Postmarket Surveillance for Drug-Eluting Coronary Stents

Abstract

HomeCirculationVol. 113, No. 6Postmarket Surveillance for Drug-Eluting Coronary Stents Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPostmarket Surveillance for Drug-Eluting Coronary StentsA Comprehensive Approach Donald S. Baim, MD, Roxana Mehran, MD, Dean J. Kereiakes, MD, Thomas P. Gross, MD, MPH, Michael Simons, MD, David Malenka, MD and Aaron V. Kaplan, MD Donald S. BaimDonald S. Baim From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author , Roxana MehranRoxana Mehran From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author , Dean J. KereiakesDean J. Kereiakes From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author , Thomas P. GrossThomas P. Gross From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author , Michael SimonsMichael Simons From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author , David MalenkaDavid Malenka From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author and Aaron V. KaplanAaron V. Kaplan From the Cardiology Section, Brigham and Women’s Hospital, Boston, Mass (D.S.B.); Cardiovascular Research Foundation and Columbia University, New York, NY (R.M.); Heart Center/Lindner Center at the Christ Hospital, Cincinnati, Ohio (D.J.K.); Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, Md (T.P.G.); and Cardiology Section, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH (M.S., D.M., A.V.K.). Search for more papers by this author Originally published14 Feb 2006https://doi.org/10.1161/CIRCULATIONAHA.105.569657Circulation. 2006;113:891–897The development and introduction of new medical devices have radically changed the practice of medicine. No area of medicine has been affected more than cardiology, with new devices facilitating the effective treatment of coronary artery disease (percutaneous coronary interventions [PCIs]/stents), valvular heart disease (mechanical and bioprosthetic valves), and electrophysiological disorders (pacemakers and automatic implantable cardiodefibrillators). In addition to fueling the growth of the medical device industry, this explosion of technology has driven the development of new medical subspecialties, eg, interventional cardiology and electrophysiology. Other areas of medicine, including orthopedics and general surgery, have witnessed similar transformations. The current regulatory pathway for a significant-risk first-in-class medical device is typically a long, expensive, and risky process, culminating in a pivotal trial designed to demonstrate safety and efficacy. The pivotal trial phase is typically the most time-consuming and costly phase of the process. In the United States, medical devices are regulated by the Center for Devices and Radiological Health at the Food and Drug Administration (FDA), which has been charged by Congress to seek the “least burdensome means” when determining the scope of data required to evaluate the safety and efficacy necessary for device approval.1 Thus, pivotal trials by intention are designed to select patient cohorts most likely to demonstrate procedural benefit while limiting patient/study subject risk within the shortest time frame that can provide meaningful data. The realities of logistics, time, and resources limit the size and duration of most new device trials to 800 to 1500 patients, limiting the power of these trials to detect events with an occurrence rate of <1%. Furthermore, pivotal trials are conducted by the most experienced physician operators at medical centers with sufficient patient volume and research infrastructure to recruit and conduct clinical studies. Some have questioned whether results obtained under these settings from such narrowly defined patient subsets can be extrapolated to the “real-world” postapproval environment. In recognition of these limitations, it is frequently desirable to collect additional data on device performance after FDA approval for commercial release, ie, postmarket surveillance. The need for accurate, timely, and comprehensive postmarket surveillance has been highlighted by the recent introduction of drug-eluting stents into general clinical use.2The Second Dartmouth Device Development Symposium (3D2) held in October 2004 in Woodstock (Vt) brought together thought leaders from the major stakeholders in the medical device community, including clinical investigators, the FDA, large and small device manufacturers, and representatives from the financial community, to examine difficult issues confronting device development. Challenges surrounding postmarket surveillance of medical devices in general with a focus on interventional cardiovascular devices were examined and discussed. This article provides a summary discussion of the following pertinent issues: (1) postmarket surveillance issues associated with the recent market release of drug-eluting coronary stents, (2) an overview of currently available major mechanisms for postmarket data acquisition, and (3) potential new approaches to postmarket device surveillance.Early Commercialization of Drug-Eluting Stents: A Case StudyThe strengths and weaknesses of currently available means to evaluate the performance of a medical device after FDA approval can be better understood by studying the recent market releases of the Cypher sirolimus-eluting coronary stent (Cordis/Johnson & Johnson) and the Taxus paclitaxel-eluting coronary stent systems (Boston Scientific).Subacute Thrombosis and the Cypher Drug-Eluting StentThe market introduction of the Cypher sirolimus-eluting coronary stent (Cypher Stent) was one of the most financially successful in the history of the medical device industry.3 The US Cypher market release was the result of a multiyear development program costing Cordis/Johnson & Johnson more than $100 million dollars. Excitement over the Cypher stent was initially sparked by results from the small, 30-patient, single-arm first-in-man study that evaluated Cypher stent deployment in stable patients with simple coronary stenoses. Angiograms obtained 6 months after stent implantation showed a 0% incidence of binary restenosis rate.4 These first-in-man results were followed by 2 well-designed prospective, randomized, controlled trials: the Randomized Study With the Sirolimus-Coated BxVelocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions (RAVEL) and the Sirolimus-Eluting Stents Versus Standard Stents in Patients With Stenosis in the Native Coronary Artery Study (SIRIUS). Target vessel failure (composite occurrence of death, myocardial infarction, and target vessel revascularization) was reduced by 68% (RAVEL) and 83% (SIRIUS) in Cypher-treated patients compared with the bare-metal stent comparator group.5,6 Thrombosis (subacute or delayed) was observed infrequently in these studies (subacute thrombosis in 1 of 653 Cypher-treated patients compared with 1 in 643 control subjects receiving bare-metal stents, late thrombosis in 2 of 653 Cypher patients and 3 of 643 bare metal control subjects). These studies were underpowered to evaluate any differences. It is important to note that these studies were performed at centers with highly experienced operators with the infrastructure necessary to participate in such a trial. Furthermore, the patient population in these studies was highly selected (clinically stable) with straightforward lesions. Review of one of our personal series (A.V.K.) indicates that <20% of cases performed during 2004 would have met these clinical and angiographic selection criteria. In April 2003, on the basis of data from 1296 patients enrolled in these studies (Cypher, 653; bare metal, 643), the Cypher stent was approved for treatment of discrete de novo coronary lesions.7On the basis of the strength of the clinical data, coupled with the successful marketing by Cordis/Johnson & Johnson, the Cypher stent was rapidly adopted and accounted for roughly half of the 800 000 annual stent implantations in the United States.3 Within the first 75 days of marketing of the Cypher stent, the FDA, through its Medical Device Reporting (MDR) system, began receiving adverse event reports of stent thrombosis after Cypher stent implantation, with >1 dozen centers reporting multiple events. In addition, of the ≈50 reports received of subacute thrombosis, many suggested off-label use and/or improper technique (eg, overexpansion or underexpansion). Because of the serious clinical consequences associated with stent thrombosis, Cordis/Johnson & Johnson, in conjunction with the FDA, issued a letter alerting the cardiology community to the initial reports and urged operators to restrict the use of Cypher stents to the approved indications as outlined in the instructions for use of the device and to use proper technique for stent deployment. The letter also served as a reminder for operators, in submitting future reports, to follow reporting procedures established by their user facilities in accordance with the Safe Medical Devices Act of 1990.8,9 After the issuance of this letter, there was a continued influx of reports of stent thrombosis through the MDR system. In addition, reports of possible hypersensitivity reactions to the Cypher sirolimus-eluting stent also were received. By the end of October 2003, >290 reports of Cypher subacute thrombosis had been received. Although it is difficult to delineate the subacute thrombosis rate, data from Cordis indicate that >260 000 units had been distributed within the United States by this time.10 Furthermore, given the limitations of the reporting system, it was not possible to determine whether these events were occurring more frequently in Cypher recipients than in those receiving bare-metal stents. The FDA then posted a public health Web notification to alert both the cardiology community and the general public to the reports of thrombosis. This notification acknowledged that there were insufficient data to determine the true rate of thrombosis events and whether they were occurring more frequently than had previously been observed with bare-metal stents. This notification again reiterated the importance of limiting Cypher stent use to the indications outlined in the instructions for use.10By the end of the following month, additional information from Cordis’ own clinical trial data, along with an FDA review of comparable data on bare-metal stents, led the FDA to conclude, in another Web notification, that there did not appear to be a higher frequency of subacute thrombosis with Cypher stents than with bare-metal stents.11 Concomitantly, data from single-center experiences suggested that the incidence of Cypher stent thrombosis was roughly ≤1% and not different from either prior randomized clinical trial data or data collected after bare-metal stent deployment.12,13 It is important to note that these reports were focused primarily on events occurring typically within the first 30 days after implantation and do not reflect late thrombosis rates. Further observation noted, not surprisingly, that a likely contributing factor to the apparent increase in stent thrombosis reporting was the publicity associated with the Cypher launch and the company and FDA announcements that underscored the importance of adverse event reporting. The FDA issued an additional Web notification in October 2004 that included these observations and softened earlier warnings of increased thrombosis associated with the Cypher stent.14 Thus, from the first FDA notification on October 2003, almost 1 year elapsed before the FDA issued a conclusive statement that “the Cypher stent remains a safe and effective device when used according to the labeling, particularly with regard to patient selection and appropriate periprocedural medications.” In the context that nearly 3000 Cypher stents were being deployed daily during that time frame on a worldwide basis, a more accurate postmarket surveillance process could have provided valuable insight into the true incidence of stent thrombosis and the relationship of off-label use to its occurrence.Nondeflation of the Taxus Stent Delivery Catheter BalloonThe Taxus paclitaxel-eluting coronary stent system (Taxus stent; Boston Scientific) was released in March 2004 and became the second drug-eluting stent commercialized in the United States.15 Similar to the Cypher stent, the market release of the Taxus stent was an extraordinary success, with >200 000 units used within the first 3 months and a market penetration of nearly 70% of drug-eluting stents used.16 During this time period, isolated cases of balloon “nondeflation,” in which the stent delivery balloon either deflated slowly or failed to deflate, were reported to the MDR database. By the end of June 2004, a total of 25 cases, including 1 death and 16 serious complications, were reported.17Careful inspection of retrieved failed units and comparison of these units with unused product (from both the same and different lots) allowed the company to quickly identify a subtle manufacturing flaw. Working in conjunction with the FDA, Boston Scientific Inc voluntarily recalled Taxus stents from lots identified as the source of the nondeflation events.17,18 All recalled stents were replaced with stents manufactured with a modified process. After reintroduction, there were 2 reports of possible nondeflation (with no associated clinical complication), during which time 105 000 stents were shipped, indicating that the instituted manufacturing changes had adequately rectified the problem.19 During this time, the Taxus stent/delivery system was also experiencing difficulties with “stickiness,” ie, difficult removal of the stent delivery balloon after stent deployment. Although distinct from nondeflation, retrieval difficulties resulting from stickiness have contributed to confusion about this issue. The Taxus recall received much attention from the public news media, which unfortunately failed to accurately identify the fact that 200 000 patients had undergone an uneventful deployment of this product.20Both the Taxus nondeflation and Cypher thrombosis episodes illustrate the strengths and weaknesses of the current postmarket surveillance systems. In the case of thrombosis (subacute and delayed) associated with drug-eluting stents, the ability to adequately characterize these events continues to be problematic. Until a more accurate understanding of stent thrombosis rates evolves, it will not be possible to develop or evaluate meaningful strategies aimed at significantly reducing the occurrence of this catastrophic event. In contrast, the current reporting system, coupled with established tracking methods (ie, identifying associated lots), allowed quick characterization of Taxus nondeflation events from which potential solutions could be rapidly developed and implemented. This observation may reflect inherent differences in the types of adverse events encountered. Nondeflation is a rare but serious problem linked temporally and physically to the device delivery system; as such, this profile facilitated precise event-device linkage. Because of a number of factors, stent thrombosis (subacute or delayed), although similar in seriousness to nondeflation, has been far more difficult to characterize. These factors include the relatively low frequency of this event, specific stent/stent delivery balloon issues (design and manufacturing), implantation technique (eg, stent-arterial wall apposition), and the specific pathobiology and pathoantomy of the treated lesion. The problem is further complicated by time delay between implantation and clinical event. Finally, the clinical manifestations of stent thrombosis, eg, ST-elevation myocardial infarction, non–ST-elevation myocardial infarction, and recurrent angina, are not specific to stent thrombosis and are associated with events occurring at other sites within the coronary vasculature. Considering the fact that >1 million drug-eluting stents may be implanted each year, even a 1% to 2% serious adverse event rate would affect 10 to 20 000 patients at a minimum. The studies used to support the approval of the Cypher stent, the SIRIUS and RAVEL trials (total of 1296 randomized patients), were underpowered to detect differences in events occurring in ≈1% of patients. More than 13 000 randomized patients would have been required to provide a study with adequate statistical power to detect a 50% reduction in thrombosis rates occurring in 1% of patients (α=0.05 [2 sided]; power=0.90). Thus, a more robust method of postmarket surveillance seems to be needed.Current Approaches to Postmarket SurveillanceObtaining high-quality data that would provide a nuanced understanding of patient selection, device performance, and clinical outcomes in a broad-based patient population is both difficult and costly. Current sources of nationwide data from which one can obtain an understanding of device use after FDA approval include the MDR system, claims-made databases, and device databases/registries (general or specific). Each of these approaches has strengths and weaknesses for providing insights into various different aspects of real-world device use and performance. When these systems are evaluated, it is useful to consider the number of patients included and the detail of data collected as a continuum (the Figure). On 1 extreme are premarket pivotal trials (upper left quadrant), which may be contrasted with the postmarket MDR system (lower right quadrant). Premarket pivotal trials are centrally coordinated studies performed at premiere institutions with dedicated resources (research nurses) to carefully screen and follow patients in a prospectively defined manner over a circumscribed period of time. Conversely, the MDR system provides limited data on a large, unselected population. Download figureDownload PowerPointPremarket to postmarket device evaluation schematic showing device evaluation strategies: data detail (y) vs population size (x). MDR (lower right quadrant) provides limited data over a very large unselected population. Premarket pivotal trials (upper left quadrant) provide detailed refined data on a small and highly selected population.MDR SystemThe medical device industry is subject to federal regulations focused on the evaluation, manufacture, marketing, and monitoring of devices. Currently, the nationwide postmarket safety and performance of a device are monitored primarily by the MDR system (and related initiatives such as the Medical Product Surveillance Network). The MDR system relies on manufacturers, importers, and user facilities to comply with mandatory reporting requirements.1,21 Manufacturers account for roughly 95% of the >150 000 reports submitted annually.Although the MDR system is an easy-to-access and relatively inexpensive means for monitoring an entire device-treated population, particularly for rare adverse events, several weaknesses exist. First, consistent and complete event identification and reporting (completeness of ascertainment) are problematic because the system relies on the recognition of a complication, on the linkage of the complication to the suspect device, and finally on the understanding that a specific event requires reporting. Event reporting is dependent on each of these steps. Underreporting of events is well known and, depending on the device and outcome of interest, may be quite significant.22 Furthermore, a negative reporting bias may exist for both doctors and hospitals to report complications. Second, the system does not provide an adequate characterization (number, demographics, clinical situation, etc) of the patient population at risk (treated denominator) or the ability to meaningfully evaluate reporting patterns for potential biases. Currently, the treated denominator is poorly defined and described only in general terms on the basis of manufacturer sales and surrogate use estimates (eg, numbers manufactured or distributed). Third, the current system provides incomplete and inconsistent data (poor data quality) that are difficult, if not impossible, to validate through review of primary data sources, ie, medical records, angiography, ultrasonography, and MRI and CT scans. Consistent data validated by review of primary sources are essential to discern whether the adverse event reported truly is related to the device used (versus other devices or the natural history of the disease being treated) or whether other extenuating circumstances may have contributed (eg, complex bifurcation stenting, incomplete stent expansion, operator error, discontinuation of thienopyridines, and patient comorbidities).Claims-Based Data From a Third PartyAnother approach to postmarket surveillance is analysis of claims-based data drawn from a third-party payer, eg, Medicare or private insurers. Federal agencies and private payers, along with hospitals, have developed an extensive billing system based on diagnosis-related groupings and procedures. This system is governed by federal regulations that are subject to audits and enforced by both civil and criminal penalties. As a result, these data banks contain accurate records with specific information about admission diagnoses and procedures.23 When the Cypher stent was released into clinical practice, a specific diagnosis-related groupings code was already established that provided a means for identifying patients who received a drug-eluting versus a bare-metal stent. Once the stent type is identified, further databank queries can discern the occurrence of subsequent hospitalizations or repeated interventions that might signal stent thrombosis or restenosis. This system removes many of the reporting biases that limit the value of registries (see below) and the MDR system. These strengths must be balanced by understanding that this system was not developed for accurate postmarket surveillance and thus provides data that may not be related to the performance of a specific device. Using this approach to evaluate the impact of drug-eluting stents on subacute stent thrombosis rates requires the use of a surrogate for stent thrombosis such as rehospitalization for acute myocardial infarction, repeated catheterization, and/or intervention. Such surrogates are intrinsically limited because acute myocardial infarction or repeated coronary intervention may occur for reasons other than subacute stent thrombosis; eg, repeated intervention may be done for planned, “staged” procedures or new coronary obstruction. Furthermore, this approach does not provide adequate data from which to discern operator/procedural behavior and selection bias, eg, limitation in drug-eluting stent availability for vessels <2.5 mm in diameter. Further limitations are related to the delay in which claims-based data are made available and the inability to review primary source data (without violation of HIPPA guidelines). The claims data also typically do not distinguish between the “same” products made by different manufacturers, thus making comparisons, if desirable, very difficult. Finally, gaps in coverage must be taken into account when longer-term outcomes are assessed. However, the combination of claims analysis and review of a randomly selected sample of medical records may establish the true frequency of an event being studied with greater accuracy than is currently possible.Regional DatabasesRegional databases provide an important means for obtaining insights into the impact of a specific technology on clinical outcomes after PCI. One example is the Northern New England Consortium, which includes all interventional cardiology and cardiac surgical programs in Maine, New Hampshire, and Vermont, that enter data using standardized research forms.24 Statewide databases that provide information similar to that in regional registries include New York, Washington, and Michigan.25 These databases allow follow-up of in-hospital complications, including rehospitalization, and survival in a large population, with minimal selection bias. Although these sources of information provide real-world understanding of both complications and survivability, they are not structured to follow outcomes associated with a specific device.Multicenter RegistriesA number of multicenter registries examine practice patterns and outcomes of procedures performed in the cardiac catheterization laboratory. The oldest and best known of these are the National Heart, Lung and Blood Institute Registry and the companion Dynamic Registry, which provide baseline features and in-hospital and 1-year outcomes on consecutive patients who underwent PCIs at large referral centers.26 These registries have provided the intervention community with important insights into the natural history of coronary artery diseases after PCI from both the prestent and stent eras. Registries such as these, however, are not structured to provide device-specific information. Furthermore, the ability of these registries to provide device-specific information is limited by their relatively small size (<3000 patients) and by the generalizability of data generated at large referral centers with highly experienced operators.26In an effort to provide a global understanding of practices in the cardiac catheterization laboratory, the American College of Cardiology has funded the National Cardiovascular Data Registry (ACC-NCDR). The ACC-NCDR is a large multicenter database in which both clinical and procedural data and adverse events occurring up to hospital discharge are collected through the use of a standard set of 143 data elements. Data sets from each clinical site are transmitted quarterly to a central center for quality control and data analysis. The ACC-NDR has reported on the evaluation of a larger number of procedures (>125 000) from a wide spectrum of clinical sites (>130), providing important insights into real-world but short-term outcomes after PCI procedures. Despite the strength of the ACC-NCDR, these data are limited with respect to postmarket surveillance in that this database is not designed to track specific devices. Furthermore, data from nearly one third of the cases are excluded by quality-control screening, introducing by definition a poorly understood selection bias.27Device-Specific RegistriesA number of device-specific registries have been established voluntarily by manufacturers as part of their postmarket surveillance programs.28,29 In addition, manufacturers may meet the requirements for a postapproval study mandated by the FDA, as a condition of its approval of the device, by establishing a registry. With regard to mandated approaches, the device-specific registries may use the preapproval clinical pivotal trial machinery and thus expand the number of subjects and reduce the level of data detail collected. These registries can provide a consistent data set, which an independent events adjudication committee may audit using source documentation. Without such provisions, it is not possible to accurately discern the relationship between an event and a specific d