Safety of Coronary Sirolimus-Eluting Stents in Daily Clinical Practice
One-Year Follow-Up of the e-Cypher Registry
Background— The expanding indications for sirolimus-eluting stents (SES) include increasingly complex coronary lesions and populations with clinical profiles markedly different from those of early pivotal controlled studies. The e-Cypher registry monitored the safety and efficacy of SES currently implanted worldwide in daily practice.
Methods and Results— Between April 2002 and September 2005, data were collected on 15 157 patients who underwent implantation of ≥1 SES at 279 medical centers from 41 countries. An independent endpoint review committee adjudicated all reported major adverse cardiovascular events, stent thromboses, and target-vessel revascularizations. Data were managed and analyzed by independent organizations. Predictors of adverse clinical events were identified by regression analysis. The mean age of the sample was 61.7±11.4 years; 77.7% were men, and 28.6% were diabetics. A total of 18 295 lesions were treated (20 503 SES) during the index procedure. The cumulative rates of major adverse cardiovascular events were 1.36% at 30 days, 3.38% at 6 months, and 5.80% at 1 year. The rates of acute, subacute, and late stent thrombosis were 0.13%, 0.56%, and 0.19% of patients, respectively, representing a 12-month actuarial incidence of 0.87%. Insulin-dependent diabetes, acute coronary syndrome at presentation, and advanced age were clinical predictors, whereas TIMI flow grade <3 after the index procedure, treatment of multiple lesions, a prominently calcified or totally occluded target lesion, and multivessel disease were the angiographic or procedural predictors of stent thrombosis at 12 months.
Conclusions— This analysis of 1-year data collected by the e-Cypher registry suggests a high degree of safety of SES, with a rate of stent thrombosis similar to that observed in randomized trials.
Received December 27, 2004; revision received December 8, 2005; accepted January 9, 2006.
In several randomized trials, sirolimus-eluting stents (SES) were highly effective in lowering rates of coronary artery restenosis and target-lesion revascularization (TLR) compared with bare metal stents (BMS) up to at least 3 years.1–5 Although these controlled observations were generally made in patients with de novo coronary lesions who met stringent study inclusion and exclusion criteria, they have now been widely extrapolated to populations with markedly different clinical profiles or disease characteristics. It is unrealistic to expect the design and conduct of controlled trials to include all possible clinical presentations, alone or in combination, including multivessel disease, diabetes, bifurcation of left main coronary artery lesions, narrow arteries, inordinately long lesions or total occlusions, saphenous vein graft stenoses, acute myocardial infarction (MI), or in-stent restenosis. Furthermore, the results of carefully controlled clinical trials, in which highly experienced operators/investigators from large medical centers typically participate, are not fully representative of “real-world” practices. Clinical registries or observational studies by single or multiple centers have also been conducted to ascertain primarily the safety and, to a lesser extent, the efficacy of SES in a wider variety of indications and coronary disease presentations and to monitor their broad utilization pattern and performance.6–13 To date, the number of patients included in these studies has been relatively small. The e-Cypher registry was developed to evaluate the performance of SES in daily clinical practice in a large sample and to monitor worldwide utilization of SES. This report presents the safety results up to 1 year among 15 157 analyzable patients enrolled in the e-Cypher registry.
Clinical Perspective p 1441
Patient Enrollment and Study End Points
e-Cypher is an Internet-based, postmarketing surveillance registry. Its predefined primary objective is to assess the safety of the Cypher coronary SES (Cordis Corp, Warren, NJ) in daily clinical practice. Secondary objectives include evaluation of the worldwide utilization of SES and the identification of predictors of major adverse cardiovascular events (MACEs). Between April 2002 and September 2005, multiple demographic, clinical, angiographic, and follow-up variables were collected for all recipients with ≥1 SES at 279 medical centers from 41 countries, excluding US institutions (see Appendix in the online-only Data Supplement). The indications for stenting were left to the operators’ discretion. This registry, in which all patients could be included, is supervised by an independent advisory board (see Data Supplement).
The management of antithrombotic therapy was left to the discretion of each institution or cardiologist participating in the registry. Data were collected with respect to the type of medications administered at the time of discharge from the hospital and at each subsequent follow-up.
Data Collection and Management
The Cordis Worldwide Postmarketing Surveillance Electronic Data Capture database was developed and implemented by Clinsights (Eminent PPD, GlobalView Web Services, New Hope, Minn). This database was tested and fully validated by both Eminent PPD and the study sponsor in multiple audits. The database included several edit verifications to ensure the integrity of the data on entry. In addition, it included technical security controls and computer-generated audit trails to maintain control of the data.
During the period of enrollment, between April 2002 and July 2004, detailed demographic, clinical, angiographic, and procedural information, including complications, were gathered for each patient. Follow-up data were collected at 30 days (1 month), 180 days (6 months), and 360 days (1 year) after the index procedure on the basis of information entered on case report forms at the time of scheduled clinical visits or telephone communications. Follow-up rates were calculated as the number of patients followed up (or with a known adverse event) relative to the number of patients who had reached each scheduled follow-up visit. At the time of follow-up contact, data were collected pertaining to current clinical status, concomitant drug therapy, and interim occurrence of adverse events. Angiographic data were evaluated on site by quantitative coronary angiography or visually by the operators and were not analyzed by a core laboratory. The data, collected via an Internet-based case-reporting system, were managed by an independent clinical research organization (Eminent PPD). Individual patient data, which were anonymously coded to protect the identity of all study participants, could only be accessed through a secured connection by the coordinating staff and by the treating physician. An independent Endpoint Review Committee (ERC; see Data Supplement) adjudicated all (1) reported MACEs, defined as death, MI, and TLRs by percutaneous coronary interventions (PCIs) or by coronary artery bypass graft surgery; (2) stent thromboses; and (3) target-vessel revascularizations by PCI or coronary artery bypass graft. The adjudications were based on the information contained in the electronic database and on the responses to queries addressed to the participating study sites. This information was gathered by questionnaires developed by the ERC and sent to the sites by the sponsor, who was in charge of coordinating the data acquisition.
Deaths were classified as cardiac or noncardiac. Deaths from undetermined causes were reported as cardiac. On the basis of ECG changes, a rise in creatine kinase enzyme concentration above twice the upper normal limit, or both, MIs were classified as Q wave, non–Q wave, or unknown when no further documentation was available. All reported reinterventions inside the stent implanted during the index procedure or within 5 mm proximal or distal to the stent were classified as TLRs. Other repeated PCIs in the same vessel were recorded as non-TLR target-vessel revascularizations. Stent thrombosis was classified as acute when it occurred within 24 hours of the index procedure, subacute when it occurred between 1 and 30 days, and late when it occurred beyond 30 days. Stent thrombosis was considered definite when confirmed angiographically or at autopsy. Stent thrombosis was considered likely when the patient had a target vessel–related MI or died of a coronary event, possibly caused by stent thrombosis, within 30 days of the index procedure.
Although the sites were not monitored, the validity and integrity of the registry data were verified by site audits performed between December 2003 and June 2004 by Eminent PPD (n=19 audits) or by the study sponsor (n=3 audits). All completed audits were reviewed by the sponsor’s quality assurance program. A total of 476 patients were selected from 22 participating centers in 14 countries, representing 3% of the original study sample. Among these 476 patients, 268 were selected on the basis of adverse-event reporting, and 208 were selected randomly. Of the 476 originally selected patients, the audits were limited to the 419 patients (88%) for whom source documents were accessible at the time of the visit.
The audits verified both the consistency and accuracy of the data contained in the source documentation versus that entered in the electronic database by using an anonymous procedure to preserve confidentiality. The data were “consistent” when present in both the source documents and the electronic database. The data were “accurate” when the electronic database fully matched the data found in the source documents. According to these definitions, the overall data consistency was 94%, whereas the overall data accuracy was 92%. When adjusted for underreporting of adverse events, an accuracy rate of 92% is expected to result in an 8.90% underestimate of the actual event rate. For example, an observed MACE rate of 5.80% would be adjusted to 6.33%, with a 95% confidence interval (CI) of 5.92% to 6.75%.
The statistical design of the registry was prepared and its analyses performed by an independent organization (Hesperion Ltd, Allschwill, Switzerland). Descriptive statistics are presented. The statistics for continuous variables include mean, standard deviation, minimum, maximum, and sample size. Categorical variables are described with numbers and percentages. The χ2 test was used for comparisons between proportions, and Student’s t test was used for comparisons of mean values. When appropriate, the odds ratio and 95% CI are presented. Single- and multiple-variable logistic-regression analyses were used to derive predictors of MACEs and stent thrombosis. Multiple-variable predictors were chosen by a stepwise procedure with an entry criterion of 0.10 with a stay criterion 0.05. Probability values <0.05 were considered to indicate statistical significance.
The authors had full access to the data and take full responsibility for their integrity. All authors have read and agreed to the article as written.
Patient Sample and Follow-Up Compliance
Data for 15 157 patients included in the registry were analyzed, representing 98% of the 15 524 patients enrolled. In 367 patients (2%), either data defining the index procedure were missing or no SES was implanted. The mean age of the sample was 61.7±11.4 years, 77.7% were men, and 28.6% were diabetics, of whom were insulin dependent. These baseline characteristics are further detailed in Table 1. Follow-up data were available for 14 298 patients at 30 days, for 13 970 patients at 6 months, and for 13 069 patients at 1 year, representing 95%, 93%, and 88% of survivors at 30 days, 6 months, and 1 year, respectively.
Index Procedure and Lesion Characteristics
A total of 20 503 SES were implanted during the index procedure. Their lengths ranged between 8 and 33 mm and their diameters between 2.25 and 3.50 mm. The most frequently used length was 18 mm (39%), and the most frequently used diameter was 3.0 mm (51%). Important procedural details are listed in Table 2. It is noteworthy that one third of stents were implanted without predilatation. A single SES was implanted in 73.7%, multiple SES in 26.3%, and other stents in 2.4% of patients. A total of 18 295 lesions were treated at the index procedure. Several clinical and lesion characteristics can be considered “high risk” (Table 2), and 8938 patients (59%) would have been excluded from the SIRIUS trial.2
At the time of discharge from the hospital, 99% of patients were being treated with clopidogrel or ticlopidine, alone or combined with aspirin, and 91.6% of patients left the hospital on combined therapy. The percentages of patients treated with aspirin or a thienopyridine alone or with combined aspirin and a thienopyridine at 1, 6, and 12 months are shown in Figure 1. At 6 months, 70.3% of patients remained on combined therapy, whereas at 1 year, this proportion had decreased to 43.0%.
Rates and Predictors of MACEs
The in-hospital, 30-day, 6-month, and 1-year rates of adverse clinical events are presented in Table 3. A total of 54 demographic, clinical, angiographic, and procedural variables were entered into the regression-analysis model in search of predictors of adverse clinical events. Among these, 39 were significantly associated with MACEs by single-variable analysis. By multiple-variable analysis, 5 clinical and 5 angiographic or procedural characteristics emerged as predictors of overall MACEs (Table 4). In a similar analysis carried out for stent thrombosis, 19 variables in the single-variable and 8 variables in the multiple-variable analysis emerged as significant predictors (Table 4).
SES thromboses developed in 126 patients (0.87% of the overall sample). The mean age of this subgroup was 65.3±10.8 years, significantly older than the remainder of the sample (61.7±11.4 years, P=0.0004). The proportion of diabetics was greater among patients who did (44%) versus those who did not (28%) develop stent thromboses (P<0.0001). In addition, among diabetics who developed stent thromboses, the proportion of insulin-dependent patients (55%) was significantly higher that that of non–insulin-dependent patients (P=0.0004). The strongest clinical and angiographic predictors of stent thrombosis are listed in Table 4.
The distribution of stent thromboses throughout the 12 months of follow-up is shown in Figure 2. It is noteworthy that 76% of thrombotic events occurred within 3 weeks of SES implantation. The rates of acute, subacute, and late SES thrombosis were 0.13%, 0.56%, and 0.19%, respectively (Table 3), and the 1-year actuarial incidence of stent thrombosis adjudicated by the ERC was 0.87%. Among these 126 patients, 53 died (42.1%), 55 suffered an MI (43.7%), and 63 underwent a TLR (50%). The relation among cardiac death, MI, and SES thrombosis is illustrated in Figure 3. At the time of SES thrombosis, 20 of the 126 patients (15.9%) were not being treated with antiplatelet medications because of noncompliance, drug intolerance, or interruption of treatment for a surgical procedure.
This report, based on a broad registry, is the first of its kind to address the issue of postmarketing surveillance in interventional cardiology on a scale until now only used by the pharmaceutical industry. The data available today suggest that routine clinical use of SES is safe and that the results from randomized, controlled trials can be replicated, despite the inclusion of patients with a variety of higher-risk clinical and angiographic characteristics. The 0.87% 12-month actuarial incidence of stent thrombosis observed in the e-Cypher registry is similar to that reported with BMS in patients treated with dual antiplatelet therapy.14 The validity of the present results is further strengthened by the narrow CI (0.7% to 1.0%) for stent thrombosis and by the large number of participating centers, indicating that these results are truly representative of the real world instead of selected patients and centers of excellence. Furthermore, in contrast to previous studies of stent thrombosis limited to 30 days of follow-up,9,13–16 the present series and a few others1–3,17 have extended the follow-up to 12 months. This longer observation period mitigates possible concerns related to late endothelialization,18,19 late thrombosis, or hypersensitivity reactions associated with drug elution20,21 or thrombotic complications associated with other modulators of fibrointimal proliferation, such as intravascular brachytherapy.22
The incidence of coronary stent thrombosis occurring despite combined antiplatelet therapy with aspirin and thienopyridine varies widely according to the patient subsets and the definitions of thrombosis applied among various published reports. With BMS, reported rates of stent thrombosis have ranged between 0.5% and 2.8%,14,16,23,24 whereas with drug-eluting stents (DES), rates have ranged between 0% and 3.5% in randomized trials1,25–27 and between 0.4% and 1.6% in registries.9,13,15,28,29 The definition of stent thrombosis used in the present registry is similar to that used in most recent randomized trials1–4,17 and thus, includes cases without definite angiographic or postmortem documentation when a diagnosis of stent thrombosis was considered likely up to 30 days after the index procedure.
By multiple-variable analysis, advanced age, insulin-dependent diabetes (2.8-fold risk increase), acute coronary syndrome presentation (1.8-fold risk increase), and multivessel coronary disease (1.6-fold risk increase) were clinical predictors of stent thrombosis. These observations are consistent with factors identified after implantation of BMS.30,31 Among the angiographic and procedural variables, the impact of moderate or heavy calcification might point to limited or insufficient stent expansion as a cause of stent thrombosis, along with a postprocedural TIMI flow grade <3 and a totally occluded lesion at baseline. Importantly, total stent length did not appear to predict the development of stent thrombosis in this analysis, in contrast to observations made by some with both DES and BMS.14,26
The low overall MACE and TLR rates at 12 months that were measured in this large and unselected patient sample are highly encouraging and suggest that the safety and efficacy of SES in routine clinical practice emulate their high performance observed in randomized trials.
Limitations of the Study
The potential underreporting of adverse events is an important limitation of all large multicenter registries. The audit process of this registry, prominently emphasized to the investigators, was designed to minimize the impact of data underreporting. The >90% accuracy of MACEs reported among the audited cases suggests reliable data collection by the registry participants. In addition, in an ongoing closely monitored registry of the routine clinical use of SES including 2067 patients in the United States, the 12-month overall stent thrombosis and MACE rates among patients who underwent stenting outside the acute phase of MI were very similar (0.8% and 7.3%, respectively),32 suggesting that underreporting of MACEs in the present study was not a major limitation. It is also noteworthy that in both trials, the rates of late thrombosis were similarly low, at ≈0.2% at 12 months. With regard to the precise nature of reported MACEs and their possible relation to stent thrombosis, each was individually reviewed and adjudicated by the ERC, and additional information was obtained directly from the participating center, as needed. Another uncertainty is related to the optimal duration of combined antiplatelet therapy after DES implantation, which was empirically defined in the pivotal randomized trials, although the earliest time point when both drugs can be safely discontinued, definitively or temporarily, remains unclear.1,2,17,33,34 In this study, this is reflected in the variable duration of antiplatelet treatment used by the various participating centers worldwide (Figure 1). However, it is well established that premature discontinuation of antiplatelet therapy is associated with a marked increase in the incidence of stent thrombosis.15 In this registry, the overall 30-day compliance with dual antiplatelet therapy was 85.6%, and only 5% of patients were reported to be taking neither aspirin nor a thienopyridine. This may explain the absence of noncompliance with treatment among the predictors of stent thrombosis.
Although late stent thrombosis was not identified as a prominent potential complication in randomized, controlled trials with up to 3 years of follow-up,1–3,17 12 months may be too short an observation period to accurately assess this risk.20,21 This issue warrants continued surveillance.
This analysis of the 1-year data collected by the worldwide e-Cypher registry demonstrates the good safety profile of SES, with a rate of stent thrombosis similar to that observed in closely monitored randomized trials, as well as those observed with the use of BMS.
Several DES that have been evaluated in randomized, controlled trials and that are now implanted routinely were shown to be as safe as BMS while markedly lowering the need for TLR during follow-up periods as long as 4 years. These trials, however, were usually performed in select medical centers, enrolled relatively small numbers of patients (typically 200 to 1200), and were limited by many inclusion and exclusion criteria to select patients with specific clinical and/or lesion characteristics. In addition, the trial design usually included mandatory angiographic follow-up, which is known to increase significantly (usually double) the rates of repeated TLR.
e-Cypher is the largest DES registry currently available. It complements the information gathered in randomized trials by analyzing the results of treatment of unselected coronary lesions with 1 or more SES in >15 000 unselected patients. This analysis provides a real-life representation of current, worldwide coronary stenting practices, including follow-up information up to 1 year, available for >13 000 patients (88% of the original sample) treated at 279 medical centers. The main finding is a high safety profile, with <6% MACE and <1% stent thrombosis rates at 12 months. A multivariate analysis of this large contemporary population also allowed for the identification of clinical predictors of MACEs and stent thrombosis.
The authors thank Rodolphe Ruffy, MD, for assisting in the composition of the manuscript and Dennis Donohoe, MD, for his constructive review.
This registry was sponsored by Cordis Corp, a Johnson & Johnson Company. Dr Urban is a consultant for Cordis J&J, Medtronic, and Boston Scientific. Dr Gershlick has received a research grant from Cordis J&J to investigate inflammatory markers after drug-eluting stent implantation, is member of the speaker’s bureau for Medtronic, Cordis J&J, and Boston Scientific, is an expert witness for Boston Scientific on patent issues, and is on Advisory Boards for Boston Scientific, Cordis J&J, and Medtronic. Dr Lotan is a consultant to Medtronic and has received honoraria from Hexacath. Dr Wijns has received 3 institutional research grants from several industrial sponsors. C. Berge is employed by Hesperion Ltd, a company paid by the study sponsor for statistical analysis of the data. Dr Deme is employed by the study sponsor. Dr Stoll is employed by the study sponsor.
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Several drug-eluting stents that have been evaluated in randomized-controlled trials, and are now implanted routinely, were shown to be as safe as bare metal stents, while markedly lowering the need for target lesion revascularization over follow-up periods as long as 4 years. These trials, however, were usually carried out in select medical centers, enrolled relatively small numbers of patients (typically 200 to 1200), and were limited by many inclusion and exclusion criteria to select patients with specific clinical and/or lesion characteristics. In addition, the trial design usually included mandatory angiographic follow-up, known to increase significantly (usually double) the rates of repeat target lesion revascularization. e-Cypher is the largest currently available drug-eluting stent registry. It complements the information gathered in randomized trials by analyzing the results of treatment of unselected coronary lesions with 1 or more sirolimus-eluting stents in >15 000 unselected patients. This analysis provides a “real-life” representation of current, worldwide coronary stenting practices, including follow-up information up to 1 year, available for over 13 000 patients (88% of the original sample) treated at 279 medical centers. The main finding is a high-safety profile, with <6% major adverse cardiovascular event and <1% stent thrombosis rates at 12 months. A multivariate analysis of this large contemporary population also allowed for the identification of clinical predictors of major adverse cardiovascular event and stent thrombosis.
The online-only Data Supplement, which contains the Appendix, can be found at http://circ.ahajournals.org/content/full/CIRCULATIONAHA.105.532242/DC1.