Temporal Changes in the Use of Drug-Eluting Stents for Patients With Non–ST-Segment–Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention From 2006 to 2008
Results From the Can Rapid risk stratification of Unstable angina patients Supress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) and Acute Coronary Treatment and Intervention Outcomes Network–Get With The Guidelines (ACTION–GWTG) Registries
Background— The risks of late stent thrombosis with drug-eluting stents (DES) were intensely debated after the presentation of a number of studies highlighting this issue in September 2006. We evaluated trends in the use of DES for patients with non–ST-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) from 2006 to 2008.
Methods and Results— Temporal patterns of DES use were examined among non–ST-elevation myocardial infarction patients in the Can Rapid risk stratification of Unstable angina patients Supress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE; January 2006 to December 2006) and Acute Coronary Treatment and Intervention Outcomes Network–Get With The Guidelines (ACTION–GWTG; January 2007 to June 2008) registries to determine how practice patterns changed for patients with acute myocardial infarction undergoing PCI. Among the 54 662 patients analyzed, the percentage of patients undergoing PCI by quarter varied from 54% to 58% during the analysis time period. More than 90% of patients undergoing PCI received a DES in the first 3 quarters of 2006 before the public debate about the risks of DES began. Thereafter, the use of DES for PCI patients declined during the fourth quarter of 2006 through the first quarter of 2007 (82% to 67%), gradually declined during quarters 2 to 4 of 2007 (63% to 63% to 59%) but then slightly increased from the first to second quarter of 2008 (58% to 60%). Hospital characteristics did not seem to correlate with temporal changes in DES use, but by the last 2 quarters of the study period, patient characteristics such as white race, hypertension, diabetes mellitus, and private or managed care insurance were more common among patients who received a DES compared with the beginning 2 quarters of the study period.
Conclusions— These findings highlight how rapidly treatment decisions in contemporary practice can be affected by public debate related to scientific presentations and publications.
Received January 12, 2009; accepted June 10, 2009.
Drug-eluting stents (DES) were introduced into US practice in April 2003, and a rapid and sustained uptake in their use in patients undergoing percutaneous coronary intervention (PCI) was demonstrated, especially in patients without a labeled indication for DES, including those with complex coronary anatomy and those with acute myocardial infarction (MI) undergoing PCI.1–3 Although the risk of restenosis was significantly
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reduced in clinical trials that compared DES with bare metal stents (BMS), the long-term complications and ideal duration of dual antiplatelet therapy with aspirin and clopidogrel after DES implantation were not initially determined through the short-term follow-up of these trials (generally, no longer than 12 months).4
Controversy regarding the risks of stent thrombosis after DES implantation began with the presentation of a number of analyses during the European Society of Cardiology (ESC) Scientific Sessions in September 2006, which demonstrated an increased risk of stent thrombosis and thrombosis-related clinical events with DES versus BMS.5–7 Another observational study published after the ESC sessions showed similar results.8 Subsequently, the Food and Drug Administration (FDA) convened a Circulatory Systems Devices Advisory Panel in December 2006 to review the issue of stent thrombosis associated with DES use (http://www.fda.gov/cdrh/news/010407.html). The deliberations from this meeting led to the release of public statements from the FDA and the Society of Coronary Angiography and Interventions in January 2007, which recommended caution with DES use in patients with an off-label indication, as well as prolonged dual antiplatelet therapy with aspirin and clopidogrel for a minimum of 12 months after DES for patients without a high risk for bleeding.9 These statements were followed by the release and publication of a consensus statement from multiple professional societies which also recommended 12 months of dual antiplatelet therapy after DES placement for patients without a high risk for bleeding, and an update to the American College of Cardiology (ACC)/American Heart Association (AHA) PCI guidelines, which gave a class IIb/C recommendation for off-label use of DES.10,11
The impact of these scientific presentations and publications on temporal patterns of use of DES for patients undergoing PCI for acute MI (an off-label indication) has not been reported. We hypothesized that DES use among non–ST-elevation MI (NSTEMI) patients undergoing PCI would decrease over a time period (2006 to 2008) spanning the public debate related to the presentations and publications in the later half of 2006.
WHAT IS KNOWN
Drug-eluting stents (DES) were introduced in 2003, and a rapid and sustained uptake in their use in patients undergoing percutaneous coronary intervention (PCI) was demonstrated, especially in patients without a labeled indication for DES, including those with complex coronary anatomy and those with acute myocardial infarction undergoing PCI.
Controversy regarding the risks of stent thrombosis after DES implantation emerged with the presentation of analyses at the European Society of Cardiology Scientific Sessions in September 2006, which demonstrated an increased risk of stent thrombosis and thrombosis-related clinical events with DES versus bare metal stents. In January 2007, the Food and Drug Administration and the Society of Coronary Angiography and Interventions released public statements recommending caution with DES use in patients with an off-label indication, as well as prolonged dual antiplatelet therapy with aspirin and clopidogrel for a minimum of 12 months after DES for patients without a high risk for bleeding. Multiple professional societies also recommended 12 months of dual antiplatelet therapy after DES placement for patients without a high risk for bleeding, and an update to the American College of Cardiology/American Heart Association percutaneous coronary intervention guidelines gave a class IIb/C recommendation for off-label use of DES.
WHAT THE STUDY ADDS
We demonstrate a rapid decline in the proportion of non–ST-elevation MI patients undergoing non–ST-elevation MI who received a DES versus a bare metal stent after these events, with stabilization in the use of DES during the beginning of 2008.
The rapid changes in practice patterns demonstrated in this analysis suggest that a collaborative partnership between the public media, professional societies, and academic organizations is needed to accurately distill and disseminate pivotal scientific information that has the potential to rapidly influence both physicians and patients.
Patient Inclusion Criteria
The Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) registry ran from 2001 to 2006 and transitioned into the Acute Coronary Treatment and Intervention Outcomes Network–Get With the Guidelines (ACTION–GWTG) registry in December 2006. NSTEMI patients included in these analyses from the CRUSADE and ACTION–GWTG registries presented with ischemic symptoms (≥10 minutes) at rest within 24 hours of hospital presentation and had positive cardiac markers (elevated troponin I or T or creatine kinase-MB >upper limit of normal for the local laboratory assay used at each institution).
Data Collection and Data Quality
The institutional review board of each hospital approved participation in CRUSADE or ACTION–GWTG. Participating sites collected data in an anonymous fashion for consecutive patients who met the inclusion criteria during the initial hospitalization, and informed consent was not obtained.
Routine procedures were established to maintain and monitor quality of the CRUSADE and ACTION–GWTG databases. During data entry and quarterly quality control procedures, values that exceeded expected ranges were flagged and excluded from analyses. Additionally, sites received quarterly reports summarizing any data quality issues.
We evaluated 68 422 NSTEMI patients from hospitals with PCI capabilities from January 2006 through June 2008. We then excluded patients with a listed contraindication to cardiac catheterization (n=10 801), those who were transferred out to another hospital (because of privacy regulations that precluded data collection after interhospital transfer; n=2759), and those patients with missing data on PCI procedure (n=200). The overall analysis population thus consisted of 54 662 patients. Of this population, 27 329 patients underwent PCI.
The rates of PCI procedures among the overall population (n=54 662) and trends in the baseline demographics, clinical characteristics, care patterns, and in-hospital outcomes among patients who underwent PCI (n=27 329) were displayed across the 10 quarters of analysis. Hospital characteristics were presented at the hospital-level across the 10 quarters. Furthermore, rates of DES versus BMS use in patients undergoing PCI were analyzed by quarter from January 2006 to June 2008 among all hospitals as well as among a stable group of 125 hospitals that consistently participated in both CRUSADE and ACTION–GWTG during the same time period.
Additionally, rates of DES use were compared among hospitals stratified by key characteristics such as teaching status, region, and bed size. Based on the observed changes in patterns of DES use, the clinical characteristics of patients who underwent DES placement in quarters 1 and 2 of 2006 were compared with those who underwent DES placement in quarters 1 and 2 of 2008 because these time periods represented the beginning and ending patterns of DES use after a rapid decline in the proportion of patients who received a DES from quarter 3 of 2006 through quarter 1 of 2007. Patient and hospital characteristics by quarter were summarized as frequencies and percentages for categorical data and as medians with 25th and 75th percentiles for continuous variables. Continuous and ordinal categorical variables were compared using stratum-adjusted Wilcoxon rank-sum tests, whereas nominal categorical variables were compared using stratum-adjusted χ2 tests (in which stratification was by hospital). All comparisons were 2-tailed, and a probability value <0.05 was considered statistically significant. No adjustments were made for multiple comparisons. All analyses were performed using SAS software (version 9.1, SAS Institute).
Among the overall analysis population of 54 662 patients, the percentage of patients undergoing PCI during each quarter of the 2.5-year time period varied from 54% to 58%.
Clinical Characteristics of the PCI Population
The baseline demographics and clinical characteristics of the PCI population (n=27 329) were fairly consistent across the 10 quarters of analysis (Table 1). Although the proportion of patients with health maintenance organization/private insurance coverage was higher and the proportion of patients with Medicare coverage was lower in ACTION–GWTG compared with CRUSADE, the proportions of patients with Medicaid coverage (3% to 4%) and self-pay/no insurance (8% to 10%) were consistent across the 2 registries.
The number of hospitals with PCI or PCI/coronary artery bypass grafting capabilities participating in each quarter of CRUSADE and ACTION–GWTG varied from 171 to 208 depending on the quarter, and hospital characteristics varied between the CRUSADE and ACTION–GWTG registries (Table 2). A total of 125 hospitals that participated in CRUSADE in 2006 continued to participate in ACTION–GWTG from 2007 to 2008.
Trends in the Use of DES Versus BMS in the PCI Population
During the first 3 quarters of 2006, approximately 90% of patients undergoing PCI received a DES (Figure 1A). A sharp decline was noted in DES use during the fourth quarter of 2006, followed by a sustained and gradual decline in DES use for the remainder of 2007. However, there was a gradual increase in DES use from the first to second quarter of 2008 (58% to 60%). Among the 125 hospitals that participated in both the CRUSADE and ACTION–GWTG registries, similar temporal trends in DES versus BMS use were demonstrated (Figure 1B). The patterns of DES use were fairly similar between teaching and nonteaching hospitals, among hospitals located in different regions of the United States, and between smaller and larger hospitals (Figure 2A through 2C).
Changes in Patient Characteristics in the DES Population
Among patients who received a DES, the proportion of white patients, those with private or managed care insurance, and those with diabetes mellitus and hypertension increased from quarters 1 and 2 of 2006 compared with quarters 1 and 2 of 2008 (Table 3). However, although there was a greater proportion of patients in the DES population with private or managed care insurance compared with Medicare coverage in quarters 1 and 2 of 2008 compared with quarters 1 and 2 of 2006, there were no differences in the proportion of patients with Medicaid (3% versus 4%) and no insurance (8% versus 8%).
We have demonstrated a rapid decline in the proportion of NSTEMI patients undergoing PCI who received a DES versus BMS after the presentation of numerous studies at the ESC 2006 meeting, with stabilization in the use of DES during the beginning of 2008.
The rapid decline in DES use among NSTEMI patients undergoing PCI appears to represent an immediate response to the ESC 2006 presentations and subsequent publications, with possibly some later influence from the release of the FDA advisory panel and professional society consensus recommendations. Other factors that may have influenced choices regarding stent selection in the NSTEMI population analyzed could not be assessed within these registries, including the costs of long-term (12 months) clopidogrel in the outpatient setting for patients who receive a DES, patient biases, and physician judgment related to patient risk and the perceived long-term medical compliance of individual patients. Nonetheless, the rapid decline in DES use after the ESC 2006 meeting contrasts with the relative lack of impact of previous clinical alerts and public health recommendations in cardiovascular medicine, thus indicating that the rapid dissemination of information through various media and scientific outlets may become the predominant stimulus for changes in practice in the future.12,13
Soon after release of the recommendations for caution with “off-label” DES use in January 2007, other registry studies were published that demonstrated an increased risk of short-term and long-term stent thrombosis and adverse ischemic events among patients who received DES for an “off-label” indication.14,15 Simultaneously, meta-analyses from randomized trials comparing DES and BMS were published and demonstrated conflicting results regarding the risk of long-term stent thrombosis with “on-label” use of DES.16–18 However, a recently published clinical trial, which included a factorial randomization to DES versus BMS and distal protection device versus no distal protection device for patients with STEMI undergoing primary PCI, demonstrated that DES use was associated with a similar risk of stent thrombosis compared with BMS but a trend for an increased risk of cardiac death.19 A meta-analysis of 7 small clinical trials demonstrated no difference in clinical outcomes and stent thrombosis through 12 months with DES versus BMS in patients with acute MI.20 Thus, the risks of DES versus BMS use for PCI for NSTEMI remain uncertain and could only be determined with a sufficiently powered contemporary clinical trial conducted over a long time period with factorial randomization of NSTEMI patients to DES versus BMS followed by randomization to 12 months of dual antiplatelet therapy (recommended for all NSTEMI patients by practice guidelines regardless of stent selection) versus a more prolonged duration of dual antiplatelet therapy for at least 18 to 24 months after the PCI procedure. However, this type of randomized controlled trial would be difficult to complete because of the large sample size needed to show a significant difference in clinical outcomes including stent thrombosis, the prolonged time period for patient enrollment and complete follow-up (at least 3 to 4 years), and rapidly emerging DES technologies which would complicate the specifications for stent selection in the DES arm during a trial that lasts 3 to 4 years, during which time DES technologies would be expected to evolve substantially.
There were several limitations to this analysis. First, we only evaluated DES versus BMS use among NSTEMI patients, so our analysis was limited to a specific patient population and cannot be extrapolated to other types of patients who underwent PCI during the same time period. Second, many factors that may have influenced the decision-making of interventional cardiologists regarding DES versus BMS use—including the physician perception of the long-term bleeding risks for patients undergoing PCI, patient socioeconomic status and biases regarding stent selection, and angiographic lesion characteristics that define the risk of restenosis after PCI—were not collected. Third, we did not collect information on the type of DES implanted, so we could not determine whether new DES technologies introduced in 2008 were responsible for the slight increase in DES use at the end of the study period. Fourth, we did not survey cardiologists at participating institutions regarding their knowledge and impressions of the presentations and publications in 2006 that commenced the public debate about DES use. Finally, we did not collect information about in-hospital stent thrombosis or long-term adverse ischemic events after hospital discharge, so we could not comment on the clinical impact of the changes we observed in the temporal trends in DES use.
A rapid and consistent decline in the use of DES versus BMS for NSTEMI patients undergoing PCI was observed after the ESC 2006 meeting but appeared to stabilize during the beginning of 2008. The rapid changes in practice patterns demonstrated in this analysis suggest that a collaborative partnership between the public media, professional societies, and academic organizations is needed to accurately distill and disseminate pivotal scientific information that has the potential to rapidly influence both physicians and patients.
Sources of Funding
CRUSADE is a national quality-improvement initiative of the Duke Clinical Research Institute. CRUSADE is funded by the Schering-Plough Corporation. Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals Partnership provides additional funding support. Millennium Pharmaceuticals Inc also funded this work.
Dr Roe has served as an investigator for BMS, Eli Lilly, Portola Pharmaceuticals, Schering-Plough, and sanofi-aventis and as a consultant for Adolor, Astra Zeneca, BMS, Daiichi-Sankyo, Eli Lilly, Merck, Novartis, Sanofi-Aventis, and Schering-Plough. Dr Cannon has received research grants from GlaxoSmithKline, Merck, AstraZeneca, Merck/Schering Plough Partnership, Sanofi-Aventis/Bristol-Myers Squibb Partnership, and Accumetrics; has served on the data safety monitoring board for Merck, Kai Pharmaceuticals, and GlaxoSmithKline; and has served as a clinical advisor and has equity interests in Automedics Medical Systems. Dr Rao has served as a speaker and clinical investigator for Johnson & Johnson; as a consultant for Sanofi-Aventis and The Medicines Company; and as a principal investigator for Momenta Pharmaceuticals and Portola Pharmaceuticals. Dr Gibler has received grants from EMCREG-International, Millennium, Schering-Plough, Sanofi-Aventis, and Bristol-Myers Squibb. Dr Ohman has served as a consultant for Abiomed, CV Therapeutics, Datascope, Inovise, Liposcience, Northpoint Domain, Pozen Inc, Response Biomedical, The Medicines Company, and WebMD (theheart.org); has received research grants from Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Sanofi-Aventis, and The Medicines Company; and is a stockholder in Inovise. Dr Peterson has received research grants from Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Merck/Schering, and Schering Plough Corp.
Guest Editor for this article was Brahmajee K. Nallamothu, MD.
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