Coronary Heart Disease

Coronary Heart Disease Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial Tracy Y. Wang, MD, MHS, MSc; Jennifer A. White, MS; Pierluigi Tricoci, MD, PhD, MHS; Robert P. Giugliano, MD, SM; Uwe Zeymer, MD; Robert A. Harrington, MD; Gilles Montalescot, MD, PhD; Stefan K. James, MD, PhD; Frans Van de Werf, MD, PhD; Paul W. Armstrong, MD; Eugene Braunwald, MD; Robert M. Califf, MD; L. Kristin Newby, MD, MHS Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 Background In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use. Methods and Results In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-st-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P 0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P 0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata. Conclusions Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-st-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials. Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier NCT00089895. (Circulation. 2011;123:722-730.) Key Words: platelets anticoagulants eptifibatide clopidogrel acute coronary syndrome Current American College of Cardiology/American Heart Association and European Society of Cardiology clinical practice guidelines recommend that, for patients with non ST-segment elevation acute coronary syndrome (NSTE ACS) treated with an early invasive management strategy, antiplatelet therapy with either clopidogrel or a glycoprotein IIb/IIIa inhibitor should be initiated upstream before diagnostic angiography (Class I recommendation, level of evidence A). 1,2 Received March 31, 2010; accepted December 17, 2010. From the Duke Clinical Research Institute (T.Y.W., J.A.W., P.T., R.A.H., L.K.N.), Durham, NC; TIMI Study Group (R.P.G., E.B.), Brigham and Women s Hospital, Boston, MA; Herzzentrum Ludwigshafen (U.Z.), Ludwigshafen, Germany; Institut de Cardiologie (G.M.), Pitié-Salpêtrière Hospital, Paris, France; Uppsala University Hospital (S.K.J.), Uppsala, Sweden; University Hospital Gasthuisberg and Leuven Coordinating Center (F.V.W.), Leuven, Belgium; University of Alberta (P.W.A.), Edmonton, Alberta, Canada; and the Duke Translational Medicine Institute (R.M.C.), Durham, NC. Guest Editor for this article was Eric R. Bates, MD. Correspondence to Tracy Y. Wang, MD, MHS, MSc, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC 27705. E-mail tracy.wang@duke.edu 2011 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.958041 722

Wang et al Early Eptifibatide With Upstream Clopidogrel in ACS 723 Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 Among patients with high-risk features, upstream initiation of both clopidogrel and glycoprotein IIb/IIIa inhibitor can be considered before coronary angiography (Class IIa recommendation, level of evidence B). Clinical Perspective on p 730 The ACS state is associated with enhanced platelet activation and aggregation, 3 and the use of more potent antiplatelet therapies improves clinical outcomes. 4,5 Among ACS patients treated with percutaneous coronary intervention (PCI), evidence increasingly shows that early upstream clopidogrel treatment prevents postprocedural ischemic complications. 6 8 However, in these studies, glycoprotein IIb/IIIa inhibitors were either rarely used or initiated later in the periinterventional setting. The Early Glycoprotein IIb/IIIa Inhibition in Patients with Non ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial randomized patients presenting with high-risk NSTE ACS for whom an invasive strategy was planned to upstream placebo or upstream eptifibatide with delayed, provisional eptifibatide use at the time of PCI. The primary results showed that use of eptifibatide 12 hours before angiography was not superior to delayed provisional use during PCI but resulted in more bleeding and transfusion. 9 The trial stratified randomization by declared intent for upstream clopidogrel use. In the overall study population, no significant between-group interactions were observed for the trial s primary and key secondary efficacy end points. In this analysis, we evaluated the patients who underwent coronary angiography to examine whether clopidogrel pretreatment influenced the benefit and safety of routine upstream eptifibatide use before angiography, considering clopidogrel use both by treatment intent and actual treatment received. Methods Study Population The design of EARLY ACS has been described in detail previously. 9,10 In brief, patients with ischemic symptoms lasting at least 10 minutes and occurring within 24 hours of randomization were eligible if 2 of the following criteria were met: new ST-segment depression or transient ST-segment elevation 0.1 mv in 2 contiguous leads, troponin or creatine kinase MB elevation, age 60 years, or age 50 to 59 years with documented coronary, cerebrovascular, or peripheral artery disease (marker elevation was required in the age 50 to 59 group). Major exclusion criteria were an increased risk of bleeding, an allergy to heparin or eptifibatide, pregnancy, renal dialysis within the previous 30 days, recent use of a glycoprotein IIb/IIIa inhibitor, and any other condition that posed an increased risk. A total of 9492 patients were randomized within 12 hours of hospital admission to receive either early administration of double bolus and infusion of eptifibatide or early placebo with delayed provisional administration of eptifibatide after angiography but before the patient underwent PCI at the treating physician s discretion. Of these, 9406 were evaluable for the primary and key secondary end points (see Giugliano et al for details 9 ), and 240 patients did not proceed to catheterization, leaving 9166 patients eligible for this analysis. Eptifibatide and Clopidogrel Treatment In EARLY ACS, randomization was performed in blocks according to study center and was stratified by the intention of the investigator to administer upstream clopidogrel (ie, before coronary angiography). By protocol, angiography was to occur at least 12 hours after initial study drug administration. Clopidogrel use and timing of initiation were determined by treating physicians. If early clopidogrel was used, the recommended loading dose was 300 mg. A 600-mg loading dose was permitted during PCI if no previous loading dose had been administered. The recommended maintenance dose of clopidogrel was 75 mg daily. Patients concomitantly received aspirin (162 to 325 mg oral or 150 to 500 mg intravenous bolus, followed by 75 mg daily thereafter), and weight-adjusted unfractionated heparin, enoxaparin, bivalirudin, or fondaparinux per investigator preference. Other medical therapies were administered according to standard practice and guidelines. Definition of Upstream Clopidogrel Use For the primary analysis, upstream clopidogrel use was defined according to the intended use declared at randomization; this information was obtained from the electronic records of the interactive voice response system used for randomization. In a sensitivity analysis, we then defined upstream clopidogrel use by actual treatment before angiography. Actual treatment was determined from the case report form and included patients already on clopidogrel at the time of study randomization and those for whom the date and time of first clopidogrel administration occurred before the time of coronary angiography. Statistical Methods Baseline clinical characteristics, concomitant medications, and index procedures are summarized by upstream clopidogrel administration using medians (25th, 75th percentiles) for continuous variables and frequencies and percentages for categorical data. P values for categorical variables are generated from 2 tests. For continuous variables, student t tests were used when variables were normally distributed; Wilcoxon nonparametric tests were used for nonnormally distributed data. The efficacy end points examined included the primary composite of death/myocardial infarction (MI)/recurrent ischemia requiring urgent revascularization (RIUR)/use of thrombotic bailout (TBO) within 96 hours, and the key secondary end point of death or MI at 30 days. Safety end points included in-hospital TIMI major bleeding, Global Utilization of Streptokinase and Tissue plasminogen activator in Occluded coronary arteries (GUSTO) severe bleeding/transfusion, and transfusion alone. End points were used as defined by the main study analyses and adjudicated by the events committee. Comparison of event rates between early eptifibatide versus delayed provisional eptifibatide groups were examined by clopidogrel use strata for each of the efficacy and safety end points. Observed event rates were determined and time-to-event curves generated using Kaplan-Meier methods. Although intent for upstream clopidogrel was part of the stratified randomization schema, this analysis focused on patients undergoing coronary angiography and also examined actual upstream clopidogrel use. Therefore, multivariable logistic regression models were used to examine adjusted comparisons between early eptifibatide and delayed provisional eptifibatide on ischemic and bleeding outcomes according to clopidogrel use subgroup (upstream or no upstream use). These models were repeated for declared intent versus actual clopidogrel use. Models for adjustment were developed independently for each of these end points within the EARLY ACS dataset using all available baseline characteristics. Significant variables were determined using bootstrapping and stepwise selection processes. The list of covariates used in adjustment for each end point is provided in footnotes to Figures 1 and 3. In each model, an upstream clopidogrel use by treatment interaction term was included to examine the interaction between upstream clopidogrel use and treatment on these clinical outcomes. P values 0.05 were considered statistically significant for all tests. No adjustments were made for multiple comparisons. All analyses were performed using SAS software version 9.1 (SAS Institute, Cary, NC). All patients gave written informed consent for participation in the EARLY ACS trial. This EARLY ACS database analysis was approved by the Duke University Institutional Review Board.

724 Circulation February 22, 2011 Table 1. Declared Intention for Upstream Clopidogrel Versus Actual Upstream Clopidogrel Use Actual Upstream Clopidogrel Use Actual No-Upstream Clopidogrel Use Missing Data on Clopidogrel Use/Timing Row Totals, n (%) Declared intent to use upstream clopidogrel, n 6668 208 19 6895 (75.2) Declared intent to not use upstream clopidogrel, n 400 1856 15 2271 (24.8) Column totals, n (%) 7068 (77.1) 2064 (22.5) 34 (0.4) 9166 Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 Results Of the 9406 evaluable patients enrolled in EARLY ACS, 9166 (97.4%) underwent coronary angiography during the index hospitalization at a median of 21.4 (16.8, 32.7) hours after randomization. An intention to use upstream clopidogrel was declared in 6895 patients (75.2%) at the time of randomization; for 2271 (24.8%), the investigator declared an intent not to use upstream clopidogrel. Overall, 7068 patients actually received upstream clopidogrel (5592 prerandomization, 1476 postrandomization, and 251 received clopidogrel 12 hours before catheterization). A total of 1223 patients had clopidogrel initiated after angiography, and 841 patients never received clopidogrel. Table 1 compares the investigator s declared intention to use upstream clopidogrel with actual clopidogrel use in each declared stratum. Among patients for whom an intent to use upstream clopidogrel was declared, 208 patients (3%) did not receive upstream clopidogrel, and among patients for whom an intent not to give upstream clopidogrel was declared, 400 (18%) actually received clopidogrel before angiography. Among patients who received upstream clopidogrel, 16.1% (n 1023) received a 600-mg loading dose, 72.7% (n 4613) received a 300-mg load, and 11.2% (n 712) did not receive a loading dose. Among patients for whom upstream clopidogrel treatment was started after randomization, the median time from randomization to clopidogrel administration was 0.80 (0.27, 3.17) hours, and the median time from the first clopidogrel dose to cardiac catheterization was 19.7 (14.5 to 29.0) hours. Clinical Characteristics and In-Hospital Treatment Patient characteristics in the intended-upstream and noupstream clopidogrel treatment groups are presented in Table 2. There was substantial geographic heterogeneity in intended-upstream clopidogrel use; 51% among patients enrolled in North American sites compared with 86% in patients enrolled in sites elsewhere (P 0.001). Patients intended for upstream clopidogrel treatment were slightly younger, more frequently male, less likely to have diabetes mellitus, hypertension, dyslipidemia, prior MI, prior coronary artery bypass grafting, or renal dysfunction, but other clinical characteristics were similar between groups. PCI was performed during the index hospitalization in 62.8% of patients with intended upstream clopidogrel use compared with 53.5% of patients without intent for upstream clopidogrel use. Coronary artery bypass grafting was performed in 11.6% and 18.8% of upstream and no-upstream clopidogrel groups, respectively. Ischemic Outcomes, Treatment Strategy, and Upstream Clopidogrel Use Among the cohort of patients undergoing coronary angiography used for our analysis, results of the overall comparison between early and delayed provisional eptifibatide were consistent with those of the main trial. The primary end point of death/mi/riur/tbo at 96 hours occurred in 9.2% of patients receiving early eptifibatide and 9.9% of those receiving the delayed provisional strategy (adjusted odds ratio [OR] 0.94, 95% confidence interval [CI] 0.81 to 1.08), and the secondary end point of death/mi at 30 days occurred in 10.9% versus 12.1%, respectively (adjusted OR 0.90, 95% CI 0.79 to 1.02). Rates of ischemic outcomes by randomized treatment assignment according to intended clopidogrel strata are shown in Table 3. Adjusted OR and 95% CI for the comparison of early eptifibatide versus delayed provisional eptifibatide use according to intended clopidogrel use strata are shown in Figure 1. After adjustment for clinical characteristics, early eptifibatide, compared with a delayed provisional strategy, was not significantly associated with lower risk of death/mi/riur/tbo at 96 hours in either patients intended for upstream clopidogrel use (adjusted OR 0.93, 95% CI 0.79 to 1.10) or patients without intended upstream clopidogrel use (adjusted OR 0.94, 95% CI 0.72 to 1.22). The clopidogrel stratum by randomized treatment interaction term was not significant (P 0.99). There was a significant reduction in death or MI at 30 days in patients randomized to early eptifibatide compared with delayed provisional eptifibatide in the upstream clopidogrel stratum (adjusted OR 0.85, 95% CI 0.73 to 0.99) but no difference in risk among patients without intended upstream clopidogrel use (adjusted OR 1.02, 95% CI 0.80 to 1.30). As shown in Figure 2, event curves diverged early in the intended upstream clopidogrel group and remained separate out to 30 days. However, the intended clopidogrel strata by randomized treatment interaction term was not significant (P 0.23). Bleeding Outcomes, Treatment Strategy, and Upstream Clopidogrel Use Compared with delayed provisional use at PCI, early eptifibatide use was associated with a higher rate of in-hospital TIMI major bleeding when intended upstream clopidogrel use was declared (Figure 3). However, in-hospital risks of GUSTO severe bleeding/transfusion and transfusion alone were significantly increased in the early eptifibatide group in both intended-clopidogrel and no intended-clopidogrel strata. The intended-clopidogrel strata by randomized treatment interaction terms were not significant for any of these bleeding end points. Sensitivity Analysis According to Actual Upstream Clopidogrel Use Although actual upstream clopidogrel administration followed very closely the declared intention to administer

Wang et al Early Eptifibatide With Upstream Clopidogrel in ACS 725 Table 2. Baseline Characteristics Stratified by Intended Upstream Clopidogrel Use Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 Variable Upstream Clopidogrel (n 6895) No-Upstream Clopidogrel (n 2271) P Demographics Age, y* 67.1 (59.9, 74.5) 68.2 (60.7, 76.0) 0.001 Female sex. % 30.6 34.3 0.001 Region, % 0.001 North America 20.6 60.4 Western Europe 48.0 17.7 Eastern Europe 11.4 9.1 Middle East/Africa/Asia-Pacific 19.9 12.8 Race, % 0.001 White 88.9 88.9 Black 1.8 6.4 Asian 8.9 3.2 Other 0.3 1.5 Clinical characteristics Weight, kg* 79.0 (69.0, 90.0) 81.0 (70.0, 94.0) 0.001 Height, cm* 170 (163, 176) 170 (163, 178) 0.002 Diabetes mellitus, % 29.4 32.4 0.006 Hypertension, % 70.2 73.7 0.001 Dyslipidemia, % 57.1 59.9 0.018 Previous myocardial infarction, % 26.9 29.2 0.037 Previous PCI, % 24.9 24.0 0.378 Previous CABG. % 12.5 16.2 0.001 Previous heart failure, % 11.8 11.9 0.915 Previous stroke, % 4.8 5.6 0.107 Peripheral vascular disease, % 10.1 9.4 0.344 Current smoker, % 26.5 27.4 0.36 TIMI risk score, % 0.001 0 2 17.4 13.9 3 4 48.0 48.8 4 34.6 37.3 Presenting features Killip class, % I 89.7 87.5 0.071 II 8.4 9.9 III 1.7 2.0 IV 0.3 0.4 Admission heart rate, bpm* 76 (66, 88) 79 (67, 92) 0.001 Admission systolic BP, mm Hg* 143 (129, 160) 145 (130, 165) 0.002 Baseline creatinine clearance, ml/min* 74.5 (56.9, 96.5) 72.9 (53.7, 95.1) 0.011 Baseline hemoglobin, g/l* 14.1 (13.0, 15.1) 14.1 (12.9, 15.1) 0.905 *Values presented as median (25th and 75th percentile). BP indicates blood pressure. clopidogrel upstream (97% of patients intended for upstream clopidogrel use actually had upstream clopidogrel administered; 17.7% of patients not intended for upstream clopidogrel use received upstream clopidogrel), a sensitivity analysis was performed using the actual-use groups. These results, presented in Table 4, were not substantially different from the results according to intended-use strata presented above. Discussion Platelets play an integral role in the pathophysiology of ACS. With acute endothelial injury, platelet activation and aggregation are initial steps in the elaboration of flow-limiting arterial thrombi. Among patients undergoing PCI, procedurerelated platelet activation poses further risk of thrombotic events, 11,12 and the extent of platelet hyperreactivity has been correlated with the degree of myocardial damage. 13,14 For this

726 Circulation February 22, 2011 Table 3. Efficacy and Safety Event Rates According to Randomized Treatment and Intended Clopidogrel Use Strata Upstream Clopidogrel Use No Upstream Clopidogrel Use Early Eptifibatide, n/n (%) Delayed Provisional, n/n (%) Adjusted OR (95% CI) Early Eptifibatide, n/n (%) Delayed Provisional, n/n (%) Adjusted OR (95% CI) Death/MI/RIUR/TBO at 96 hours, n/n (%) 302/3443 (8.8) 324/3452 (9.4) 0.93 (0.76, 1.10) 120/1157 (10.4) 125/1114 (11.2%) 0.94 (0.72, 1.22) Death/MI at 30 days 348/3443 (10.1) 406/3452 (11.8) 0.85 (0.73, 0.99) 152/1157 (13.1) 143/1114 (12.8) 1.02 (0.80, 1.30) In-hospital TIMI major bleeding 75/3371 (2.2) 48/3393 (1.4) 1.54 (1.07, 2.24) 39/1140 (3.4) 31/1100 (2.8) 1.13 (0.69, 1.84) In-hospital GUSTO severe bleeding/ 245/3386 (7.2) 203/3397 (6.0) 1.41 (1.07, 1.87) 152/1135 (13.4) 102/1097 (9.3) 1.26 (1.03, 1.54) transfusion In-hospital transfusion 235/3419 (6.8) 196/3431 (5.7) 1.38 (1.04, 1.83) 150/1149 (13.1) 102/1108 (9.2) 1.23 (1.01, 1.51) Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 reason, use of thienopyridines and glycoprotein IIb/IIIa inhibitors targets various levels of the hemostatic pathway and can improve short- and long-term outcomes. The benefit of upstream clopidogrel in ACS patients treated with PCI was initially established by the Percutaneous Coronary Intervention Clopidogrel in Unstable angina to Prevent Recurrent Events (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) studies, both of which showed that pre-pci clopidogrel treatment reduced cardiovascular event rates compared with placebo. 6,7 In CREDO, patients who received clopidogrel at least 6 hours before PCI had a 38.6% risk reduction compared with patients treated later; the event curves started to diverge 3 to 4 days after randomization. 7 Interestingly, although glycoprotein IIb/IIIa inhibitor use rates were low in this study, a benefit of clopidogrel pretreatment was suggested only in patients concomitantly receiving glycoprotein IIb/IIIa inhibitor (30% relative reduction, P 0.12). In the second Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) study, ACS patients who received a 600-mg load of clopidogrel at least 2 hours before PCI had a 25% reduction in risk of the primary end point of death/mi/urgent target vessel revascularization at 30 days with periprocedural glycoprotein IIb/IIIa inhibitor use. 8 These results did not vary with the duration of Figure 1. Adjusted risks according to intended clopidogrel use strata for early routine versus delayed provisional eptifibatide use among NSTE ACS patients undergoing coronary angiography. The end point of death/mi/riur/tbo at 96 hours was adjusted for troponin positivity, ST-segment changes on the qualifying event ECG, age, heart rate, diastolic blood pressure, and estimated creatinine clearance determined by the Cockroft- Gault method. The end point of death/mi at 30 days was adjusted for troponin positivity, ST-segment ECG changes, Killip class, age, estimated creatinine clearance, weight, and history of peripheral vascular disease. clopidogrel pretreatment, but the possibility of a greater benefit from glycoprotein IIb/IIIa inhibitor therapy had this been started earlier (before coronary angiography and PCI) could not be assessed in these studies. In contrast, EARLY ACS found no significant differences in ischemic outcomes between early versus delayed provisional eptifibatide therapy among NSTE ACS patients expected to undergo an early invasive strategy. 9 Our current prespecified subgroup analysis found that the results of the early eptifibatide versus delayed provisional use comparison for the 96-hour end point of death/mi/riur/tbo did not vary according to intended or actual use of upstream clopidogrel versus no intended or actual upstream use. However, despite limitations of power in the subgroup analyses, we found that early clopidogrel initiation may be associated with lower 30-day ischemic risk. Early eptifibatide use was associated with increased bleeding risk regardless of upstream clopidogrel treatment. Patterns of Clopidogrel Use In EARLY ACS, the decision for upstream clopidogrel use was not randomized. Clopidogrel-treated patients were younger with fewer cardiovascular risk factors (lower TIMI risk score), reflecting patients who were less likely to have multivessel coronary disease by angiography and who subsequently were less likely to require surgical revascularization. In this large international study, regional variability in practice patterns was apparent, as has been observed in other geographically diverse studies, 15,16 and is attributed to differences in patient characteristics, provider preferences, and treatment cultures. Notably, North American sites were more likely to defer the decision on clopidogrel use until after angiography compared with sites elsewhere. Consistent with registry findings, there was also significant heterogeneity in clopidogrel loading. 17 Although guidelines recommend at least a 300-mg loading dose, 11% of patients who were not already receiving clopidogrel prior to randomization were initiated on clopidogrel without a loading dose. Upstream Clopidogrel and Treatment Effect With Early Versus Delayed Provisional Eptifibatide Glycoprotein IIb/IIIa inhibitors block the final common pathway to platelet aggregation by preventing fibrinogen cross-linking on the activated platelet cell surface. A synergistic effect between glycoprotein IIb/IIIa inhibitors and

Wang et al Early Eptifibatide With Upstream Clopidogrel in ACS 727 Figure 2. Event curves comparing early routine with delayed provisional eptifibatide use among NSTE ACS patients undergoing coronary angiography (A) with a declared intent for upstream clopidogrel treatment and (B) without a declared intent for upstream clopidogrel treatment. Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 clopidogrel might be considered because clopidogrel targets the more-upstream P2Y 12 receptor, thereby inhibiting ADPdependent stimulation of glycoprotein IIb/IIIa receptor expression. 18,19 Early eptifibatide use was not associated with treatment benefit at 96 hours, regardless of upstream clopidogrel use. In contrast, a significant reduction in 30-day death/mi was observed with early eptifibatide use among patients treated with upstream clopidogrel. Although the P value for the interaction term for upstream clopidogrel treatment randomized treatment was not statistically significant for either intended upstream use or actual use, the interaction term for actual use was nearly nominally significant (P interaction 0.058) in the setting of an underpowered subgroup analysis. These results suggest a potential effect of early combined treatment that is manifest well beyond the actual eptifibatide treatment period. Previous studies have demonstrated a sustained state of platelet hyperreactivity months after an ACS event that contributes to the risk of recurrent ischemic events. 20 Furthermore, 15% to 30% of clopidogrel-treated patients have insufficient levels of platelet inhibition after clopidogrel loading, 21 which has been associated with higher risk of thromboembolic events such as MI, stent thrombosis, and cardiovascular death. 22 24 One might postulate that the robustness of acute platelet activation defines, in part, the magnitude of long-term reactivity. As glycoprotein IIb/IIIa inhibitors have rapid onset and result in a high level of platelet inhibition, 25 early use with clopidogrel may substantially lower both acute and sustained levels of platelet reactivity (more than either agent alone) and synergistically Table 4. Treatment Effect for Early Eptifibatide Versus Delayed Provisional Eptifibatide Stratified by Actual Upstream Clopidogrel Use Strata Adjusted OR (95% CI) Figure 3. Adjusted risks according to intended clopidogrel use strata for early routine compared with delayed, provisional eptifibatide use among NSTE ACS patients undergoing coronary angiography. The composite bleeding and transfusion end points were adjusted for baseline hemoglobin, baseline hematocrit, white blood cell count, serum creatinine, qualifying event ST-segment changes on ECG, sex, heart rate, Killip class, positive cardiac markers, prior angina, age, age by sex interactions, and age by Killip class interactions. The transfusion end point was adjusted for age, baseline hemoglobin, white blood cell count, baseline hematocrit, time from presentation to randomization, Killip class, heart rate, and creatinine clearance; for TIMI major bleeding we adjusted for age, prior angina, weight, heart rate, qualifying event ST-segment changes on ECG, study drug received, and age by treatment interaction. Variable Ischemic end points Death/MI/RIUR/ TBO at 96 hours Death/MI at 30 days Safety end points In-hospital TIMI major bleeding In-hospital GUSTO severe bleeding/ transfusion In-hospital transfusion Actual Upstream Clopidogrel Actual No-Upstream Clopidogrel Interaction P Value 0.88 (0.75, 1.04) 1.10 (0.84, 1.45) 0.165 0.83 (0.71, 0.97) 1.11 (0.86, 1.43) 0.058 1.44 (1.01, 2.07) 1.26 (0.76, 2.11) 0.67 1.26 (1.03, 1.53) 1.42 (1.07, 1.88) 0.50 1.39 (1.05, 1.85) 1.22 (1.00, 1.50) 0.471

728 Circulation February 22, 2011 Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 reduce long-term risks of cardiovascular events. In contrast, more potent and consistent oral platelet inhibition with agents such as prasugrel would not be expected to and did not show any significant interaction with glycoprotein IIb/IIIa inhibitor use (P interaction 0.83). 26 Randomized clinical trials with longitudinal follow-up are needed to test the hypothesis, particularly to address the question of the best first agent to choose for patients expected to undergo early invasive management. Interestingly, although earlier studies showed a benefit of glycoprotein IIb/IIIa inhibition in the absence of clopidogrel, 27,28 in the present analysis, benefit was not observed among patients without clopidogrel pretreatment. This may in part reflect differences in the study population compared with earlier trials. Despite higher-risk patient profiles (median age 67 versus 64 years, prevalence of diabetes mellitus 31% versus 23%, creatine kinase MB positive in 63% versus 46%), event rates were lower in EARLY ACS compared with Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) In Upstream Clopidogrel and Treatment Effect With Early Versus Delayed Provisional Eptifibatide, third paragraph, please confirm expansions of PURSUIT and PRISM-PLUS. trial (30-day death/mi rate 11% versus 15%). This difference may also be attributed to differences in treatment intensity between EARLY ACS and earlier studies: a shorter duration of glycoprotein IIb/IIIa inhibitor infusion (median 36 hours in EARLY ACS versus 72 hours in PURSUIT), as well as earlier revascularization (median 21.4 hours after randomization in EARLY ACS versus 48 to 96 hours in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms [PRISM- PLUS] trial). Finally, in these earlier studies, only subgroups of the overall trial population underwent coronary angiography, and upstream clopidogrel was not available during the time of conduct of these trials. Early glycoprotein IIb/IIIa inhibitor use was associated with increased bleeding, a risk that was slightly accentuated by the addition of clopidogrel. For this reason, further investigation is needed to identify the subgroup likely to benefit from more intensive platelet inhibition without a significant excess in bleeding risk. Ongoing studies are examining clinical and laboratory risk factors that may aid in stratifying ischemic and bleeding risks in these ACS patients. 29,30 Study Limitations This analysis compared the effects of a randomized treatment within subgroups, but in EARLY ACS this limitation was attenuated by the randomization scheme that stratified by declared intention of upstream clopidogrel use with the result that clopidogrel stratum is a proper, prespecified subgroup. Still, regional differences were apparent in clopidogrel treatment patterns. Because of the high degree of confounding between clopidogrel use and geographic region, it was not possible to adjust for region in the multivariable models. Second, patients randomized into clinical trials represent a unique cohort of patients whose clinical characteristics, treatment, and outcomes may not always reflect actual clinical practice (eg, shorter delays to angiography). However, with regard to time to angiography, the EARLY ACS cohort was remarkably similar to both the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) and Global Registry of Acute Coronary Events (GRACE) observations of practice, and EARLY ACS patients were selected to reflect high-risk populations including patients of older age and with 84% troponin positivity. 9,31,32 Third, use of clopidogrel 24 hours before randomization was not captured in the EARLY ACS case report form; thus, we were unable to assess the influence of long-term prior use with outcomes. Because of the small number of patients, this analysis cannot offer insight into the effect of clopidogrel initiation within 12 hours of angiography. Finally, the power to detect interactions in this study is limited. For example, the reduction in 30-day death/mi risk with early eptifibatide use was statistically significant both among patients with a declared intent for upstream clopidogrel use and among patients actually pretreated with clopidogrel. However, the interaction term between upstream clopidogrel use and randomized treatment assignment did not quite reach statistical significance; thus, these results are hypothesis-generating and need to be confirmed in future studies. Conclusions Among patients undergoing coronary angiography for NSTE ACS, early preprocedure use of eptifibatide did not improve short-term ischemic outcomes but may be associated with a reduction in 30-day ischemic risk after upstream treatment with clopidogrel. The addition of clopidogrel accentuated bleeding risks associated with early eptifibatide use. These findings lend support to the concept of enhanced value for additive antiplatelet therapies, and future investigations are needed to identify those patients who may benefit from more intensive platelet inhibition without a significant excess in bleeding risk. Acknowledgments We thank Amanda McMillan for editorial support in preparation of the manuscript. Sources of Funding The EARLY ACS trial and this work were funded by research grants from Schering-Plough Inc and Merck Pharmaceuticals. Disclosures Dr Wang has received research grants from Bristol-Myers Squibb/ Sanofi Partnership, Schering-Plough, The Medicines Company, Heartscape, Canyon Pharmaceuticals, and Eli Lilly/Daiichi-Sankyo Alliance. Dr Tricoci has received research grants from Merck & Co Inc through the Duke Clinical Research Institute and is on the advisory board for Merck & Co Inc. Dr Giugliano has received research grant support from Daiichi-Sankyo and Schering-Plough, honoraria from Schering-Plough, Bristol-Myers Squib, and Sanofi- Aventis and is on the advisory board for Schering-Plough and Merck & Co Inc. Dr Zeymer has received research grants from Schering- Plough (now Merck). Dr Harrington has received research funding from and consults with Schering-Plough (now Merck). A complete listing of Dr Harrington s relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. Dr Montalescot has received research grants (to his institution) from Bristol-Myers Squibb,

Wang et al Early Eptifibatide With Upstream Clopidogrel in ACS 729 Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 Boston Scientific, Centocor, Cordis, Eli-Lilly, Fédération Françcaise de Cardiologie, Fondation de France, Guerbet Medical, INSERM, ITC Edison, Medtronic, Pfizer, Sanofi-Aventis Group, and Société Françcaise de Cardiologie and consulting or lecture fees from Accumetrics, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol- Myers Squibb, Daiichi-Sankyo, Eisai, Eli-Lilly, Menarini, MSD, Novartis, Portola, Sanofi-Aventis Group, Schering-Plough, and The Medicines Company. Dr James has received research grants and speaker fees from Astra-Zeneca, Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, and Schering-Plough. Dr Van de Werf has received research grants from Schering-Plough (now Merck) and Roche and advisory board and speaker s fees from Schering-Plough, Merck, and Roche. Dr Armstrong has provided consulting or other services that generate personal income to Sanofi-Aventis, Bristol-Myers Squibb Canada, Merck Frosst Canada Ltd, Abbott Laboratories, Glaxo- SmithKline, Bristol-Myers Squibb/Pfizer, Regado Biosciences, and F. Hoffmann-La Roche Ltd and has received research grants or contracts from Boehringer Ingelheim (Canada) Ltd, Sanofi-Aventis Canada, Eli Lilly, Schering-Plough Research Institute, Scios Inc/ Ortho-Biotech, GlaxoSmithKline, Portola Pharmaceutical Inc, Uppsala Clinical Research Center and AstraZeneca, and Merck & Company Inc that partially support his university salary and/or research projects. Dr Braunwald is chair of the TIMI Study Group at the Brigham and Women s Hospital, which receives (or has received within the past 24 months) grant support for the TIMI Study Group from the following pharmaceutical companies (all $10 000): Eli Lilly, Merck & Co Inc, Schering-Plough Research Institute, and Daiichi-Sankyo. Dr Braunwald has also participated occasionally (maximum 2 to 3 times/y) in symposia/advisory board meetings/ consultancies for the following companies, for which he receives an honorarium (always $10 000) and reimbursement of travel-related expenses: Daiichi-Sankyo, Eli Lilly, Merck & Co Inc, and Schering- Plough. Dr Califf has received research funding from and consulted for Schering-Plough (now Merck; all consulting funds donated to not-for-profit organizations). A complete listing of Dr Califf s relationships with industry is available at http://www.dcri.duke.edu/ research/coi.jsp. Dr Newby has received research grants from Schering-Plough and Merck & Co Inc through the Duke Clinical Research Institute and consulting honoraria from Schering-Plough. A complete listing of Dr. Newby s relationships with industry is available at http://www.dcri.duke.edu/research/coi.jsp. J. White reports no conflicts. References 1. 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Downloaded from http://circ.ahajournals.org/ by guest on April 13, 2017 Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome: An Analysis From the Early Glycoprotein I Ib/IIIa Inhibition in Patients With Non ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial Tracy Y. Wang, Jennifer A. White, Pierluigi Tricoci, Robert P. Giugliano, Uwe Zeymer, Robert A. Harrington, Gilles Montalescot, Stefan K. James, Frans Van de Werf, Paul W. Armstrong, Eugene Braunwald, Robert M. Califf and L. Kristin Newby Circulation. 2011;123:722-730; originally published online February 7, 2011; doi: 10.1161/CIRCULATIONAHA.110.958041 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2011 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/123/7/722 Data Supplement (unedited) at: http://circ.ahajournals.org/content/suppl/2016/04/13/circulationaha.110.958041.dc1 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/