PCI with and without Abciximab after Upstream Eptifibatide Use: Outcomes in High-Risk Patients

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 patients^1,2,4 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. Methods 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.¹²Study 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. Results There was a significantly higher percentage of patients with acute or MI (within 7 days before the index PCI) in the EA group compared to the EE group: 80% versus 53%; p p = 0.284. TIMI bleeding rates were similar for the two treatment groups: 4.1% EA versus 2.6% EE; p = 0.25. The incidence of any vascular complications was comparable for the two treatment groups. No adverse events occurred in-lab for either of the two treatment groups. The in-hospital outcomes for patients stratified by clinical presentation are shown in Table 2. In-hospital outcomes for both treatment groups in patients with unstable angina paralleled the overall outcomes outlined above and were not significantly different. For the MI subgroup, overall MACE was lower for EA, 0.9%, than for EE, 4.3%; p = 0.017. For the entire study population, overall MACE at 30 days was 4.8% for the EE group and 4.2% for the EA group (p = 0.66), and at 1 year, overall MACE rates were similar (25.2% for the EE group and 26.0% for the EA group; p = 0.82). The early and late clinical outcomes following PCI stratified by clinical presentation are shown in Table 3. Kaplan-Meier plots of MACE-free, MI or death-free and revascularization-free survival for patients stratified by clinical presentation and treatment group are shown in Figure 2. In patients with unstable angina, overall MACE at 30 days was lower for the EE group (3.4%) than for the EA group (10.0%) because of a significantly higher rate of nontarget revascularization in the EA group compared to the EE group. At 1 year, overall MACE remained lower in the EE group than the EA group (23.9% vs. 41.7%, respectively; p = 0.013), primarily because of a lower rate of revascularization during follow up in the EE group than in the EA group (20.3% vs. 33.3%, respectively; p = 0.054). In patients with MI, overall MACE was similar at 30 days in the two treatment groups, although recurrent MI or death was lower in the EA group than in the EE group (0.9% vs. 4.4%, respectively; p = 0.017). At 1 year, overall MACE was nonsignificantly lower in the EA group than in the EE group (21.7% vs. 26.3%, respectively; p = 0.285). At 1 year, there was a significantly lower incidence of recurrent MI or death in the EA group than in the EE group (6.9% vs. 15.6%, respectively; p = 0.007). Because of the difference in baseline characteristics in the two treatment groups, we also assessed risk-adjusted outcomes. Standard multivariate analysis using Cox proportional hazards modeling of any MACE at 1 year identified multivessel disease (two- or three-vessel disease) and diabetes as independently predictive of increased overall MACE, and stent use and current smoking as independently predictive of decreased overall MACE (Table 4). A history of MI, diabetes and a MI within 7 days of the index PCI were all independently predictive of a recurrent MI or death. Stent use was independently predictive of a decrease in any revascularization: hazard ratio (HR) 0.57 (0.40–0.80). The risk-adjusted HRs of outcomes at 1 year, EA compared to EE, stratified by clinical presentation, are shown in Figure 2. In patients with unstable angina, the risk-adjusted hazard of overall MACE at 1 year was 1.80 (1.09–2.96), EA compared to EE. The risk-adjusted hazard of any revascularization, however, was no longer significantly higher in the EA group than the EE group: 1.64 (0.95–2.84). In patients with an MI within 7 days of their index PCI, the risk-adjusted HR of overall MACE was 1.16 (0.86–1.56), EA compared to EE. The risk-adjusted HR of MI or death at 1 year remained significantly lower in the EA group compared to the EE group, HR 0.53 (0.28–0.98). Platelet Studies Receptor-binding studies. The receptor-binding study results are shown in Table 5 and Figure 3. In Figure 3, the number of receptor-binding sites identified as MAB1 and MAB2 are shown prior to abciximab administration and 10 minutes and 8 hours after abciximab infusion, with and without pretreatment with eptifibatide. There were no differences in MAB2 at any time period after abciximab use in the absence of eptifibatide. There was a significant increase in MAB2 after abciximab administration following pretreatment with eptifibatide, consistent with washout of eptifibatide. Receptor occupancy increased from 11.2 ± 6.7% to 94.7 ± 1.6% after abciximab without eptifibatide at 10 minutes (p p p p p = NS) versus 10 minutes. Baseline PAU values were available in only 6 patients in the EA group, but the absolute PAU values for all 25 patients at 10 minutes (16 ± 17) and 8 hours (20 ± 17) were similar to the PAU values seen in the abciximab-alone group at the same time periods (p = NS). Discussion This observational, single-center study examined the safety and efficacy of using abciximab for high-risk patients undergoing PCI after upstream treatment with eptifibatide. We found that the incidences of bleeding and vascular complications were similar in patients who received eptifibatide as initial treatment for ACS and abciximab for PCI, compared to patients who received eptifibatide for both medical and interventional therapy. We also observed that the potential benefit of abciximab usage for PCI after upstream treatment with eptifibatide depended on the clinical presentation of the patient at the time of the index PCI. In patients with unstable angina but no MI, the use of abciximab, chosen primarily because of high-risk lesion and procedural characteristics, appeared to be less beneficial than the use of eptifibatide alone. In patients treated with abciximab, revascularization rates were significantly higher than with eptifibatide alone, possibly reflecting the higher-risk characteristics of these patients at the time of their index PCI. In the subgroup of patients who presented with an MI within 7 days of their index PCI, the incidence of MI or death at 1 year was substantially lower in the abciximab group than in the eptifibatide-alone group, although an overall benefit in the subgroup was not observed because of a somewhat higher rate of revascularization in the abciximab group compared to the eptifibatide-alone group. These findings suggest that abciximab in unstable angina patients does not ameliorate high-risk patient or lesion characteristics that are associated with increased rates of restenosis and/or repeat revascularization. These observations, however, are also consistent with recent findings indicating that abciximab during PCI is of benefit in patients with NSTEMI,¹⁷ but not in elective cases.¹⁸ We also examined platelet function in this study and found that abciximab-mediated platelet inhibition after upstream treatment with eptifibatide was comparable to platelet inhibition achieved with abciximab alone. Platelet function has been examined after use of a second GP IIb/IIIa receptor blocker following initial treatment or use of another GP IIb/IIIa receptor blocker.^19,20 In animal studies, platelet aggregability and receptor-binding studies indicated that prior exposure to eptifibatide or tirofiban did not alter the inhibition of platelet aggregability or receptor-binding of abciximab compared to the activity of abciximab alone on these indices of platelet function. In the clinical setting, Lev et al¹⁹ measured several indices of platelet function including receptor occupancy, as was done in this study, and demonstrated that receptor occupancy after administration of abciximab to patients was similar whether they had been previously exposed to tirofiban or eptifibatide compared to receptor occupancy after exposure abciximab alone. Our findings confirm the earlier results of Lev et al. The GP IIb/IIIa inhibitors, eptifibatide and tirofiban,^21,22 but not abciximab,²³ have become standard treatments for patients with an ACS based on several randomized clinical trials. Moreover, both eptifibatide and abciximab have been shown to be of significant benefit in reducing adverse events following PCI, principally MIs.^{1–3,10,24,25} Whether one GP IIb/IIIa inhibitor is superior to another for either ACS or PCI treatment has surprisingly been evaluated in only one randomized clinical trial.⁵ In the TARGET study,⁵ abciximab was shown to be superior to tirofiban for use during PCI based on 30-day outcomes, although it is not certain that the dose of tirofiban used in the study was optimal.^26,27 Whether abciximab would be superior to eptifibatide during PCI has not been examined in a randomized clinical trial, although multiple single-center experiences have been published with varying results.^7,28,29 Based on a strategy of using abciximab selectively for higher-risk patients⁶ in a single-center observational study, we previously observed superior early outcomes with abciximab compared to eptifibatide in patients undergoing PCI.⁷ Since that time, however, upstream use of eptifibatide for patients with ACS has become standard practice.^21,22 Moreover, data from the recent EVEREST trial,¹¹ a randomized comparison of upstream low-dose tirofiban versus high-dose tirofiban or abciximab at the time of PCI, found that the low-dose tirofiban arm was associated with improved tissue level perfusion and attenuated myocardial damage. Whether selective use of abciximab after upstream use of GP IIb/IIIa inhibition confers additional benefit, however, has not been extensively studied.^19,30 Recent studies have more clearly defined the circumstances when abciximab is beneficial during PCI. In the ISAR REACT study,¹⁸ PCI outcomes were evaluated after 600 mg of oral clopidogrel, with or without abciximab, in low- to moderate-risk patients. Abciximab did not provide additional benefit to clopidogrel in these patients, suggesting that potent antiplatelet effects are not necessary in lower-risk patients. Similarly, in the present study, in patients with upstream treatment with eptifibatide for ACS, abciximab did not confer additional benefit in patients with unstable angina but no MI. By contrast, in the ISAR-REACT 2 trial,¹⁷ abciximab use conferred additional benefits to 600 mg of clopidogrel in patients with ACS and elevated troponin undergoing PCI. These latter data, and observations from this study suggest that abciximab may have incremental benefit in the highest-risk subgroup of patients with ACS (positive cardiac markers) undergoing PCI, even with upstream treatment with eptifibatide or clopidogrel. Study limitations. There are limitations that should be addressed. This is a single-center, observational study, and thus is subject to biases that might have affected the study outcomes. While only a carefully performed randomized trial could minimize these potential biases, the present observations reflect real-world experience. Angiographic follow up was performed for clinically indicated reasons only, thus the actual incidence of restenosis could not be assessed. Finally, this study was performed prior to the availability of drug-eluting stents. Whether similar late results would occur in the drug-eluting stent era is uncertain, but it is likely that the early results would still be relevant. Conclusion In this single-center, observational study of patients with ACS, the strategy of abciximab use for PCI after initial ACS treatment with eptifibatide resulted in bleeding and vascular complications that were similar to complication rates observed in patients who received eptifibatide for both treatment of ACS and PCI. In patients with unstable angina, the use of abciximab for PCI after upstream use of eptifibatide appeared less beneficial than the use of eptifibatide alone, while in the subgroup of patients with MI within 7 days of their index PCI, the incidence of MI or death at 1 year appeared lower with abciximab than with eptifibatide alone. Finally, receptor occupancy was similar after abciximab use whether or not eptifibatide was used as initial treatment. These observations are consistent with recent findings indicating that abciximab is of benefit in patients with NSTEMI, but not in lower-risk patients. Acknowledgement. The authors acknowledge the expert secretarial assistance of Tammy Davis.

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