa receptor inhibition reduces the ischemic complications of percutaneous coronary interventions (PCI).1–4 Comparative data between agents, however, are very limited,5 and no large, randomized trials exist comparing the efficacy and safety of the two most commonly used agents, eptifibatide and abciximab. Based on clinical trials demonstrating a clear benefit of abciximab in high-risk patients1,2,4 and a more modest benefit of eptifibatide use in the ESPRIT trial,4 a strategy for use of GP IIb/IIIa inhibitors during PCI with abciximab for high-risk patients and eptifibatide for lower-risk patients has been proposed.6 We previously reported results from a single-center observational study in acute coronary syndrome (ACS) patients undergoing PCI that early outcomes were superior with abciximab compared to eptifibatide.7
In addition to the clinical trials demonstrating a benefit of GP IIb/IIIa inhibitor use in the catheterization laboratory at the time of the PCI, there has also been increasing usage of GP IIb/IIIa inhibitors to treat patients with ACS in the early phase of their hospitalization.8–10 Recent data suggest that in patients with high-risk ACS features that upstream use of a low-dose of tirofiban prior to and following PCI may be superior to high-dose bolus tirofiban or abciximab administered at the time of the PCI.11 Whether the strategy of selective use of abciximab for high-risk ACS patients as noted above, after upstream use of eptifibatide, is superior to continued eptifibatide use for PCI, however, is uncertain. We report our experience of the selective use of abciximab for high-risk ACS patients following upstream use of eptifibatide and compare it to the use of eptifibatide for both upstream and PCI treatment of patients with ACS.
Patients. Patients were eligible for the study if they had unstable angina: an episode of angina with an accelerating pattern, prolonged pain (> 20 minutes) or recurrent episodes of pain at rest or with minimal effort within the preceding 24 hours of hospital admission; non-ST-elevation myocardial infarction (NSTEMI): elevation of cardiac markers above institutional normal values in the absence of Q-waves; or STEMI: elevated cardiac markers and ST-elevation or new Q-waves. All patients in the study underwent PCI between 1999 and 2003. The control group consisted of patients who received upstream treatment with eptifibatide (180 mcg/kg bolus followed by 2.0 mcg/kg/minute intravenous drip) and heparin, and eptifibatide during PCI and for up to 18 hours post-PCI. The study group consisted of patients who also received eptifibatide (same dose as the control group) as upstream treatment for ACS, but who received abciximab during the PCI and for 12 hours post-PCI. Patients were not excluded from the study for any clinical reasons. The study was approved by the Institutional Review Board of Wake Forest University Baptist Medical Center.
Percutaneous revascularization procedure. Patients underwent percutaneous revascularization procedures, including atherectomy, using standard techniques. The choice of the type of PCI procedure was at the discretion of the interventionalist performing the procedure. No patient received drug-eluting stents, as they were not available during the study period. The method of arterial access site management was chosen by the interventionalist.12
Study medications. The choice of GP IIb/IIIa inhibitor to be used during the PCI was left to the discretion of the interventionalist. In general, the decision to use abciximab was made if high-risk patient (recent NSTEMI or STEMI), lesion (diffuse disease, multivessel disease, visible thrombus, bifurcation disease) or procedural (atherectomy) features were present. In those patients in whom abciximab was used, the eptifibatide infusion was stopped in the catheterization laboratory and abciximab was administered in standard fashion as a 0.25 mg/kg bolus followed by 0.125 µg/kg/minute (maximum 10 mcg/minute) intravenous infusion for 12 hours. In those patients in whom upstream treatment with eptifibatide was followed by eptifibatide administration during the PCI procedure, the eptifibatide infusion was continued at the same dose, with an additional bolus (180 mcg/kg) administered at the discretion of the interventionalist in 72% of patients. Heparin was administered as needed during the PCI procedure to maintain an activated clotting time between 200 and 250 seconds. No additional heparin was administered while the GP IIb/IIIa inhibitor was administered following the interventional procedure. All patients were pretreated with aspirin (325 mg) on admission and received aspirin on a daily basis thereafter. Ticlopidine 250 mg po bid or clopidogrel 300 mg po load followed by 75 po qd were given prior to or immediately after the procedure.
Platelet Function Studies
Glycoprotein IIb/IIIa receptor-binding assay. Blood samples were obtained in 25 patients receiving abciximab in standard fashion without pretreatment with eptifibatide, and in 25 patients receiving abciximab following eptifibatide pretreatment as outlined above. Samples were obtained prior to administration of abciximab, 10 minutes after administration of abciximab and 8 hours following administration of abciximab in all patients. We used the platelet GP IIb/IIIa occupancy kit (Biocytex, France) to determine MAB1 and MAB2 binding in our study groups. The method uses a flow cytometric assay to quantify binding of two monoclonal antibodies LYP18 (MAB1) and 4F8 (MAB2) to GP IIb/IIIa receptors.13 Binding of MAB1 to GP IIb/IIIa receptors has been shown to be inhibited by abciximab, whereas MAB2 binding is unaffected by it. In contrast, small molecular- weight antagonists inhibit MAB2, but not MAB1-binding.13 This kit employs whole blood diluted 1:4 in PBS BSA buffer, a negative isotypic control, MAB1 reagent, MAB2 reagent, a calibrated bead suspension and a polyclonal antimouse IgG-FITC. Samples were analyzed in a FACS Calibur (Becton-Dickenson, Franklin Lakes, New Jersey) and gated on log-forward versus log-side scatter to identify the platelet or bead populations. A calibration curve was plotted using the mean fluorescence intensity of the beads and their corresponding number of monoclonal antibody molecules. Results were expressed as the total number of binding sites/platelet for MAB1 and MAB2. Receptor occupancy was determined as (MAB2-MAB1)/MAB2 x 100% in the presence of abciximab, and as (MAB1-MAB2)/MAB1 x 100% in the presence of eptifibatide.
Ultegra RPFA. Determination of Ultegra RPFA (rapid platelet function assay) platelet activation units (PAU) was made with the same blood samples used to assess platelet receptor binding. Details of this method have been reported elsewhere.14 The RPFA is based on an interaction between platelet GP IIb/IIIa receptors and fibrinogen-coated beads, leading to the agglutination of the beads. Pharmacological blockade of GP IIb/IIIa receptors prevents this interaction and thereby diminishes agglutination in proportion to the degree of receptor blockade achieved. The light absorbance of the sample is measured as a function of time, and the rate of agglutination is quantified as PAU.
Outcomes evaluation. The procedural and hospital outcomes of all patients in the study were evaluated by dedicated research nurses for occurrence of complications and entered into a database following each procedure (CAOS, IBS, Winston-Salem, North Carolina).12 As a supplement to the database query, an independent chart review of all patients was performed. CK measurements were performed prior to and every 8 hours and up to 24 hours after each coronary intervention or until discharge from the hospital, whichever came first. In the event of a myocardial infarction (MI) postprocedure, CK measurements were obtained until a peak was determined. Electrocardiography, blood and chemistry assays were performed on the morning of, 2 hours following the administration of abciximab and the day following each coronary intervention. Outcome measures conformed to the outcomes defined in the ACC-NCDR.15 Bleeding was defined according to TIMI classification.16 In-hospital and follow-up major adverse cardiac events (MACE) were defined as recurrent MI, any revascularization or death.
Postprocedural MI was determined by clinical criteria including prolonged chest pain with elevated cardiac markers: STEMI was defined as the presence of new Q-waves with an elevated CPK-MB > 15 units/ml; NSTEMI was defined as the presence of elevated CPK-MB > 15 units/ml in the absence of Q-waves. In patients in whom cardiac markers were elevated prior to the PCI procedure, a postprocedural MI was determined to have occurred if there was postprocedural elevation of cardiac markers (CPK-MB) to > 3 times the preprocedural baseline. Chronic renal insufficiency was defined as a preprocedural serum creatine > 2 mg/dl. Congestive heart failure was defined as New York Heart Association class ? II. Target lesion revascularization (TLR) was defined as either re-do CABG or PCI for the same lesion. Follow-up data were collected from outpatient clinic visits, scripted telephone follow up, and the Social Security Death Registry.
Statistical methods. Data are presented as mean ± standard deviation (continuous variables), or as percent (categorical variables). Baseline covariates were compared by Chi-square testing (categorical) or the Wilcoxon rank sum test (continuous). Kaplan-Meier plots of MACE-free survival were constructed from the index procedure to 1 year of follow up. The log-rank test was used to test for significant differences in the survival curves of the two treatment groups. Predictors of MACE to 1 year were evaluated by univariate and multivariate Cox proportional hazards models. SAS, version 8.02 statistical software package (SAS Institute, Cary, North Carolina) was used for all statistical analysis.