Stent Parameters Predict Major Adverse Clinical Events and the Response to Platelet Glycoprotein IIb/IIIa BlockadeCLINICAL PERSPECTIVE
Findings of the ESPRIT Trial
Background— Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters.
Methods and Results— In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of <15, 15 to <18, 18 to <30, and ≥30 mm), and total stented vessel area (by quartiles of area <141, 141 to <188, 188 to <292, and ≥292 mm2). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to <30 mm (odds ratio [OR], 0.55; 95% CI, 0.32 to 0.94; P=0.030) and ≥30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length).
Conclusions— Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.
Received July 28, 2008; accepted December 1, 2008.
Acute ischemic complications after percutaneous coronary intervention (PCI), including death, myocardial infarction (MI), and urgent target vessel revascularization, occur in ≈5% to 10% of patients. The American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions Guidelines for PCI recommend treatment with a combination of antithrombotic and antiplatelet therapies to mitigate these adverse events.1,2 Candidate pharmacotherapies include oral antiplatelet agents (aspirin, clopidogrel), intravenous platelet glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), and anticoagulants (unfractionated heparin, low molecular weight heparins, bivalirudin). A key underpinning is the tailoring of the pharmacotherapeutic regimen to the individual patient via risk assessment based on clinical presentation (eg, stable angina versus acute coronary syndrome, troponin-negative versus troponin-positive cardiac biomarkers), with higher risk scenarios warranting more potent regimens.1–5
Clinical Perspective see p 43
In terms of procedural parameters, variables including lesion morphology and absolute stenosis severity remain predictive of outcomes in the stent era.1–4,6–9 However, in practice target lesion length and reference vessel diameter seem to be the primary determinants of stent selection with respect to the stent parameters of length and nominal diameter. The extent to which these parameters serve as a proxy, integrating clinical, angiographic, and procedural factors, is unknown; few data describe relationships between stent parameters and outcomes. Even less well defined is the potential for mitigating the risks associated with increasing procedural complexity (using stent parameters as a surrogate for complexity) through pharmacotherapy. This study was conducted to examine the relationships of stent parameters, clinical outcomes, and the mitigation of major adverse cardiac event (MACE) with the glycoprotein IIb/IIIa integrin blocker eptifibatide as observed in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial.10–12
This report describes the findings of an exploratory post hoc analysis of data from the ESPRIT trial. Details of study design and principal findings of ESPRIT have been previously reported.10–12 Briefly, the ESPRIT trial was a 2064-patient, randomized, parallel-group, double-blind, multicenter, controlled clinical trial of eptifibatide versus placebo as an adjunct to stent PCI. Target lesions were required to be in native coronary vessels; enrollment of patients with multiple lesions in multiple (native) vessels was allowed. Per the treating physician, sufficient equipoise had to exist such that glycoprotein IIb/IIIa inhibition was not absolutely indicated. Before PCI, eptifibatide was initiated as a 180-μg/kg bolus followed by a 2.0-μg/kg per min infusion, with a second 180-μg/kg bolus given 10 minutes after the initial bolus. The control arm was blinded placebo; crossover to open-label glycoprotein IIb/IIIa blockade therapy was permitted for intraprocedural complications. Pretreatment with aspirin and a 300-mg loading dose of clopidogrel were also specified per protocol. Along with clinical and procedural variables, stent parameters (manufacturer, brand, nominal stent length, and nominal stent diameter) were captured prospectively on case report forms specific to ESPRIT. Any stent approved by the regulatory authority of the country of the enrolling site could be implanted; only bare-metal stents were available during the enrollment period (June 1999 to February 2000). The primary end point of ESPRIT was a composite of MACEs inclusive of death, MI, urgent target vessel revascularization, and open-label GP IIb/IIIa therapy for a thrombotic complication (termed “thrombotic bailout”) at 48 hours. Periprocedural MI was defined as 2 separate creatine kinase-muscle brain (CK-MB) values ≥3 times the upper limit of normal. Patients were followed to 1 year. The 1-year MACE end point was the composite of death, MI, and urgent target vessel revascularization. The protocol MACE definitions were used in this analysis. All end points were adjudicated by a blinded clinical events committee.
For this analysis, the number of stents implanted was categorically grouped as 1, 2, or ≥3 implanted devices. Stent length and diameter were defined as the nominal values per the manufacturer’s label. In patients receiving multiple stents, length was defined as the sum of the length of all stents implanted during the index procedure, assuming no overlap. Total stent length was grouped as lengths of <15, 15 to <18, 18 to <30, and ≥30 mm, corresponding to quartiles of the observed distribution of stent length to the nearest millimeter. Stent diameter was categorized into 3 groups (≤2.5, >2.5 to <3.5, ≥3.5 mm), reflecting commercially available stent diameters. In patients receiving multiple stents, the mean of the diameters of the stents implanted was used as the nominal stent diameter. In addition to these groupings, an exploratory analysis was constructed to examine the relationship of the total surface area subtended by all stents implanted (termed stented vessel area) with outcomes. In this analysis, the stented vessel area was calculated as the area of the vessel that would have been covered had the stent been a solid metal tube with the nominal stent parameters of the stent device itself, where
In patients receiving multiple stents, the total stented vessel area was determined by adding the stented vessel area of each stent calculated individually.
Patients not receiving a stent during the index procedure (n=57)11 were excluded from the analysis. All statistical tests were conducted at a 2-sided significance level of 0.05. Baseline characteristics are presented using percentages for categorical data and mean±standard deviation for age. The Cochran-Mantel-Haenszel test of association between treatment and the occurrence of an event, adjusting for the number of stents, was conducted for each of the MACE components. The odds ratios (ORs) of MACE for eptifibatide versus placebo were computed for each of the 3 categories of number of stents (1, 2, and ≥3), 4 quartiles of stent length, 3 categories of stent diameter (≤2.5, >2.5 to <3.5, ≥3.5 mm), and 4 quartiles of stented vessel area. CIs are provided for these ORs as well as probability values based on the Wald χ2 test, rejecting a null hypothesis of an OR of unity. CIs for the ORs were plotted using a logarithmic scale. Analyses of the stent parameters were conducted using a generalized linear model with a logit link, assuming a binomial distribution for the occurrence of MACE. This procedure is the analogue, for binary end points, of the standard 2-way ANOVA. SAS PROC GENMOD (SAS version 9.1 for Windows, SAS Institute) was used to analyze the stent parameter in question as the second factor of treatment. Linear trend contrasts were used to assess the linearity of trends in the placebo arm. The likelihood ratio χ2 statistic was used as a gauge of the relative magnitude of the linear relationship between the increasing procedural complexity parameter and MACE. The flattening of the gradient of this relationship was assessed by testing for differences in linear trends between placebo and eptifibatide using the likelihood ratio χ2 test.
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Of the 2064 patients enrolled in the ESPRIT trial, 1983 were included in this analysis; 57 (2.9%) of those enrolled did not receive a stent during the index intervention and were therefore excluded. As observed in the ESPRIT trial proper,11 baseline characteristics were generally well balanced among treatment groups. Baseline patient and stent characteristics by number of implanted stents are shown in Table 1. Approximately one third (n=657; 33.1%) of patients enrolled in the ESPRIT trial received ≥2 stents. The mean number of stents implanted per patient was 1.45. No clear correlations were observed between the number of implanted stents and baseline clinical characteristics. Similarly, there were no clear correlations between baseline characteristics and quartiles of total length of implanted stent, groupings of stent diameter, or quartiles of stented vessel area (data not shown).
Incidence of MACE at 48 Hours by Stent Parameters: Placebo Group Observations
The event rates for the composite of death, MI, target vessel revascularization, or thrombotic bailout at 48 hours (the primary end point of ESPRIT) by stent parameter are listed in Table 2 and depicted in Figure 1. The overall MACE rate in the placebo group was 10.5%. In the placebo treatment group, evaluated by number of stents implanted, MACE rates at 48 hours incrementally increased with increasing numbers of stents (1 stent [6.3%], 2 stents [17.8%], and ≥3 stents [20.0%]). Relative to implantation of 1 stent, the fold increase in the odds of MACE with 2 implanted stents was 3.2 (2.03 to 5.07) and with ≥3 implanted stents was 3.7 (2.09 to 6.59), with a linear trend χ2 of 17.67 (P<0.0001).
As stents are available in varying lengths, we hypothesized that total stent length might be more directly correlated with MACE than number of stents implanted. Indeed, MACE rates increased incrementally by quartiles of stent length. Relative to the <15 mm quartile, the fold increase in the odds of MACE in the 15 to <18 mm quartile was 2.9 (0.99 to 8.55), 18 to <30 mm was 5.3 (2.06 to 13.67), and ≥30 mm was 8.9 (3.49 to 22.91). The linearity trend χ2 was 36.93 (P<0.0001), a much stronger relationship than that observed by number of stents. Analyzed in 5-mm increments, the fold increase in the odds of MACE was 1.15 (1.09 to 1.22) with every 5 mm greater than 15 mm.
MACE rates analyzed by stent diameters demonstrated that patients receiving the smallest stent diameters (≤2.5 mm) experienced lower rates than those in the intermediate (>2.5 to <3.5 mm) and largest diameter (≥3.5 mm) groups (Table 2). The linearity of the trend, however, was not statistically significant (linear trend, χ2=2.24; P=0.13). Figure 2 demonstrates a possible explanation for this observation. The distributions of length by diameter were not proportional, with a clustering of longer total stent length in the intermediate diameter group. The higher event rates in the intermediate and largest diameter groups would thus remain consistent with the hypothesis that total amount (rather than diameter) of implanted stent correlates with adverse event rates.
MACE, Stent Parameters, and Eptifibatide Treatment
Inclusive of all 2064 patients in the main ESPRIT trial, the primary end point of MACE at 48 hours was reduced from 10.5% to 6.6% (37% relative risk reduction [RRR]; P=0.0015).11 Similarly, in the cohort in this report, MACE was reduced from 10.5% to 6.6% in patients randomly assigned to eptifibatide treatment (37% RRR; P=0.0019). The benefit of eptifibatide was primarily driven by a reduction in the incidence of MI (from 8.9% to 5.6%; 37% RRR; P=0.008), with the directionality of benefit being consistent in the urgent target vessel revascularization (from 0.9% to 0.3%; 67% RRR; P=0.080) and thrombotic bailout (from 2.2% to 1%; 55% RRR; P=0.055) components of the primary end point.
Analyzed by number of stents implanted, when 1 stent was implanted, treatment with eptifibatide resulted in an insignificant 0.8% absolute risk reduction (6.3% to 5.5%). However, with the implantation of 2 stents, a 57% RRR was observed (10.1% absolute risk reduction, 17.8% to 7.7%, P=0.001; Figure 1A). When 3 or more stents were implanted, MACE decreased from 20.0% to 13.2% (6.8% absolute and 34% relative reduction, P=NS). Note that the number of observations (n=181) was small in this latter group, possibly accounting for the lack of statistical significance.
The efficacy of eptifibatide was even more strongly related to total length of implanted stent. As described previously, there was a stepwise progression in MACE rates in patients assigned to the placebo group, ranging from a low of 2.4% in the <15-mm quartile to a high of 17.9% in the ≥30-mm quartile. No effect of eptifibatide was seen in the lowest 2 quartiles; in the third quartile (18 mm to <30 mm), a 42% RRR was observed (11.5% to 6.6%; P=0.030), whereas in the fourth quartile, the benefit was even more marked, with a RRR of 52% (17.9% to 8.6%; P=0.003). Treatment with eptifibatide did not completely eliminate the incremental risk, as in both the placebo and eptifibatide groups, a direct relationship was present between increasing total length of inserted stents and MACE (both, P<0.001). Nonetheless, treatment with eptifibatide did result in a demonstrable flattening of the incremental risk gradient attributable to increasing length of implanted stent at 48 hours (Figure 1B; linear trend interaction, χ2=7.9; P=0.005).
Persistence of Observations: 1-Year Analysis
One-year follow-up was available in 1964 (95%) of the 2064 patients in ESPRIT.12 This included 1889 of the 1983 (95%) of the cohort reported on in this manuscript. As expected, event rates in both the placebo and eptifibatide groups increased between 48 hours and 1 year, reflecting the natural history of coronary artery disease and the post-PCI patient. Nonetheless, the observations at 48 hours persisted to 1 year, driven primarily by the differences created with initial treatment (Table 3 and Figure 3). For example, in the analysis by quartiles of length of implanted stent, the statistically significant differences seen at 48 hours in the 18- to <30-mm and the ≥30-mm quartiles remained significant at 1 year; similarly, the lack of efficacy in the <15-mm and the 15- to <18-mm quartile at 48 hours did not change substantively at 1 year (there continued to be no difference between treatment groups in either of these quartiles). These temporal observations are displayed as OR plots of stent parameter versus eptifibatide effect in Figure 4.
Outcomes Modeling: MACE by Stented Vessel Area
Intuitively, it had been expected that the incidence of MACE would be inversely related to nominal stent diameter; however, the opposite trend was observed (Tables 2 and 3⇑; Figures 1 and 3⇑). An exploratory analysis was therefore constructed to evaluate whether stented vessel area, defined as the surface area of the vessel subtended by stents, might even more powerfully correlate with MACE, because this derived parameter combines both vessel diameter and total length of implanted stent into one value. Indeed, the linearity of the relationship of MACE at both 48 hours and 1 year was greatest for stented vessel area compared with number of stents, stent length, or stent diameter (Table 4). Treatment with eptifibatide resulted in a flattening of the incremental risk gradient attributable to increasing stented vessel area at 48 hours (Figure 1D; linear trend interaction, χ2=5.04; P=0.0248). From a dichotomous perspective, eptifibatide treatment reduced MACE at 48 hours for stented vessel areas of ≥188 mm2 and at 1 year for surface areas ≥292 mm2 (Figure 4).
The randomized clinical trial is well established as the standard for identifying optimal therapeutic regimens and strategies. However, many large clinical trials, including ESPRIT, incorporate broad entry criteria, raising the issue of the applicability of population-based results to the individual patient. As demonstrated in this analysis, risk stratification pre-PCI using simple variables such as stent parameters can predict not only the risk of an adverse event or consequence but also the potential for benefit with an adjunctive treatment. Direct (and clinically substantive) correlations were observed between both the parameters of the number of stents implanted and the nominal total length of implanted stents and MACE event rates. The differential between patients with the lowest and highest event rates was over 7-fold (shortest versus longest quartiles of total implanted length of stent), suggesting that this stent parameter is of particularly high a priori discriminatory value.
The analyses by stented vessel area, conducted on an exploratory basis, proved to have the greatest overall linearity, suggesting a generalizable model—that MACE is directly correlated with the total surface area of vessel wall injured (and subsequently stented) during PCI. It is well understood that PCI produces an obligate injury to the vessel wall. Models of MI, as detected by the release of cardiac biomarkers, suggest that embolization of platelet microthrombi may be the primary pathogenesis of this complication13,14; the largest component of MACE in ESPRIT was indeed peri-PCI MI. Another contributory etiology may have been side branch compromise—as stented vessel area increases, the number of covered side branches should necessarily also increase. Side branch closure was observed in 4.1% (85 of 2064) of patients enrolled in the main ESPRIT trial, with 29% (25 of 85) of these patients developing a peri-PCI MI.11 The clinically unanticipated finding that MACE rates increased as stent diameter increased actually supports the model that stented vessel area may be a primary predictor of peri-PCI MACE events since stented vessel area is directly proportional to diameter.
Given the direct correlation between stented parameters and MACE, a less likely explanation would be that stent parameters are a proxy for the “total burden” of atherosclerosis. A prospective ultrasound study by Mehran et al indirectly supports this assertion. In their landmark study, 2256 patients with 2780 native coronary lesions were interrogated with intracoronary ultrasound before PCI.15 Disease in the reference vessel segment was associated with an OR for elevation of CK-MB of only 1.01 in patients with cross-sectional narrowing in the reference vessel segment; a much stronger predictor was plaque burden associated with the target lesion itself (OR, 1.14; P=0.021).
Post hoc analyses of randomized, drug-eluting stent trials also suggest a relationship between the implantation of multiple stents, total implanted stent length, and periprocedural MI.16,17 In 5 clinical trials of sirolimus-eluting stent implantation, the incidence of MI at 30 days increased progressively from <18, 18 to 36, and 36 to 54 mm in both bare-metal and sirolimus-eluting stent cohorts. For each stent length group, MI rates were higher with bare-metal than sirolimus-eluting stents.16 In the TAXUS V trial comparing paclitaxel-eluting stents with bare-metal stents, the placement of multiple paclitaxel-eluting stents was associated with a significant increase in MI compared with multiple bare-metal stents (8.3% versus 3.3%, respectively, P=0.047).17 Of note is that these studies did not examine the interaction between multiple stents, periprocedural antithrombotic regimens, and MACE. Nonetheless, this body of work suggests that procedural complexity in the drug-eluting stent era remains as relevant as in the bare-metal stent timeframe of the ESPRIT trial.
Treatment with eptifibatide provided greater benefits both relatively and absolutely as event rates increased. Specifically, the increased hazard associated with increasing numbers of stents, increasing total length of implanted stent, and increasing diameter of stents was largely (although not completely) mitigated by eptifibatide treatment. Approached in a dichotomous fashion, the benefits of eptifibatide were realized in those patients where 18 mm or more of stent (by length) was implanted. On the other hand, nominal stent diameter did not prove discriminatory in identifying a group receiving a differential benefit from eptifibatide; this is probably because there was only a 2-fold difference in MACE event rates from the lowest to highest diameter groups. Although admittedly an unconventional parameter, stented vessel area proved to be the most powerful differentiating predictor; efficacy was observed only in patients in whom 188 mm2 or more of vessel was covered.
An extensive literature exists correlating baseline angiographic variables and clinical outcomes.1–9 Of note, increasing lesion length has been generally predictive of adverse events. For example, in the Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial? (TARGET) of 4809 patients undergoing elective stent implantation, the most powerful independent angiographic predictor (after adjustment) of the composite of death, MI, or urgent target vessel revascularization at 30 days was found to be lesion length >20 mm (hazard ratio, 1.89; P<0.001).7
These angiographic variables should be considered in the context of the clinical predictors of risk such as those identified previously by Puma et al.18 In an approach similar to this analysis, Puma et al identified simple clinical predictors of both risk and response to treatment with eptifibatide in ESPRIT. Specifically, the modeling identified unstable angina, non-ST elevation MI, and recent ST elevation MI clinical presentations as independent predictors of death or MI at 30 days and 1 year, with a preponderance of female gender, hypertension, peripheral vascular disease, and stroke being present in higher risk patients. Combining these clinical factors with easily classified device parameters may thus further refine the risk-benefit paradigm used to identify patients undergoing PCI who would be most likely to benefit from platelet glycoprotein IIb/IIIa blockade.
The present study has several limitations, including the usual limitations of retrospective analyses. We neither quantitatively measured lesion parameters before PCI nor was disease distant from the target lesion assessed. In cases of implantation of multiple stents, we did not capture whether additional stents were deployed as a planned approach or were for “bailout” purposes. The analysis thus cannot directly address whether the primary correlates of MACE are stent parameters or the total burden of coronary disease. The model did not use either actual final stent diameter or account for areas of stent overlap. The variables evaluated are not independent; in particular, stent number and total length of implanted stent are correlated, and stented vessel area is obviously mathematically derived from diameter and length. Neither ESPRIT nor this analysis was designed to address the strategy of “spot” stent implantation. Finally, whether a loading dose of 600 mg of clopidogrel more typical of current PCI practice would have influenced the results remains unknown.
Establishing risk is an imprecise science. Even today, a compilation of clinical and morphological variables does not seem to completely define the risk of PCI of a given lesion in a specific patient. Still less has been described regarding the attributable risk of procedural variables; stent parameters, particularly stented vessel area, seem to be a potent predictor of risk, and thus may independently provide some of this missing information. The efficacy of platelet glycoprotein IIb/IIIa integrin blockade is correlated with risk defined by stented vessel area, even in low to moderate (clinical) risk patients felt not to otherwise warrant treatment. Finally, these findings should not be construed as an endorsement of “spot stenting” or other measures to minimize the amount of implanted stent. Instead, what is suggested is that a new risk model that encompasses multiple factors—clinical, morphological, and procedural—may better predict risk and further distinguish patients benefitting from intensive periprocedural antiplatelet therapy.
The authors thank Paul Burton, MD, PhD, formerly of Millennium Pharmaceuticals (Boston, Mass), for formulating the original hypothesis and for his contributions to and critique of the manuscript and Yan Wei, Schering Plough Corporation (Kenilworth, NJ), for assistance in programming of the analyses. Editorial assistance was provided by Rina Kleege, MS, at Adelphi, Inc.
Sources of Funding
Funding for the ESPRIT trial was provided by COR Therapeutics (South San Francisco, Calif) and the Schering-Plough Research Institute. Editorial assistance was funded by Schering-Plough.
Dr Tcheng is a consultant for and has received research grant support and speaker’s honoraria from COR Therapeutics and Schering-Plough. He has received speaker’s honoraria from Sanofi-Aventis, Cordis/Johnson & Johnson, and Medtronic. Dr Lim has no conflicts of interest. Dr Srinivasan is a statistician at Schering-Plough. Dr Jozic has no conflicts of interest. Dr Gibson has received honoraria, consulting fees, and research support from Schering-Plough. Dr O'Shea has no conflicts of interest. Dr Puma is a consultant for and has received speaker’s honoraria from Schering-Plough. Dr Simon is a consultant for and has received research grant support and speaker’s honoraria from Schering-Plough. He has participated in a speaker bureau and advisory board for and received fellowship support from Cordis/Johnson & Johnson. He is a consultant for Sanofi-Aventis and is on the advisory board for Medtronic.
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This article describes a post-hoc analysis of the 1,963 patients who underwent stent implantation in the ESPRIT trial, analyzing the relationships between stent parameters (length, diameter, and stented vessel area) and major adverse clinical events (MACE) at 48 hours and 1 year. Near-linear “dose-responses” were identified between both total implanted length of stent and stented vessel area with MACE in the placebo arm. Eptifibatide substantially flattened the slope of the dose-response curve, with outcomes significantly improved only in those groups with higher MACE event rates. The potential clinical impacts of this article are several. First, the findings suggest that a novel, yet quite straightforward construct exists for predicting complications of stent PCI. Specifically, MACE rates correlate directly with total stented vessel area – the greater the amount of stent implanted, the more likely an adverse event. Second, the analyses identified specific parameters that might be useful, in a dichotomous fashion, for deciding whether or not to administer adjunctive platelet GP IIb/IIIa blockade during a PCI procedure. Treatment was beneficial when the total length of implanted stent was 18 mm or greater (and conversely, there was no benefit at stent lengths <18 mm). This simple parameter may thus provide additional guidance to the interventional cardiologist for the appropriate application of antithrombotic therapies.
Guest Editor for this article was Antonio Colombo, MD.