Author + information
- Received April 8, 2005
- Revision received July 29, 2005
- Accepted August 12, 2005
- Published online February 21, 2006.
- Joseph A. Puma, DO, FACC⁎,⁎ (, )
- Lesan T. Banko, MD⁎,
- Karen S. Pieper, MS†,
- Terrence J. Sacchi, MD, FACC⁎,
- J. Conor O’Shea, MD†,
- Jean Pierre Dery, MD† and
- James E. Tcheng, MD, FACC†
- ↵⁎Reprint requests and correspondence:
Dr. Joseph A. Puma, New York Methodist Hospital-Cornell Heart Center, 506 6th Street, 2 Buckley Pavilion, Brooklyn, New York 11215.
Objectives In order to determine a differential benefit from treatment, we compared the long-term outcome of high-risk versus low-risk patients and evaluated survival free from death or myocardial infarction at one year.
Background Newer anticoagulant strategies during percutaneous coronary intervention have necessitated a reanalysis of the role of intravenous GP IIb/IIIa inhibitors. The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy trial randomized 2,064 patients undergoing nonurgent coronary stent implantation to eptifibatide or placebo.
Methods High-risk characteristics were defined as age >75 years, diabetes, elevated cardiac markers, ST-segment elevation myocardial infarction within 7 days, or unstable angina within 48 h of randomization. Age <5 years, absence of diabetes, and any other reason for admission were considered low risk characterstics.
Results There were 1,018 patients in the high-risk group (50.8% eptifibatide, 49.2% placebo) and 1,045 patients in the low-risk group (50.0% eptifibatide, 50.0% placebo). Baseline demographics were similar in both groups except for more hypertension (63% vs. 55%, respectively), peripheral vascular disease (8.2% vs. 5.2%, respectively), prior stroke (5.5% vs. 3.2%, respectively), and female gender (33% vs. 22%, respectively) in the high-risk than the low-risk group. At one year, the composite end point of death or myocardial infarction occurred in 15.89% of placebo patients and 7.99% of eptifibatide patients in the high-risk group and 9.02% of the placebo and 8.11% of eptifibatide patients in the low-risk group.
Conclusions Although eptifibatide treatment improved outcomes for all patients, preprocedural clinical characteristics can define a subgroup of patients who may derive greatest benefit from its use during coronary stent placement.
Platelet aggregation plays a central role in the pathogenesis of coronary thrombosis, which in turn is responsible for the ischemic complications of percutaneous coronary intervention (PCI) (1). Blockade of the platelet surface glycoprotein (GP) IIb/IIIa receptor interrupts the final common pathway of platelet aggregation. Agents that antagonize the platelet GP IIb/IIIa receptor mitigate the thrombosis cascade and as a result offer clinically significant protection against ischemic complications of PCI (2–7). Several large randomized clinical trials have clearly indicated that inhibition of platelet aggregation with platelet GP IIb/IIIa antagonists improve clinical outcomes in patients undergoing elective coronary intervention (5–8).
Three GP IIb/IIIa antagonists have been evaluated in phase III randomized clinical trials and approved for use (2–6). One of these agents, eptifibatide, is an intravenous, rapidly reversible, highly specific competitive inhibitor of the GP IIb/IIIa receptor. Treatment with eptifibatide has been shown to reduce both short- and long-term adverse cardiac events when used for several indications, including PCI (9–11).
The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial evaluated the efficacy and safety of a novel dosing regimen of eptifibatide in nonurgent coronary stenting (9). The study demonstrated a 37% relative risk reduction in the primary composite end point of death, myocardial infarction (MI), need for urgent target vessel revascularization, or crossover to GP IIb/IIIa inhibitor therapy for thrombosis within 48 h compared to placebo (6.6% vs. 10.5%; p = 0.002). Subsequent substudies showed that the 48-h and 30-day benefits of eptifibatide in reducing the ischemic complications of PCI with stent implantation were sustained to at least one year (11).
Given the potential for bleeding and the costs of treatment, many physicians tailor therapy to the cohort of patients most likely to derive benefit. The purpose of this study was to determine whether the clinical characteristics of patients in the ESPRIT trial could predict and discriminate those most likely to benefit from eptifibatide therapy in nonurgent coronary stenting.
The ESPRIT trial was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted in North America. The design and methods of the trial have been previously described in detail (9). Briefly, among patients who were scheduled to undergo nonurgent coronary stenting at 92 tertiary care centers in the U.S. and Canada, 2,064 were randomized to receive either eptifibatide or placebo. Patients with coronary artery disease scheduled to undergo PCI with stent implantation without planned use of GP IIb/IIIa inhibitor therapy were included in the study. The exclusion criteria were MI within 24 h before randomization, continuing chest pain triggering urgent referral for PCI, previous stent implantation at the target lesion, PCI within 90 days, treatment with GP IIb/IIIa inhibitor or a thienopyridine in the 30 days before randomization, stroke or transient ischemic attack within 30 days before randomization, any history of hemorrhagic stroke, history of bleeding diathesis or evidence of abnormal bleeding within 30 days before randomization, major surgery within the previous 6 weeks; uncontrolled hypertension with a systolic blood pressure >200 mm Hg or diastolic >110 mm Hg, documented thrombocytopenia with a platelet count <100 × 109/l, or a serum creatinine >350 μmol/l.
Patients were assigned to receive either placebo or eptifibatide in a one-to-one distribution. After pretreatment with aspirin and a thienopyridine on the day of randomization, the study drug was started immediately before initiation of PCI. Eptifibatide (Integrilin, Millennium Pharmaceuticals, Cambridge, Massachusetts, and Schering-Plough Research Institute, Kenilworth, New Jersey) was administered as two boluses followed by a maintenance infusion. The first bolus of 180 μg/kg was immediately followed by initiation of 2 μg/kg/min continuous infusion for 18 to 24 h. A second bolus of 180 μg/kg was given 10 min after the first bolus. All patients received weight-adjusted heparin with a target activated clotting time of 200 to 300 s. Local standards were used during PCI, and any approved stent could be implanted.
For the purpose of this analysis, the patients randomized in the ESPRIT trial were categorized into high or low risk. High risk was defined as any patient who had at least one of the following characteristics: >75 years of age, diabetes (diet or medically treated), baseline creatine kinase-MB (CK-MB) above the upper limit of normal (ULN), baseline troponin-T (Tn-T) greater than the ULN, primary reason for admission of unstable angina within 48 h of randomization or ST-segment elevation mycardial infarction (STEMI) within the previous seven days. A patient with none of these characteristics was considered low risk. A patient who met the low risk criteria but had missing baseline cardiac biomarkers (CK-MB and/or Tn-T) also was considered low risk.
The composite of death and MI at 30 days and 12 months was evaluated as the end point for this analysis. End point MI included those identified by elevation of CK-MB to at least three times the ULN on two occasions measured 6 h apart and those confirmed as MI after adjudication by a clinical events committee. The latter required corroboration in the form of a clinical syndrome consistent with MI and supportive electrocardiographic or cardiac marker data. Follow-up of end point clinical events was obtained by physician visit or phone contact at 30 days and 12 months after randomization. More than 95% of the patients had >380 days of follow-up.
Categorical factors are expressed as percentages and continuous as medians with 25th and 75th percentiles. Differences in baseline factors for the two risk groups are compared using a Pearson chi-square test for categorical factors and a Wilcoxon rank-sum test for continuous. Event rates are expressed using Kaplan-Meier rates. Cox proportional hazard modeling techniques were used to test the association between risk class and death or MI. A univariable model tested risk classification alone. A model also including randomized treatment and the interaction of risk group with treatment tested whether the treatment effect varied for the two risk groups. Analyses were performed on an intention-to-treat principle using SAS version 8.2 (SAS Institute, Cary, North Carolina).
A p value of 0.05 or less was considered statistically significant.
Among the 2,064 ESPRIT trial patients, 1,018 (49.3%) and 1,045 (50.6%) were categorized as high and low risk respectively. One patient was excluded owing to missing diabetes information. Baseline characteristics were similar in both groups except for more hypertension (63% vs. 55%, respectively), peripheral vascular disease (8.2% vs. 5.2%, respectively), prior history of stroke (5.5% vs. 3.2%, respectively), and female gender (33% vs. 22%, respectively) in the high-risk than the low-risk group (Table 1)Of the 1,018 high-risk patients, 517 (50.8%) received eptifibatide, as did 1,045 of the low-risk patients 522 (50.0%) (Fig. 1).
Among the high-risk patients, the 30-day composite end point of death or MI occurred in 12.38% (95% confidence interval [CI] 9.49 to 15.26) of patients randomized to placebo and in 6.19% (95% CI 4.11 to 8.27) of those randomized to eptifibatide (p < 0.001), and in the low-risk group it occurred in 8.03% (95% CI 5.70 to 10.36) of the placebo patients and in 6.51% (95% CI 4.40 to 8.63) of the eptifibatide patients (p = 0.341).
At 12 months, the composite end point of death or MI occurred in 15.89% of placebo patients and 7.99% of eptifibatide patients among the high-risk group (p < 0.001) and in 9.02% of placebo and 8.11% of eptifibatide low-risk patients (p = 0.571) (Table 2).The effect of eptifibatide in preventing death or MI was significantly higher among the high-risk group when compared to the low risk population (p= 0.032 for interaction test) (Fig. 2).The same trend was seen at 30 days, but the interaction was not statistically significant (p = 0.104). Multivariate analysis showed that unstable angina or STEMI and abnormal CK-MB independently predicted death or MI at 30 days or 12 months. Bleeding complications were higher in the eptifibatide-treated patients but did not reach statistical significance.
The acute benefits of eptifibatide have been established in a number of settings, including treatment of patients with acute coronary syndromes and as adjunctive therapy for patients undergoing PCI (10). The 6- and 12-month follow-up of patients in the ESPRIT trial shows the efficacy of eptifibatide in coronary stenting to be statistically significant and clinically relevant (10,11). The absolute difference in the incidence of the end points of death or MI between days 30 and 360 remained constant (11). This suggests a benefit of therapy beyond what would be expected from the procedural antiplatelet effects of treatment.
There is only a limited amount of data available describing the relationship of clinical risk profile with degree of benefit from GP IIb/IIIa therapy during coronary intervention. After classifying the patients randomized in the ESPRIT trial to high risk and low risk, we were able to demonstrate an enhanced beneficial effect of GP IIb/IIIa inhibition in the high-risk group compared with the low-risk group. This fairly straightforward classification scheme may thus help direct therapy to those most likely to achieve benefit.
Interestingly, patients who did not meet the high risk criteria also demonstrated a trend favoring benefit from eptifibatide therapy compared with placebo. However, the favorable effect was not as strong as in the high-risk group and did not reach statistical significance.
Compared to the low risk group, more patients in the high-risk group had hypertension, peripheral vascular disease, and prior history of stroke. Statistical adjustment for these parameters would likely have demonstrated the favorable effect of eptifibatide to be more pronounced in the high-risk patients compared with the low-risk group than was observed in the study.
Despite consistent short and long term benefits of GP IIb/IIIa blockade in patients undergoing PCI, widespread use of these agents has not become standard. Initially, institutional or physician concerns with procedural costs or the potential for bleeding may have limited the use of this class of antiplatelet agents to “bail out” situations (where efficacy has not been established) or in high-risk groups. Subsequently, the approval of the direct thrombin inhibitor bivalirudin, less expensive and easier to use than combination unfractionated heparin and GP IIb/IIIa inhibitors, may have further limited the widespread utilization of GP IIb/IIIa inhibitors. The nearly 50% reduction in death or MI in high-risk patients at 30 days and 12 months in our study should serve to abate these issues.
Clinical outcomes of patients undergoing elective PCI can be improved significantly through inhibition of the platelet GP IIb/IIIa receptor. This treatment modality confers enhanced benefit among patients with a high-risk clinical profile. Widespread and consistent use of platelet GP IIb/IIIa inhibition remains standard in the care of high-risk patients undergoing elective PCI.
- Abbreviations and Acronyms
- creatine kinase-MB
- Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy trial
- myocardial infarction
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received April 8, 2005.
- Revision received July 29, 2005.
- Accepted August 12, 2005.
- American College of Cardiology Foundation
- The RESTORE Investigators
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