Temporal Spectrum of Ischemic Complications with Percutaneous Coronary Intervention: The ESPRIT Experience

Percutaneous coronary intervention (PCI) is an effective treatment for myocardial ischemia in patients with coronary artery disease. More than one million PCI procedures were performed worldwide in 1998.1 A major limitation of percutaneous revascularization is the risk of acute ischemic complications associated with the procedure, including myocardial infarction (MI), urgent target vessel revascularization (TVR), and death. Approximately 10% of angioplasty procedures are complicated by one or more of these events.2 The timing of such events is crucial to understanding the pathophysiology of ischemic complications and determining the optimal duration of antithrombotic therapy. By using data from the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, we sought to determine the incidence, timing, and predictors of ischemic complications after non-urgent stent PCI. Materials and Methods Study Population. The design and results of the ESPRIT trial have been previously published.3,4 Briefly, 2,064 patients undergoing non-urgent coronary stenting in the United States or Canada were randomly assigned to receive eptifibatide, given as two 180 µg/kg boluses 10 minutes apart and a continuous infusion of 2.0 µg/kg/min for 18–24 hours, or placebo. Randomization was undertaken in the cardiac catheterization laboratory immediately prior to study drug administration and balloon inflation. A weight-adjusted heparin regimen was recommended; in patients not on heparin prior to PCI, an initial bolus of 60 U/kg was to be given to achieve a target activated clotting time of 200–300 seconds. Administration of heparin after the PCI was discouraged. Per protocol, a thienopyridine was to be given, with 98% of patients receiving thienopyridine treatment as an adjunct to the PCI procedure. By protocol, blood samples were collected in all patients at baseline (within 4 hours before study drug administration), and every 6 hours after randomization up to 24 hours. Although the 24-hour sample was not required if patients were discharged home earlier than 24 hours, the 6-hour, 12-hour, and 18-hour samples were required in all patients. Assays for levels of creatine kinase (CK) and CK-MB cardiac markers were performed by a central core biochemical laboratory. In order to include results from samples drawn within 2 hours of the scheduled time, the reported CK and CK-MB results for the 6-hour time point includes samples drawn in the 6- to 8-hour window after PCI. Endpoints and timing of events. Death, MI, and urgent TVR within 30 days after the index PCI were evaluated. To identify an endpoint MI, we used an algorithm that evaluated the core laboratory CK-MB assay results and clinical criteria.4 Enzymatic criteria for an endpoint MI required at least two of the core laboratory CK-MB values within 24 hours of PCI to be >= 3, the upper limit of normal (with at least a 25% increase in CK-MB if the last pre-randomization value was abnormal). MI events fulfilling enzymatic criteria did not undergo adjudication or require clinical corroboration. MI events reported on the case report forms but not fulfilling the enzymatic criteria were adjudicated by the Clinical Events Committee by evaluating source documents. Adjudication of MI required corroboration of a clinical syndrome consistent with MI, as well as supportive electrocardiographic or cardiac marker data. All reported TVR events were adjudicated to identify urgent TVR events. TVR procedures were considered urgent if performed within 24 hours of documented ischemic episodes that included one of the following: rest pain, presumed ischemic in origin and lasting at least 5 minutes; new ischemic electrocardiographic changes; acute pulmonary edema; ventricular arrhythmias; or other signs or symptoms presumed secondary to coronary ischemia. The following criteria were used to determine timing of events: for death, the time reported on the case report form; for urgent TVR and for adjudicated MI, the time reported on the case report form and confirmed or modified by the Clinical Events Committee; and for MI fulfilling core-laboratory enzymatic criteria, the time based on the first elevation of CK-MB to >= 3, the upper limit of normal (even though two elevations were required to meet the definition of an MI). Comparisons were performed between groups with early events (within 24 hours of randomization), late events (24 hours, 30 days after randomization), and no events. The cutoff for early events was 24 hours, as this was the maximum duration for study drug infusion. The timing of events within the first 24 hours, particularly for MI, was examined in detail. Statistical Analysis. Baseline, procedural, and angiographic characteristics are summarized as medians with 25th and 75th percentiles for continuous measures and as percentages for discrete measures. Event rates are summarized as percentages or odds ratios with 95% confidence intervals (CIs). For comparisons between groups, the Pearson chi-square test was used for categorical variables, and the Wilcoxon rank-sum test was used for continuous variables. Patient records were repeated for the following intervals: 0–6 hours on drug, 6–12 hours on drug, > 12 hours on drug, 0–6 hours off drug, 6–12 hours off drug, 12–18 hours off drug, and > 18 hours off drug. Patients were counted as being event free during each interval they experienced without an event. Thus, a patient could have up to seven records. If the patient had an event (death, MI, and/or repeat revascularization), then the endpoint was attributed to only the period in which it occurred and the repetitions of records were stopped. By using these multiple intervals for each patient, a generalized linear model of the 30-day endpoint was developed. This model could test the treatment effect overall, the event rates by time interval, and the difference in change in event rates over time for placebo versus treated patients. The rates on versus off drug for the two treatment groups were also used to determine rebound from the drug. Cumulative distribution plots of death, MI, and revascularization to 30 days were generated for the patients. Other methods were used to illustrate the change in risk over time. Cumulative distribution plots of death, MI, and revascularization to 30 days were generated for the patients who had an event overall and by treatment. An actuarial life table was created across all patients, dividing the data into 6-hour intervals. This method calculated the hazard at each interval along with the corresponding 95% confidence interval. Finally, for the timing of MI, the percent change in CK-MB from baseline was plotted at each time of the recording. Although the protocol designated the time points at which the CK-MB measures were to occur, there was some fluctuation in actual blood specimen collection times. For comparisons of CK-MB values across specific time points, all CK-MB values recorded within a 2-hour window of the designated time point (e.g., 6 and 12 hours after PCI) were considered to have been performed at the designated time. An intention-to-treat analysis was used for all comparisons between treatment groups. All p values 80%) occur within the first 24 hours after randomization, corresponding to the maximum duration of study drug infusion in both arms of ESPRIT. A small number of events occur up to 30 days after randomization; however, there is a rise in the event curves after 12 hours, with a “plateau” at 18–24 hours. The highest hazard for ischemic events occurred 12–18 hours after the first balloon inflation, raising the possibility that post-procedural MI may occur well after the PCI procedure. These findings appear contradictory to those of the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) study in which most ischemic events were reported to have occurred within the first 6 hours after PCI;13 however, the IMPACT-II investigators assumed that any MI detected within 24 hours of PCI without clinically evident ischemia occurred at the time of balloon inflation. In all ESPRIT patients, CK-MB was first measured 6 hours after intervention. Given the early “washout” kinetics of CK-MB release after successful primary angioplasty,14 myonecrosis that is directly attributable to the balloon inflation and stent deployment should be detectable at 8 hours. In ESPRIT, 37% of patients who developed MI (per the core laboratory CK-MB criteria) within 24 hours of PCI had normal CK and CK-MB levels at 6 hours. The delayed rise in cardiac enzymes may thus reflect distal embolization and microvascular plugging that occur during PCI with slow washout of the microvasculature. Alternatively, ongoing platelet adhesion and embolization or delayed side-branch closure may contribute to the pathophysiology of early ischemic events after PCI. In any event, these findings indicate that early measurement of CK-MB may not identify all peri-procedural myocardial infarctions, and they highlight the importance of measuring CK-MB levels 12 to 18 hours after PCI. Cessation of heparin can result in a rebound effect characterized by increased thrombin activity and myocardial reinfarction.15 In our study, the similar pattern of events for the eptifibatide and placebo groups, both on and off the study drug, indicates no discernible rebound effect after the discontinuation of eptifibatide. These findings are consistent with a previous study showing no evidence of rebound ischemia after stopping eptifibatide.16 Furthermore, the similar timing of events between the two treatment groups provides additional evidence that eptifibatide prevents, rather than simply delays, the occurrence of ischemic complications. Event curves from the primary ESPRIT analysis reveal a benefit seen with eptifibatide at 48 hours that is still significant at 30 days4 and 6 months.17 Baseline characteristics may assist clinicians in targeting patients for extended in-hospital monitoring and possibly more potent or prolonged antithrombotic therapy. In our analysis, the baseline characteristics that predicted early ischemic events were advanced age, absence of diabetes, prior PCI, lower TIMI grade flow, and presence of thrombus prior to intervention. Patients with advanced age have been shown to be at higher risk for complications after PCI in some studies, but not in others.18–20 Elderly patients in general have more complex coronary artery disease, with a higher incidence of multivessel disease and more calcified lesions.21 Similarly, patients with prior angioplasty may have more multivessel disease. Angiographic thrombus has been documented as a risk factor for abrupt closure and other thrombotic complications in numerous studies.22–25 Reduced coronary flow may represent either acute or chronic occlusion. Reduced TIMI grade flow prior to primary angioplasty for acute MI has been associated with lower procedural success rates and higher mortality rates at 30 days.26 A higher complication rate after angioplasty for chronic occlusions has been well documented.27 The lower rate of ischemic complications in patients with a history of diabetes was an unexpected finding in this analysis. Diabetes usually increases the risk for ischemic events,27 yet it appeared to have a protective influence in the IMPACT-II7 and Do Tirofiban and ReoPro Give Similar Efficacy? (TARGET) trials.28 This paradox may be related to a bias in enrolling only diabetic patients who were otherwise at low risk for complications. In our multivariable model, there was no significant interaction with treatment assignment, indicating that the benefit of eptifibatide applied to all ESPRIT patients, regardless of risk profile. Furthermore, eptifibatide treatment was the only modifiable risk factor identified in the model. A previous analysis from the ESPRIT trial showed only a minimal and nonsignificant reduction in angiographic complications (including thrombus formation and reduced flow) with eptifibatide.29 The main benefit of eptifibatide is a significant reduction in myocardial infarction after otherwise uneventful PCI procedures. There are several limitations of our analysis. The definition of MI used in this study excluded small CK-MB elevations, which have been associated with adverse outcomes in some studies.30,31 Use of a different definition of MI might have altered these findings. Blood samples for CK-MB analysis were collected every 6 hours. More frequent sampling might provide a clearer picture of the temporal profile of ischemic events after PCI. This study showed no evidence of rebound phenomenon for the composite endpoint of death, MI, and urgent TVR, but was not adequately powered to assess for rebound affecting only urgent revascularization. By study protocol, eptifibatide was to be used for 18–24 hours after PCI for all patients enrolled in ESPRIT. In this study, we cannot determine whether a rebound phenomenon may occur when eptifibatide is used for a shorter duration. Conclusions Ischemic complications are common after stent PCI procedures, usually occurring within 24 hours after the procedure. The early hazard for such complications extends to approximately 18 hours after PCI. Post-procedural MI is frequently not detected until >= 12 hours after PCI. Although baseline clinical and angiographic characteristics can help identify the highest risk patients, glycoprotein IIb/IIIa inhibitors significantly reduce the incidence of ischemic complications across the spectrum of risk. Acknowledgment. The authors wish to thank Rebecca Teaff for her editorial assistance in reviewing and preparing the manuscript.

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