- Email: [email protected]
Design of a registry to characterize “real-world” outcomes of percutaneous coronary revascularization in the drug-eluting stent era
Design of a registry to characterize b real-worldQQ outcomes of percutaneous coronary revascularization in the drug-eluting stent era Sonia Jacob, MD,a David J. Cohen, MD, MSc,b Joseph Massaro, PhD,b Paulette Niemyski, RN, BSN,b Kelly Maresh, RN,a and Neal Kleiman, MD,a for the EVENT Investigators Houston, Tex, and Boston, Mass
Background
Clinical trials have shown drug-eluting stents (DES) to be superior to bare metal stents (BMS) in preventing in-stent restenosis and target vessel revascularization. Although these results have ushered in a sea change in the practice of myocardial revascularization, important questions remain unanswered concerning rates of ischemic complications when DES are used in a broader population not represented in the clinical trials.
Study Design
The EVENT registry will include 7500 to 10 000 patients enrolled at approximately 60 sites across the United States. The intent of the registry is to characterize a population of consecutive patients undergoing percutaneous coronary intervention with stent deployment using BMS and DES in terms of processes and outcomes of care. A unique aspect of EVENT is the prospective assessment of rates of periprocedural myocardial infarction among all patients. These data will allow us to compare rates of periprocedural myocardial infarction and other ischemic complications between patients receiving DES and BMS. In addition, the EVENT registry will characterize temporal changes in the patterns of DES use and the relationship between any such changes and both short- and long-term outcomes. (Am Heart J 2005;150:887 - 92.)
The adoption of intracoronary stenting has revolutionized the practice of myocardial revascularization. Stent implantation reduced the frequency of recurrent stenosis to 20% to 30%.1- 3 The introduction of drugeluting stents (DES) has further reduced this frequency to b10% in clinical trials, with revascularization of the target vessel performed in approximately 5% of patients.4- 6 Major adverse cardiac events during the first 2 years after percutaneous intervention have also been shown to be reduced significantly in patients receiving DES compared with bare metal stents (BMS); however, this reduction is driven almost entirely by reductions in target vessel revascularization (TVR) rather than in more serious irreversible events.7 Although there is much enthusiasm for this therapeutic advance, several key questions remain unanswered. First, the population represented in early clinical trials is highly selected and intentionally excludes certain patient groups such as patients with
From the aBaylor College of Medicine and The Methodist DeBakey Heart Center, Houston, Tex, and bHarvard Clinical Research Institute, Boston, Mass. Funding for EVENT is provided by Millennium Pharmaceuticals Inc and Schering Plough Inc. Submitted November 11, 2004; accepted March 26, 2005. Reprint requests: Neal S. Kleiman, MD, 6565 Fannin, MS F-1090, Houston, TX 77030. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.03.030
recent myocardial infarction (MI), patients undergoing multivessel revascularization, and patients undergoing percutaneous coronary intervention (PCI ) of venous bypass grafts or of chronically occluded vessels. In clinical practice, DES are likely to be used in more complex and higher-risk cases than have been represented in the clinical trials. It is also likely that as confidence in the safety and ability of these devices to prevent restenosis increases, more complex cases will be undertaken than were previously approached with BMS. It is unclear whether the benefit of DES will be sustained in the broader population undergoing stent placement. As a consequence of increasing complexity, the rate of periprocedural ischemic complications (eg, MI, stent thrombosis, and urgent TVR) may increase. A second major concern is that drug interference with the cell cycle or with mitosis may also delay endothelial growth and injury site healing in patients with atherosclerotic coronary artery disease.8,9 If impaired healing permits ongoing microembolization, the time course of periprocedural myonecrosis may be extended over a period of days to weeks after stent implantation. Soon after the market approval of the sirolimus-eluting (Cypher) stent, the Food and Drug Administration issued an alert indicating that the frequency of subacute stent thrombosis (SAT ) may be increased in patients receiving a Cypher stent.10 One year later, however, the notification was updated based on a registry of 2063 patients with 30 - day follow-up stating that the Cypher stent, when implanted in accordance with the
888 Jacob et al
approved indications for use, bis not associated with an excess of SATs.Q11 However, device implantation is frequently performed outside the window of approved indications. The frequency of this practice is not known, nor is the true complication rate. Although the randomized clinical trials comparing BMS and DES do not support an increased frequency of SAT after DES implantation, at least 1 clinical trial performed in a group of patients with more complex lesions than those studied previously suggested that the rate of SAT may be as high as 1.6% 30 days after implantation of a paclitaxel-eluting stent.12 Similarly, the occurrence of late events after DES implantation is not well characterized. Indeed, emerging reports of events occurring months to years after stent implantation13 have raised concerns about the need for prolonged antiplatelet therapy and the appropriateness of implantation in high-risk cases. Recently, an observation by Ferrari et al14 suggested that cessation of antiplatelet therapy may also be associated with late thrombosis of BMS. Finally, the pharmacotherapeutic milieu surrounding intracoronary stent placement is changing rapidly. Considerable uncertainty surrounds selecting appropriate doses of aspirin,15 heparin,16,17 and clopidogrel18,19 and the appropriate use of platelet glycoprotein IIb/IIIa (GPIIb-IIIa) antagonists and other novel anticoagulation strategies,19,20 and it is likely that the use patterns for such drugs will continue to evolve rapidly. The adoption of DES, the enthusiasm surrounding their use, and the inevitable learning curve that is occurring soon after DES release to the cardiology community offer a unique opportunity to study the effects of the new technology on patterns of care, the frequency of periprocedural ischemic events, and longterm clinical outcomes. The EVENT registry was thus designed to investigate event rates as detected by elevations in cardiac enzymes and clinical end points in patients receiving both DES and BMS.
Study objectives The primary objective of EVENT is to determine whether implantation of DES in clinical practice is associated with an increased frequency of periprocedural ischemic complications compared with BMS implantation. The key secondary objective is to compare the characteristics of patients receiving DES versus BMS with respect to clinical and angiographic characteristics. Particular attention will be paid to collecting detailed information concerning the use of pharmacotherapies. Other secondary objectives are to characterize the temporal changes in the pattern of DES use over the relatively early adoption period; to determine at 6 months and 1 year the unadjusted and risk-adjusted incidence of the composite and individual components
American Heart Journal November 2005
of death, new/reinfarction, or urgent TVR, each stratified by the administration or lack of administration of a GPIIb-IIIa inhibitor; to determine whether elevations of troponin T occurring 24 hours after PCI with stent deployment are associated with a higher rate of major adverse cardiac events (composite and individual events) at 6 months and 1 year than in patients with normal troponin levels 24 hours after PCI; and to describe the patterns of use for thienopyridines and temporal changes in these patterns. The EVENT registry will also examine each of these secondary objectives separately in patients presenting with or without ST-elevation MI (STEMI ) at the time of PCI.
Patient population The study population will consist of approximately 7500 to 10 000 consecutively treated PCI patients enrolled at about 50 to 60 centers in the United States. Inclusion and exclusion criteria Patients will be included if they are aged z18 years and undergo PCI with attempted stent deployment. Data will be collected for both planned and unplanned stent placement. Exclusion criteria are minimal. Patients will be excluded if PCI is undertaken without attempted stent implantation; if they have had previous PCI or cardiac surgery within 4 weeks; or if they are concurrently enrolled in a study of an investigational drug or device whose protocol specifically excludes concurrent enrollment or that involves blinded placement of DES or BMS. Concurrent enrollment in other registries is permitted.
Study procedure and follow-up Recruitment of patients The registry will consist of consecutive patients undergoing stent placement recruited in 3 waves, each wave consisting of discontinuous recruiting periods. The purpose of recruiting in waves is to examine changes in the patterns of use of DES and other pharmacologic adjuncts during the early phase of the implementation. Because of the intense effort involved in registering consecutive patients in a busy laboratory and because of the large volume of data accumulated during recruitment, the period between waves will be used to initiate queries when appropriate and to prepare progress reports. Each wave will last approximately 3 months with a maximum enrollment of 125 patients per site. To ensure capture of virtually all eligible patients while minimizing the burden to the sites, several alternative recruitment strategies will be allowed. Sites will employ 1 of 3 recruiting strategies: recruitment will occur on consecutive days of the week, fixed day or days of the week, or rotating days each week of enrollment. Sites
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are required to prespecify their enrollment strategy at the beginning of each wave. Each site will be allowed to change its strategy only once during the wave. To avoid the patient selection issues that surround participation of only some operators at many sites, a site requirement for participation is the inclusion of a minimum of 70% of the institution’s operators and at least 70% of the institution’s PCI volume. Although patients undergoing primary or rescue PCI for acute MI are eligible, to identify a sufficient number of postprocedural MIs (see bAnalytic planQ section), such patients are limited to not N10% of the entire patient population during any wave. To ensure that the registry is representative of routine clinical practice, a deidentified log will be kept of patients who receive stents but who do not consent to participation.
Data collection Data concerning patient risk factors, presentation, and treatment will be collected prospectively on standardized case report forms. The fields collected include demographic, angiographic, and procedural variables as well as considerable detail about the timing and dosing of pharmacologic regimens. After the index procedure, creatine kinase (CK) and CK-MB will be collected every 8 hours for a minimum of 2 samples and assayed at each site’s clinical laboratory using sitespecific reference values. Routine troponin collection before discharge is also encouraged. If an MI is suspected clinically at a later point, additional CK and CK-MB levels will be obtained as well. Ascertainment and definition of MI will be performed as in prior studies of pharmacologic intervention (elevation of CK exceeding 3 the local upper limit of normal with preference given to MB values or persistent ST-segment elevation N1 mm in 2 contiguous electrocardiographic limb leads or N2 mm in 2 contiguous precordial leads). Adjudication of MI will be performed centrally through computer algorithms applied to the case report forms. In addition to assessment of periprocedural MI, inhospital outcomes including death, bypass surgery, repeat PCI, and major and minor bleeding will be assessed for all patients. Repeat revascularization procedures will be categorized as urgent or planned (ie, staged) and in terms of the involvement of the original target vessel.
Late follow-up All patients will be contacted by telephone at 6 months and 1 year after the index PCI. Events noted at the telephone follow-up will include death, coronary revascularization (PCI or coronary artery bypass graft [CABG] and whether the revascularization involved any of the index target vessels), noncardiac surgery, and hospitalization for documented or suspected MI. All
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follow-up events will be source-verified by the site coordinator. In addition, use of clopidogrel and lipidlowering therapy will be assessed at each time point.
Analytic plan The primary statistical analysis will seek to determine whether use of DES is associated with an increase in the incidence of periprocedural ischemic complications compared with implantation of BMS. For the purposes of this primary analysis, patients receiving a combination of both DES and BMS will be analyzed as having received DES.
Sample size calculation The primary hypothesis is that the rate of inhospital periprocedural ischemic complications (including death, MI, or urgent TVR) with use of DES is not inferior to (ie, higher than) that of BMS in unselected patients. For the purpose of this analysis, patients undergoing primary PCI for STEMI will be analyzed separately. Exclusion of primary PCI patients from these main analyses is reasonable because the specific nature of ischemic complications is likely to differ substantially between primary PCI and all other PCI patients, and reliable ascertainment of periprocedural MI among such patients will not be possible. At a 1-sided .05 level of significance, assuming that the population DES and BMS complication rates are 6.0%, a sample size of 6750 subjects (the number of patients without STEMI expected of the 7500 -10 000 enrolled patients) yields 80% power to reject the statistical null hypothesis of inferiority (DES periprocedural ischemic complication rate exceeds that of BMS by at least 1.6%) in favor of the alternative hypothesis of noninferiority (DES periprocedural ischemic complication rate is not N1.6% greater than that of BMS), assuming that the ratio of DES to BMS patients is 3:1. Given the expected control group rate of 6.0%, a 50% relative reduction would yield a noninferiority margin of 3.0%. Given the large sample size of EVENT, we felt we could reduce this margin even further while still maintaining noninferiority. Thus, the margin is reduced to 1.6%. Based on current practice, this ratio (indicating 75% DES use among eligible patients at the investigator sites) would appear to be realistic; however, the 1.6% margin allows additional latitude should the observed rate of DES use be greater than predicted. This noninferiority assessment will be carried out using a 1-sided 95% CI of the difference between treatments (DES minus BMS) with respect to the percentage of patients with periprocedural complications for all waves combined. A comparison of the rates of periprocedural ischemic complications between DES and BMS will also be carried out for each wave separately.
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Table I. Planned variables to be entered into the propensity analysis Study center Wave no. (1, 2, or 3) ACC/AHA lesion score N2 Ejection fraction b 0.35 Multivessel intervention performed Operator estimated reference vessel size Presence of thrombus ACC/AHA, American College of Cardiology/American Heart Association.
Given the nonrandomized nature of the study, it is very unlikely that DES and BMS groups will be comparable at baseline with regard to clinically important covariates (study center, wave, presence of acute coronary syndrome, troponin elevation at baseline, pharmacotherapy, age, American College of Cardiology/ American Heart Association lesion score, depressed ejection fraction, multivessel intervention, vessel size, and lesion characteristics). According to the study plan, to account for this likelihood, propensity scores for treatment selection will be calculated, and the CIs for the difference between stent groups will be calculated adjusting for propensity score quintile. Specifically, a propensity score will be generated for each patient as follows. A logistic regression model will be developed in which the outcome is treatment group (DES or BMS) and the independent variables are the above-mentioned important baseline characteristics that may be related to inhospital periprocedural ischemic complications. From this logistic regression model, a predicted probability of being treated with DES will be calculated for each patient, based on the patient’s values of these baseline covariates (Table I ). This predicted probability is the propensity score for selection of stent type. Patients will then be grouped into quintiles based on propensity score and the CIs for the difference between stent groups will be calculated adjusting for propensity score quintile.
Implications The applicability of clinical trial results to clinical practice poses a particularly nettlesome problem whenever a new technology is introduced. Having perceived a need to assess longer-term outcomes in patients undergoing stent placement, the Food and Drug Administration has mandated postmarketing surveillance of approved stents. In addition, stent manufacturers have initiated registry studies both within and outside the United States. As one of several ongoing registry studies, EVENT is distinguished by 3 facets. First, consecutive patients undergoing attempted stent placement are enrolled, thus providing a clear picture of the patterns of stent use in the United States. Enrollment is not device specific; patients receiving DES, BMS, or both
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are included to represent the broad population of patients undergoing intracoronary stent placement. Second, detailed pharmacotherapeutic information and detailed data on biomarker release are being collected. Third, propensity analyses are specified in the study protocol to help adjust for anticipated differences between individuals in comparing rates of ischemic complications according to stent type and other nonrandomly selected treatment characteristics. The authors of a recent meta-analysis pointed out that patients included in the randomized trials of DES placement constitute a group at low risk for restenosis as well as for mortality.21 In fact, several registries that preceded the use of DES indicated that PCI procedures are performed on a substantial number of patients who would have been excluded from the trials of DES placement. In the NHLBI DYNAMIC registry, Wilensky et al22 reported that 13% of patients had total coronary occlusions, whereas 24% had moderately to severely tortuous vessels. In another broadly inclusive database, Kugelmass et al23 noted that 24% of patients undergoing PCI had dilation of 2 or 3 vessels, 18% had lesions exceeding 20 mm in length, and 15% had moderately or extremely tortuous vessels. Each of these patient groups would have been excluded from the pivotal trials of DES. Mack et al24 also reported that the proportion of patients in their PCI database who underwent multivessel PCI increased each year from 1999 to 2003. This observation reflects a broad trend toward increasing use of multivessel PCI in populations who have traditionally undergone bypass surgery. As the anticipated shift from surgical coronary revascularization toward stent placement accelerates, it will become critical to obtain data concerning the safety of DES placement in patients who would have otherwise undergone CABG. Powell et al25 reviewed 192 angiograms of patients referred for CABG surgery between 1999 and 2001. They found that only 6% of patients had lesions suitable for stenting that would have met entry criteria for pivotal DES trials, 40% had lesions suitable for stenting that would have been excluded, and 17% had bdifficult Q lesions but would have been candidates for stent placement.25 Although more recent trials of DES have included more liberal entry criteria, they have thus far been limited to patients undergoing single-vessel PCI and have excluded patients undergoing PCI of totally occluded vessels. A second goal of the registry is to determine the frequency of periprocedural myocyte necrosis and its sequelae in the current PCI population. An early detailed report of 4775 patients undergoing otherwise b uncomplicated Q PCI indicated that CK release occurred in 12% of patients and was associated with increased long-term mortality26—a finding that has subsequently been replicated by several other investigators.27 In another report, as many as 38% of unselected patients undergoing PCI had elevations in CK after the
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procedure.28 Numerous randomized clinical trials have indicated that treatment with a GPIIb-IIIa antagonist reduces this event rate by 40% to 50% with a corresponding reduction in long-term mortality.29 However, a recent trial, albeit in a low-risk cohort of patients, suggested in the current era that high doses of clopidogrel given before the procedure reduce the rate of periprocedural infarction to b4% and eliminate the need for GPIIb-IIIa antagonists.19 It has also been suggested that given modern stent placement techniques allowing more complete revascularization with lower rates of restenosis, the impact of mild elevations in CK may be blunted in comparison with observations made during the previous decade.30 These findings imply that it is possible to identify a group of patients in whom an efficiently performed procedure carries an extremely low risk of periprocedural events. Given the economic and safety implications of this finding, it becomes imperative to confirm what the risk of periprocedural infarction is in an unselected population and whether a simple model can be constructed to identify a group of patients at exceptionally low risk. Finally, the EVENT registry is unique in that a propensity model is prespecified as one of the analyses to be performed. Propensity adjustment was originally developed by Rosenbaum and Rubin31,32 to reduce bias when comparing outcomes among patients who were not randomly assigned to different treatments. Although not designed to provide definitive assessments of the superiority of one treatment over another, this technique is useful to allow qualified comparisons of event rates. At a time when it appears likely that many patient groups currently treated with CABG surgery will undergo stent-based techniques, obtaining practical information on outcomes among patients receiving various stent types under different settings will become crucially important for mapping future revascularization strategies.
References 1. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496 - 501. 2. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable –stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331:489 - 95. 3. Serruys PW, van HB, Bonnier H, et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II). Lancet 1998;352:673 - 81. 4. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315 - 23.
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5. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221 - 31. 6. Holmes Jr DR, Leon MB, Moses JW, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimuseluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004;109:634 - 40. 7. Katritsis DG, Karvouni E, Ioannidis JPA. Meta-analysis comparing drug-eluting stents with bare metal stents. Am J Cardiol 2005;95:640 - 3. 8. Guagliumi G, Virmani R, Musumeci G, et al. Drug-eluting versus bare metal coronary stents: long-term human pathology. Findings from different coronary arteries in the same patient. Ital Heart J 2003;4:713 - 20. 9. Virmani R, Farb A, Guagliumi G, et al. Drug-eluting stents: caution and concerns for long-term outcome. Coron Artery Dis 2004; 15:313 - 8. 10. http://www.fda.gov/cdrh/safety/cypher.html. 11. http://www.fda.gov/cdrh/safety/cypher3.html. 12. REALITY Trial. Presented by Dr MC Morice at the American College of Cardiology Annual Scientific Sessions; 2005. 13. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drugeluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519 - 21. 14. Ferrari E, Benhamou M, Cerboni P, et al. Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45:456 - 9. 15. Quinn MJ, Aronow HD, Califf RM, et al. Aspirin dose and six-month outcome after an acute coronary syndrome. J Am Coll Cardiol 2004;43:972 - 8. 16. Denardo SJ, Davis KE, Reid PR, et al. Efficacy and safety of minimal dose (b or = 1000 units) unfractionated heparin with abciximab in percutaneous coronary intervention. Am J Cardiol 2003;91:1 - 5. 17. Choussat RR, Montalescot G, Collet JP, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol 2002;40:1943 - 50. 18. Muller I, Seyfarth M, Rudiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001;85:92 - 3. 19. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232 - 8. 20. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853 - 63. 21. Babapulle MN, Joseph L, Belisle P, et al. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583 - 91. 22. Wilensky RL, Selzer F, Johnston J, et al. Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI dynamic registry). Am J Cardiol 2002;90:216 - 21. 23. Kugelmass AD, Cohen DJ, Houser F, et al. The influence of diabetes mellitus on the practice and outcomes of percutaneous coronary intervention in the community: a report from the HCA database. J Invasive Cardiol 2003;15:568 - 74. 24. Mack MJ, Brown PP, Kugelmass AD, et al. Current status and outcomes of coronary revascularization 1999 to 2002: 148,396 surgical and percutaneous procedures. Ann Thorac Surg 2004;77:761 - 6.
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25. Powell BD, Rihal CS, Bell MR, et al. Anticipated impact of drugeluting stents on referral patterns for coronary artery bypass graft surgery: a population-based angiographic analysis. Mayo Clin Proc 2004;79:769 - 72. 26. Abdelmeguid AE, Whitlow PL, Sapp SK, et al. Long-term outcome of transient, uncomplicated in-laboratory coronary artery closure. Circulation 1995;91:2733 - 41. 27. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241 - 51. 28. Brener SJ, Lytle BW, Schneider JP, et al. Association between CK-MB elevation after percutaneous or surgical revascularization and three-year mortality. J Am Coll Cardiol 2002;40: 1961 - 7.
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29. Kong DF, Hasselblad V, Harrington RA, et al. Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions. Am J Cardiol 2003;92:651 - 5. 30. Jeremias A, Baim DS, Ho KKL, et al. Differential mortality risk of postprocedural creatine kinase-MB elevation following successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44:1210 - 4. 31. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41 - 55. 32. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification in the propensity score. J Acoust Soc Am 1984;79:516 - 24.
Background
Clinical trials have shown drug-eluting stents (DES) to be superior to bare metal stents (BMS) in preventing in-stent restenosis and target vessel revascularization. Although these results have ushered in a sea change in the practice of myocardial revascularization, important questions remain unanswered concerning rates of ischemic complications when DES are used in a broader population not represented in the clinical trials.
Study Design
The EVENT registry will include 7500 to 10 000 patients enrolled at approximately 60 sites across the United States. The intent of the registry is to characterize a population of consecutive patients undergoing percutaneous coronary intervention with stent deployment using BMS and DES in terms of processes and outcomes of care. A unique aspect of EVENT is the prospective assessment of rates of periprocedural myocardial infarction among all patients. These data will allow us to compare rates of periprocedural myocardial infarction and other ischemic complications between patients receiving DES and BMS. In addition, the EVENT registry will characterize temporal changes in the patterns of DES use and the relationship between any such changes and both short- and long-term outcomes. (Am Heart J 2005;150:887 - 92.)
The adoption of intracoronary stenting has revolutionized the practice of myocardial revascularization. Stent implantation reduced the frequency of recurrent stenosis to 20% to 30%.1- 3 The introduction of drugeluting stents (DES) has further reduced this frequency to b10% in clinical trials, with revascularization of the target vessel performed in approximately 5% of patients.4- 6 Major adverse cardiac events during the first 2 years after percutaneous intervention have also been shown to be reduced significantly in patients receiving DES compared with bare metal stents (BMS); however, this reduction is driven almost entirely by reductions in target vessel revascularization (TVR) rather than in more serious irreversible events.7 Although there is much enthusiasm for this therapeutic advance, several key questions remain unanswered. First, the population represented in early clinical trials is highly selected and intentionally excludes certain patient groups such as patients with
From the aBaylor College of Medicine and The Methodist DeBakey Heart Center, Houston, Tex, and bHarvard Clinical Research Institute, Boston, Mass. Funding for EVENT is provided by Millennium Pharmaceuticals Inc and Schering Plough Inc. Submitted November 11, 2004; accepted March 26, 2005. Reprint requests: Neal S. Kleiman, MD, 6565 Fannin, MS F-1090, Houston, TX 77030. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.03.030
recent myocardial infarction (MI), patients undergoing multivessel revascularization, and patients undergoing percutaneous coronary intervention (PCI ) of venous bypass grafts or of chronically occluded vessels. In clinical practice, DES are likely to be used in more complex and higher-risk cases than have been represented in the clinical trials. It is also likely that as confidence in the safety and ability of these devices to prevent restenosis increases, more complex cases will be undertaken than were previously approached with BMS. It is unclear whether the benefit of DES will be sustained in the broader population undergoing stent placement. As a consequence of increasing complexity, the rate of periprocedural ischemic complications (eg, MI, stent thrombosis, and urgent TVR) may increase. A second major concern is that drug interference with the cell cycle or with mitosis may also delay endothelial growth and injury site healing in patients with atherosclerotic coronary artery disease.8,9 If impaired healing permits ongoing microembolization, the time course of periprocedural myonecrosis may be extended over a period of days to weeks after stent implantation. Soon after the market approval of the sirolimus-eluting (Cypher) stent, the Food and Drug Administration issued an alert indicating that the frequency of subacute stent thrombosis (SAT ) may be increased in patients receiving a Cypher stent.10 One year later, however, the notification was updated based on a registry of 2063 patients with 30 - day follow-up stating that the Cypher stent, when implanted in accordance with the
888 Jacob et al
approved indications for use, bis not associated with an excess of SATs.Q11 However, device implantation is frequently performed outside the window of approved indications. The frequency of this practice is not known, nor is the true complication rate. Although the randomized clinical trials comparing BMS and DES do not support an increased frequency of SAT after DES implantation, at least 1 clinical trial performed in a group of patients with more complex lesions than those studied previously suggested that the rate of SAT may be as high as 1.6% 30 days after implantation of a paclitaxel-eluting stent.12 Similarly, the occurrence of late events after DES implantation is not well characterized. Indeed, emerging reports of events occurring months to years after stent implantation13 have raised concerns about the need for prolonged antiplatelet therapy and the appropriateness of implantation in high-risk cases. Recently, an observation by Ferrari et al14 suggested that cessation of antiplatelet therapy may also be associated with late thrombosis of BMS. Finally, the pharmacotherapeutic milieu surrounding intracoronary stent placement is changing rapidly. Considerable uncertainty surrounds selecting appropriate doses of aspirin,15 heparin,16,17 and clopidogrel18,19 and the appropriate use of platelet glycoprotein IIb/IIIa (GPIIb-IIIa) antagonists and other novel anticoagulation strategies,19,20 and it is likely that the use patterns for such drugs will continue to evolve rapidly. The adoption of DES, the enthusiasm surrounding their use, and the inevitable learning curve that is occurring soon after DES release to the cardiology community offer a unique opportunity to study the effects of the new technology on patterns of care, the frequency of periprocedural ischemic events, and longterm clinical outcomes. The EVENT registry was thus designed to investigate event rates as detected by elevations in cardiac enzymes and clinical end points in patients receiving both DES and BMS.
Study objectives The primary objective of EVENT is to determine whether implantation of DES in clinical practice is associated with an increased frequency of periprocedural ischemic complications compared with BMS implantation. The key secondary objective is to compare the characteristics of patients receiving DES versus BMS with respect to clinical and angiographic characteristics. Particular attention will be paid to collecting detailed information concerning the use of pharmacotherapies. Other secondary objectives are to characterize the temporal changes in the pattern of DES use over the relatively early adoption period; to determine at 6 months and 1 year the unadjusted and risk-adjusted incidence of the composite and individual components
American Heart Journal November 2005
of death, new/reinfarction, or urgent TVR, each stratified by the administration or lack of administration of a GPIIb-IIIa inhibitor; to determine whether elevations of troponin T occurring 24 hours after PCI with stent deployment are associated with a higher rate of major adverse cardiac events (composite and individual events) at 6 months and 1 year than in patients with normal troponin levels 24 hours after PCI; and to describe the patterns of use for thienopyridines and temporal changes in these patterns. The EVENT registry will also examine each of these secondary objectives separately in patients presenting with or without ST-elevation MI (STEMI ) at the time of PCI.
Patient population The study population will consist of approximately 7500 to 10 000 consecutively treated PCI patients enrolled at about 50 to 60 centers in the United States. Inclusion and exclusion criteria Patients will be included if they are aged z18 years and undergo PCI with attempted stent deployment. Data will be collected for both planned and unplanned stent placement. Exclusion criteria are minimal. Patients will be excluded if PCI is undertaken without attempted stent implantation; if they have had previous PCI or cardiac surgery within 4 weeks; or if they are concurrently enrolled in a study of an investigational drug or device whose protocol specifically excludes concurrent enrollment or that involves blinded placement of DES or BMS. Concurrent enrollment in other registries is permitted.
Study procedure and follow-up Recruitment of patients The registry will consist of consecutive patients undergoing stent placement recruited in 3 waves, each wave consisting of discontinuous recruiting periods. The purpose of recruiting in waves is to examine changes in the patterns of use of DES and other pharmacologic adjuncts during the early phase of the implementation. Because of the intense effort involved in registering consecutive patients in a busy laboratory and because of the large volume of data accumulated during recruitment, the period between waves will be used to initiate queries when appropriate and to prepare progress reports. Each wave will last approximately 3 months with a maximum enrollment of 125 patients per site. To ensure capture of virtually all eligible patients while minimizing the burden to the sites, several alternative recruitment strategies will be allowed. Sites will employ 1 of 3 recruiting strategies: recruitment will occur on consecutive days of the week, fixed day or days of the week, or rotating days each week of enrollment. Sites
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are required to prespecify their enrollment strategy at the beginning of each wave. Each site will be allowed to change its strategy only once during the wave. To avoid the patient selection issues that surround participation of only some operators at many sites, a site requirement for participation is the inclusion of a minimum of 70% of the institution’s operators and at least 70% of the institution’s PCI volume. Although patients undergoing primary or rescue PCI for acute MI are eligible, to identify a sufficient number of postprocedural MIs (see bAnalytic planQ section), such patients are limited to not N10% of the entire patient population during any wave. To ensure that the registry is representative of routine clinical practice, a deidentified log will be kept of patients who receive stents but who do not consent to participation.
Data collection Data concerning patient risk factors, presentation, and treatment will be collected prospectively on standardized case report forms. The fields collected include demographic, angiographic, and procedural variables as well as considerable detail about the timing and dosing of pharmacologic regimens. After the index procedure, creatine kinase (CK) and CK-MB will be collected every 8 hours for a minimum of 2 samples and assayed at each site’s clinical laboratory using sitespecific reference values. Routine troponin collection before discharge is also encouraged. If an MI is suspected clinically at a later point, additional CK and CK-MB levels will be obtained as well. Ascertainment and definition of MI will be performed as in prior studies of pharmacologic intervention (elevation of CK exceeding 3 the local upper limit of normal with preference given to MB values or persistent ST-segment elevation N1 mm in 2 contiguous electrocardiographic limb leads or N2 mm in 2 contiguous precordial leads). Adjudication of MI will be performed centrally through computer algorithms applied to the case report forms. In addition to assessment of periprocedural MI, inhospital outcomes including death, bypass surgery, repeat PCI, and major and minor bleeding will be assessed for all patients. Repeat revascularization procedures will be categorized as urgent or planned (ie, staged) and in terms of the involvement of the original target vessel.
Late follow-up All patients will be contacted by telephone at 6 months and 1 year after the index PCI. Events noted at the telephone follow-up will include death, coronary revascularization (PCI or coronary artery bypass graft [CABG] and whether the revascularization involved any of the index target vessels), noncardiac surgery, and hospitalization for documented or suspected MI. All
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follow-up events will be source-verified by the site coordinator. In addition, use of clopidogrel and lipidlowering therapy will be assessed at each time point.
Analytic plan The primary statistical analysis will seek to determine whether use of DES is associated with an increase in the incidence of periprocedural ischemic complications compared with implantation of BMS. For the purposes of this primary analysis, patients receiving a combination of both DES and BMS will be analyzed as having received DES.
Sample size calculation The primary hypothesis is that the rate of inhospital periprocedural ischemic complications (including death, MI, or urgent TVR) with use of DES is not inferior to (ie, higher than) that of BMS in unselected patients. For the purpose of this analysis, patients undergoing primary PCI for STEMI will be analyzed separately. Exclusion of primary PCI patients from these main analyses is reasonable because the specific nature of ischemic complications is likely to differ substantially between primary PCI and all other PCI patients, and reliable ascertainment of periprocedural MI among such patients will not be possible. At a 1-sided .05 level of significance, assuming that the population DES and BMS complication rates are 6.0%, a sample size of 6750 subjects (the number of patients without STEMI expected of the 7500 -10 000 enrolled patients) yields 80% power to reject the statistical null hypothesis of inferiority (DES periprocedural ischemic complication rate exceeds that of BMS by at least 1.6%) in favor of the alternative hypothesis of noninferiority (DES periprocedural ischemic complication rate is not N1.6% greater than that of BMS), assuming that the ratio of DES to BMS patients is 3:1. Given the expected control group rate of 6.0%, a 50% relative reduction would yield a noninferiority margin of 3.0%. Given the large sample size of EVENT, we felt we could reduce this margin even further while still maintaining noninferiority. Thus, the margin is reduced to 1.6%. Based on current practice, this ratio (indicating 75% DES use among eligible patients at the investigator sites) would appear to be realistic; however, the 1.6% margin allows additional latitude should the observed rate of DES use be greater than predicted. This noninferiority assessment will be carried out using a 1-sided 95% CI of the difference between treatments (DES minus BMS) with respect to the percentage of patients with periprocedural complications for all waves combined. A comparison of the rates of periprocedural ischemic complications between DES and BMS will also be carried out for each wave separately.
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Table I. Planned variables to be entered into the propensity analysis Study center Wave no. (1, 2, or 3) ACC/AHA lesion score N2 Ejection fraction b 0.35 Multivessel intervention performed Operator estimated reference vessel size Presence of thrombus ACC/AHA, American College of Cardiology/American Heart Association.
Given the nonrandomized nature of the study, it is very unlikely that DES and BMS groups will be comparable at baseline with regard to clinically important covariates (study center, wave, presence of acute coronary syndrome, troponin elevation at baseline, pharmacotherapy, age, American College of Cardiology/ American Heart Association lesion score, depressed ejection fraction, multivessel intervention, vessel size, and lesion characteristics). According to the study plan, to account for this likelihood, propensity scores for treatment selection will be calculated, and the CIs for the difference between stent groups will be calculated adjusting for propensity score quintile. Specifically, a propensity score will be generated for each patient as follows. A logistic regression model will be developed in which the outcome is treatment group (DES or BMS) and the independent variables are the above-mentioned important baseline characteristics that may be related to inhospital periprocedural ischemic complications. From this logistic regression model, a predicted probability of being treated with DES will be calculated for each patient, based on the patient’s values of these baseline covariates (Table I ). This predicted probability is the propensity score for selection of stent type. Patients will then be grouped into quintiles based on propensity score and the CIs for the difference between stent groups will be calculated adjusting for propensity score quintile.
Implications The applicability of clinical trial results to clinical practice poses a particularly nettlesome problem whenever a new technology is introduced. Having perceived a need to assess longer-term outcomes in patients undergoing stent placement, the Food and Drug Administration has mandated postmarketing surveillance of approved stents. In addition, stent manufacturers have initiated registry studies both within and outside the United States. As one of several ongoing registry studies, EVENT is distinguished by 3 facets. First, consecutive patients undergoing attempted stent placement are enrolled, thus providing a clear picture of the patterns of stent use in the United States. Enrollment is not device specific; patients receiving DES, BMS, or both
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are included to represent the broad population of patients undergoing intracoronary stent placement. Second, detailed pharmacotherapeutic information and detailed data on biomarker release are being collected. Third, propensity analyses are specified in the study protocol to help adjust for anticipated differences between individuals in comparing rates of ischemic complications according to stent type and other nonrandomly selected treatment characteristics. The authors of a recent meta-analysis pointed out that patients included in the randomized trials of DES placement constitute a group at low risk for restenosis as well as for mortality.21 In fact, several registries that preceded the use of DES indicated that PCI procedures are performed on a substantial number of patients who would have been excluded from the trials of DES placement. In the NHLBI DYNAMIC registry, Wilensky et al22 reported that 13% of patients had total coronary occlusions, whereas 24% had moderately to severely tortuous vessels. In another broadly inclusive database, Kugelmass et al23 noted that 24% of patients undergoing PCI had dilation of 2 or 3 vessels, 18% had lesions exceeding 20 mm in length, and 15% had moderately or extremely tortuous vessels. Each of these patient groups would have been excluded from the pivotal trials of DES. Mack et al24 also reported that the proportion of patients in their PCI database who underwent multivessel PCI increased each year from 1999 to 2003. This observation reflects a broad trend toward increasing use of multivessel PCI in populations who have traditionally undergone bypass surgery. As the anticipated shift from surgical coronary revascularization toward stent placement accelerates, it will become critical to obtain data concerning the safety of DES placement in patients who would have otherwise undergone CABG. Powell et al25 reviewed 192 angiograms of patients referred for CABG surgery between 1999 and 2001. They found that only 6% of patients had lesions suitable for stenting that would have met entry criteria for pivotal DES trials, 40% had lesions suitable for stenting that would have been excluded, and 17% had bdifficult Q lesions but would have been candidates for stent placement.25 Although more recent trials of DES have included more liberal entry criteria, they have thus far been limited to patients undergoing single-vessel PCI and have excluded patients undergoing PCI of totally occluded vessels. A second goal of the registry is to determine the frequency of periprocedural myocyte necrosis and its sequelae in the current PCI population. An early detailed report of 4775 patients undergoing otherwise b uncomplicated Q PCI indicated that CK release occurred in 12% of patients and was associated with increased long-term mortality26—a finding that has subsequently been replicated by several other investigators.27 In another report, as many as 38% of unselected patients undergoing PCI had elevations in CK after the
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procedure.28 Numerous randomized clinical trials have indicated that treatment with a GPIIb-IIIa antagonist reduces this event rate by 40% to 50% with a corresponding reduction in long-term mortality.29 However, a recent trial, albeit in a low-risk cohort of patients, suggested in the current era that high doses of clopidogrel given before the procedure reduce the rate of periprocedural infarction to b4% and eliminate the need for GPIIb-IIIa antagonists.19 It has also been suggested that given modern stent placement techniques allowing more complete revascularization with lower rates of restenosis, the impact of mild elevations in CK may be blunted in comparison with observations made during the previous decade.30 These findings imply that it is possible to identify a group of patients in whom an efficiently performed procedure carries an extremely low risk of periprocedural events. Given the economic and safety implications of this finding, it becomes imperative to confirm what the risk of periprocedural infarction is in an unselected population and whether a simple model can be constructed to identify a group of patients at exceptionally low risk. Finally, the EVENT registry is unique in that a propensity model is prespecified as one of the analyses to be performed. Propensity adjustment was originally developed by Rosenbaum and Rubin31,32 to reduce bias when comparing outcomes among patients who were not randomly assigned to different treatments. Although not designed to provide definitive assessments of the superiority of one treatment over another, this technique is useful to allow qualified comparisons of event rates. At a time when it appears likely that many patient groups currently treated with CABG surgery will undergo stent-based techniques, obtaining practical information on outcomes among patients receiving various stent types under different settings will become crucially important for mapping future revascularization strategies.
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5. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxeleluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221 - 31. 6. Holmes Jr DR, Leon MB, Moses JW, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimuseluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004;109:634 - 40. 7. Katritsis DG, Karvouni E, Ioannidis JPA. Meta-analysis comparing drug-eluting stents with bare metal stents. Am J Cardiol 2005;95:640 - 3. 8. Guagliumi G, Virmani R, Musumeci G, et al. Drug-eluting versus bare metal coronary stents: long-term human pathology. Findings from different coronary arteries in the same patient. Ital Heart J 2003;4:713 - 20. 9. Virmani R, Farb A, Guagliumi G, et al. Drug-eluting stents: caution and concerns for long-term outcome. Coron Artery Dis 2004; 15:313 - 8. 10. http://www.fda.gov/cdrh/safety/cypher.html. 11. http://www.fda.gov/cdrh/safety/cypher3.html. 12. REALITY Trial. Presented by Dr MC Morice at the American College of Cardiology Annual Scientific Sessions; 2005. 13. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drugeluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519 - 21. 14. Ferrari E, Benhamou M, Cerboni P, et al. Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45:456 - 9. 15. Quinn MJ, Aronow HD, Califf RM, et al. Aspirin dose and six-month outcome after an acute coronary syndrome. J Am Coll Cardiol 2004;43:972 - 8. 16. Denardo SJ, Davis KE, Reid PR, et al. Efficacy and safety of minimal dose (b or = 1000 units) unfractionated heparin with abciximab in percutaneous coronary intervention. Am J Cardiol 2003;91:1 - 5. 17. Choussat RR, Montalescot G, Collet JP, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol 2002;40:1943 - 50. 18. Muller I, Seyfarth M, Rudiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001;85:92 - 3. 19. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232 - 8. 20. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853 - 63. 21. Babapulle MN, Joseph L, Belisle P, et al. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:583 - 91. 22. Wilensky RL, Selzer F, Johnston J, et al. Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI dynamic registry). Am J Cardiol 2002;90:216 - 21. 23. Kugelmass AD, Cohen DJ, Houser F, et al. The influence of diabetes mellitus on the practice and outcomes of percutaneous coronary intervention in the community: a report from the HCA database. J Invasive Cardiol 2003;15:568 - 74. 24. Mack MJ, Brown PP, Kugelmass AD, et al. Current status and outcomes of coronary revascularization 1999 to 2002: 148,396 surgical and percutaneous procedures. Ann Thorac Surg 2004;77:761 - 6.
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25. Powell BD, Rihal CS, Bell MR, et al. Anticipated impact of drugeluting stents on referral patterns for coronary artery bypass graft surgery: a population-based angiographic analysis. Mayo Clin Proc 2004;79:769 - 72. 26. Abdelmeguid AE, Whitlow PL, Sapp SK, et al. Long-term outcome of transient, uncomplicated in-laboratory coronary artery closure. Circulation 1995;91:2733 - 41. 27. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241 - 51. 28. Brener SJ, Lytle BW, Schneider JP, et al. Association between CK-MB elevation after percutaneous or surgical revascularization and three-year mortality. J Am Coll Cardiol 2002;40: 1961 - 7.
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29. Kong DF, Hasselblad V, Harrington RA, et al. Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions. Am J Cardiol 2003;92:651 - 5. 30. Jeremias A, Baim DS, Ho KKL, et al. Differential mortality risk of postprocedural creatine kinase-MB elevation following successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44:1210 - 4. 31. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983;70:41 - 55. 32. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification in the propensity score. J Acoust Soc Am 1984;79:516 - 24.