Author + information
- Received February 14, 2008
- Revision received June 2, 2008
- Accepted June 3, 2008
- Published online September 23, 2008.
- Mehdi H. Shishehbor, DO, MPH,
- Sachin S. Goel, MD,
- Samir R. Kapadia, MD,
- Deepak L. Bhatt, MD,
- Peter Kelly, MD,
- Russell E. Raymond, DO,
- John M. Galla, MD,
- Sorin J. Brener, MD,
- Patrick L. Whitlow, MD and
- Stephen G. Ellis, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Stephen G. Ellis, Department of Cardiovascular Medicine, Desk F25, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195
Objectives Our purpose was to examine the incidence of all-cause mortality among drug-eluting stents (DES) and bare-metal stents (BMS) while adjusting for many confounding factors generally not considered in prior studies.
Background DES use in the U.S. declined by up to 50% in recent years, primarily due to concerns about late stent thrombosis and possibly increased mortality. However, recent data suggest that DES are as safe as BMS and may actually be associated with a lower incidence of myocardial infarction and mortality.
Methods All patients undergoing percutaneous coronary intervention with a DES or BMS alone from March 1, 2003, to June 30, 2007, at a tertiary care center were assessed. Multivariable Cox proportional hazards modeling was performed for overall and propensity-matched patients. Socioeconomic status was calculated using U.S. Census 2000 data. The primary end point was all-cause mortality.
Results There were a total of 832 deaths over a 4.5-year interval among 8,032 patients. Of these, 6,053 received a DES and 1,983 patients had a BMS. All-cause mortality was significantly lower in unadjusted and adjusted Cox proportional models with DES (hazard ratio: 0.62, 95% confidence interval: 0.53 to 0.73; p < 0.001). Similarly, in the propensity-matched group, DES remained associated with lower mortality compared with BMS (adjusted hazard ratio: 0.54, 95% confidence interval: 0.45 to 0.66; p < 0.001).
Conclusions DES were associated with lower mortality in this “real-world” setting. However, despite multiple adjustments, potential confounding may still play a role.
Unlike earlier studies that raised concern about drug-eluting stents (DES) (1), a recent meta-analysis of randomized trials has shown that DES, in addition to reducing restenosis and, hence, target vessel revascularization, may also reduce the rate of myocardial infarction (MI) (2). Additionally, others have shown lower mortality with DES compared with bare-metal stents (BMS) up to 2 years (3–5). While these data are reassuring, there remains concern over whether selection bias may have led to a lower event rate in the DES group. Specifically, since the published reports in late 2004 and 2005, patients with extensive comorbidities or terminal illnesses such as malignancy, medical noncompliance, and those with a low socioeconomic status (SES) typically receive BMS because of concern regarding abrupt withdraw of dual antiplatelet therapy. This policy regarding stent implantation based on aforementioned variables may explain the lower event rate with DES noted in recent studies (3,4). Additionally, maximum duration of follow-up in the most recent studies has been 2 years (3,4). Therefore, we sought to examine the rate of long-term all-cause mortality among patients who received DES versus BMS in a “real-world” setting, while adjusting for SES, malignancy, depression, anemia, renal function, and other confounding variables.
The study population was obtained from the prospective percutaneous coronary intervention (PCI) patient registry at Cleveland Clinic. All patients from March 1, 2003, to June 30, 2007, who underwent an index PCI procedure with a BMS or DES alone were included. Baseline characteristics, cardiac history, risk factors, medications, and angiographic and procedural data were prospectively obtained and recorded by experienced research coordinators. The primary end point was all-cause mortality, which was assessed by querying the Social Security Death Index. The institutional review board waived requirements for informed consent for the institutional PCI registry.
Additional confounding variables
Blood studies are routinely obtained on all patients before PCI including white blood cell count, serum hemoglobin, hematocrit, and creatinine. Using electronic records, levels of the above variables were merged with patients undergoing PCI. The closest blood work before and within 3 weeks of procedural date was selected. Similarly, using ICD-9 coding and procedural date, all malignancies and the presence of depression were identified within 1 year before the index procedure.
Individual socioeconomic level data were not available; therefore, each patient's home address was geocoded and matched to the U.S. 2000 census data. Census block level data, a geographical unit containing approximately 1,000 residents, was used to calculate a composite SES score for each patient as described previously (6). Previous work in population-based cohorts demonstrated the value of this score as an independent predictor of cardiovascular risk and an excellent surrogate for individual level SES data (6–8).
Continuous variables are presented as mean ± standard deviation. Differences in baseline and angiographic characteristics were compared using the Wilcoxon rank sum test for continuous variables and the chi-square test for categorical variables. We used Cox proportional hazards modeling to examine the association between the use of BMS and DES and all-cause mortality while accounting for the differences in baseline demographic features, angiographic variables, SES, cancer, depression, blood levels of hematocrit, creatinine, white blood cell count, and other confounders (Table 1).
In order to address potential selection bias that may have occurred in mid-2005 due to concerns about late stent thrombosis, we conducted our analysis for each year starting in 2003, separately. Additionally, in order to minimize the impact of confounding, we employed the technique of propensity analysis and matching. We used a nonparsimonious logistic regression model to generate a propensity score for the type of stent used (BMS vs. DES) using most variables listed in Table 1, except stent length and procedural success; however, lesion length was included. We then matched each subject from the BMS group to an individual that had PCI with DES using the derived propensity score. Matches were made if the propensity score between the 2 patients from different groups was identical by 5 digits. If this could not be achieved, then matching was made by 4, 3, 2, or 1 digit. Once this threshold was reached, the BMS-treated individual was excluded. Subsequently, we performed Cox proportional hazards modeling where we incorporated all baseline characteristics shown in Table 2,in addition to the propensity score, for the propensity-matched patients.
The proportional hazards assumption was tested by calculating weighted Schoenfeld residuals and by inspecting the hazard ratio (HR) against time plots (9). Model overfitting was tested using bootstrapping, which for all models turned out to be trivial; the reported c-statistics are “optimism corrected,” meaning that they have been adjusted for any overfitting. This is done by applying the model obtained from the bootstrap sample to the original data. Average optimism is then computed by subtracting accuracy index obtained from 100 bootstrap resamplings minus the index computed on the original sample (9). The overfitting-corrected estimate is then calculated by subtracting the average optimism from the final model fit's apparent accuracy (9). Model calibration was assessed by plots of observed versus predicted values derived from 100 bootstrap resamplings. Colinearity was assured by calculation of variance inflation factors. A number of subgroup analyses were also performed for pre-specified groups of interest. Pre-specified interaction testing between DES and age, diabetes, malignancy, serum creatinine, SES, and white blood cell count was also performed.
All statistical analyses were performed using SAS software (version 9.1, SAS Institute, Cary, North Carolina) and S-plus 7.0 (Insightful, Inc., Seattle, Washington). All tests were 2-tailed; a p value of <0.05 was considered significant.
Overall, there were 11,181 PCIs performed between March 2003 and June 2007. After excluding patients that did not receive a stent and those that underwent repeat procedures, 8,036 met our study criteria. Of these, 6,053 patients underwent PCI with DES and 1,983 patients with BMS (53% were stainless steel and 47% were cobalt/chromium stents). Patients who received BMS had higher prevalence of comorbidities such as malignancy (Table 1). However, patients undergoing intervention on chronic total occlusions, in-stent restenosis, longer lesions, and multivessel disease were more likely to receive DES (Table 1).
Outcome for overall population
A total of 832 deaths occurred. The rate of death was significantly lower in the DES group compared with that in the BMS group during the 4.5 years of follow-up (8% vs. 17%, p < 0.001) (Fig. 1A).Similarly, DES use was associated with lower mortality for each consecutive year (Table 3).In a multivariable Cox proportional hazard analysis after adjusting for all variables shown in Table 1, DES use was associated with a 38% relative risk reduction for all-cause mortality (Table 3). Similarly, this association remained significant for each consecutive year from 2003 to 2007 except for 2004 (Table 3). Additional analysis that divided the whole population into those that received a stent from March 2003 to May 2005 and those from June 2005 to June 2007 also showed similar results with lower mortality in the DES group (Table 4).Similar results were also obtained by subgroup analysis for stent diameter <2.5 mm (DES vs. BMS, adjusted HR: 0.52, 95% confidence interval [CI]: 0.32 to 0.84, p = 0.008), stent diameter <3.5 mm (DES vs. BMS, adjusted HR: 0.65, 95% CI: 0.55 to 0.78, p < 0.001), and stent diameter >3.5 mm (DES vs. BMS, adjusted HR: 0.42, 95% CI: 0.26 to 0.66, p < 0.001).
Of the 1,983 patients who received BMS, 1,801 (91%) matched with an individual who received a DES (c-statistic for overall group = 0.79). Baseline characteristics of the propensity-matched group are shown in Table 2. In general, both groups were well matched for over 50 confounding variables. The only 2 variables that were statistically different among the 2 groups were stent length and lesion length, both of which favored BMS (Table 2).
A total of 472 deaths occurred in the propensity-matched population. In unadjusted analysis, DES use was significantly associated with lower all-cause mortality (Fig. 2).In the multivariable Cox proportional hazard model that adjusted for all baseline characteristics in addition to the propensity score, DES use remained significantly associated with lower mortality (Table 3).
A series of subgroup analyses were also performed; in all cases both in the overall nonpropensity-matched and the propensity-matched patients, DES was significantly associated with lower mortality (Table 4). Of the interactions tested, only the interaction between DES and pre-treatment white blood cell count had a trend toward significance (p = 0.08).
Multivariable predictors of all-cause mortality
Of the over 50 variables included in the saturated Cox proportional hazard model, only age, DES, body mass index, insulin-dependent diabetes, peripheral vascular disease, left ventricular ejection fraction, intervention to the right coronary artery, New York Heart Association functional class IV, chronic obstructive lung disease, history of stroke or transient ischemic attack, statin therapy, heart rate, socioeconomic score, serum creatinine, white blood cell count, and presence of malignancy were predictive of all-cause mortality. Of the variables mentioned above, only age (chi-square: 91.89, p < 0.001), serum creatinine (chi-square: 72.12, p < 0.001), chronic obstructive lung disease (chi-square: 62.36, p < 0.001), cancer (chi-square: 50.73, p < 0.001), hematocrit (chi-square: 45.69, p < 0.001), and left ventricular ejection fraction (chi-square: 45.09, p < 0.001) had higher predictive value than intervention with DES (chi-square: 43.66, p < 0.001).
In patients undergoing PCI with DES or BMS in the “real-world” setting, the use of DES appears to be associated with lower all-cause mortality. This result was persistent despite multiple adjustments, including propensity analysis, stratified analysis by procedure year, and by subgroup analysis. Additionally, adjustment for SES, presence of cancer, anemia, or renal insufficiency did not change this result.
In October of 2004, McFadden et al. (10) reported 4 cases of late stent thrombosis after DES placement. Subsequently, a series of studies raised concerns regarding DES and the risk of late stent thrombosis (11–15). Collectively, this led to a significant reduction in DES use. These concerns resulted in a significant decline in DES use from 80% to 90% in 2004 to 40% to 50% in 2006 in most institutions. However, despite these earlier concerns, recent studies indicate that DES may actually result in lower mortality or MI (2,3). Tu et al. (3) evaluated 3,751 matched patients who received DES or BMS from 2003 to 2005 and showed a reduction in target vessel revascularization and death up to 3 years. Similarly, Mauri et al. (5) evaluated 17,000 patients treated with PCI in the non-U.S. government hospitals in Massachusetts between April 1, 2003, and September 30, 2005, for a 2-year follow-up and showed a significantly lower mortality with DES use. Stettler et al. (2) conducted a pooled head-to-head analysis of randomized DES trials and showed a reduction in MI with sirolimus-eluting stents. Our study adds to the above findings by considering the presence of cancer, anemia, renal insufficiency, depression, and an aggregate SES.
The exact mechanism for the apparent decrease in mortality seen with DES is unknown. While reduction in restenosis-related death and MI may play a substantial role, it does not completely explain the lower incidence of death seen with DES use (16–18). Additionally, it seems that patients with complex lesions benefit the most from DES, and these individuals were typically excluded from randomized control trials (19). Patients undergoing stenting with DES receive longer duration of therapy with dual antiplatelet agents, aspirin, and clopidogrel. This could partially explain the lower mortality seen in these patients, as dual antiplatelet therapy in the setting of acute coronary syndromes and PCI has been associated with lower events (20–26). An alternative reason for the significant mortality difference with recent studies compared with that seen in randomized trials is the duration of follow-up. To our knowledge, the current study has one of the longest follow-ups to date.
While our results indicate that DES use was associated with lower mortality, unmeasured confounding factors may still play an important role. Our study provides long-term follow-up with adequate statistical power. Multiple adjustments were performed, including for the presence of malignancy, depression, anemia, renal insufficiency, aggregate SES, propensity analysis, and individualized year-by-year evaluation, and in all instances, DES was associated with better outcome.
The current study has limitations in that it is an observational study and is prone to biases related to unmeasured factors. However, interventional registry data are prospectively collected by professional staff and contain detailed clinical and angiographic data. Additional information such as the presence of malignancy, depression, and anemia, serum levels of white blood cell count and creatinine, and SES was also obtained. In all cases, results consistently favored DES. Another limitation is that the study is from a single center and may not be easily generalized to all patients. For example, about one-third of our patients had prior coronary bypass graft surgery; therefore, our cohort has higher risk features compared with that of other studies. Also, before 2005, only the first 1,000 consecutive patients were followed prospectively for events such as stent thrombosis, revascularization, or MI. Therefore, we did not have complete data on these important end points, and, hence, they were not included in this analysis. However, all-cause mortality is likely the most unbiased and clinically relevant outcome (27). Additionally, the association between DES and stent thrombosis has been well investigated (2,3,28,29). Also, data on dual antiplatelet therapy was not available. Lastly, because of the observational nature of the present study, we still remain cautious in suggesting that DES use actually results in lower mortality.
In this analysis, DES use was associated with lower mortality in long-term analysis and despite multiple adjustments. Given the significance of this outcome, long-term randomized clinical trials that include patients with complex coronary lesions should examine this association. In the meantime, this study and the preponderance of the evidence support the notion that the overall risk of stent thrombosis with DES does not translate into higher mortality in these patients.
The authors are grateful to Dr. Anil Jain (Managing Director, eResearch, Information Technology, staff physician, Medicine Institute, Cleveland Clinic) for assistance with data on laboratory values, malignancy, and depression. The authors also would like to thank Ms. Kathryn Brock (Editorial Service Manager, Cardiovascular Medicine, Cleveland Clinic) for her editorial assistance.
Dr. Shishehbor is supported, in part, by Case Western Reserve University/Cleveland Clinic CTSA (1KL2RR024990). Dr. Bhatt has received research grants (directly to the institution) from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, The Medicines Company; honoraria (donated to nonprofits for >2 years): AstraZeneca, Bristol-Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL, Sanofi-Aventis, Schering-Plough, The Medicines Company, tns Healthcare; Speakers' Bureau (>2 years ago): Bristol-Myers Squibb, Sanofi-Aventis, The Medicines Company; consultant/advisory board (any honoraria donated to nonprofits): Astellas, AstraZeneca, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi-Aventis, Schering-Plough, Scios, The Medicines Company, tns Healthcare, Vertex; expert testimony regarding clopidogrel (the compensation was donated to a nonprofit organization); Cleveland Clinic Coordinating Center currently receives or has received research funding from: Abraxis, Alexion Pharma, AstraZeneca, Atherogenics, Aventis, Biosense Webster, Biosite, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardionet, Centocor, Converge Medical Inc., Cordis, Dr. Reddy's, Edwards Lifesciences, Esperion, GE Medical, Genentech, Gilford, GlaxoSmithKline, Guidant, Johnson & Johnson, Kensey-Nash, Eli Lilly, Medtronic, Merck, Mytogen, Novartis, Novo Nordisk, Orphan Therapeutics, Procter & Gamble Pharma, Pfizer, Roche, Sankyo, Sanofi-Aventis, Schering-Plough, Scios, St. Jude Medical, Takeda, The Medicines Company, VasoGenix, and Viacor. Dr. Whitlow has received research grant support from Abbott Vascular, Boston Scientific, and Evalve Inc. and has received consulting fees from Medlogics and Icon International Systems Inc. Dr. Ellis has received consulting fees from Boston Scientific, Cordis, and Abbott Vascular.
- Abbreviations and Acronyms
- bare-metal stent(s)
- confidence interval
- drug-eluting stent(s)
- hazard ratio
- myocardial infarction
- percutaneous coronary intervention
- socioeconomic status
- Received February 14, 2008.
- Revision received June 2, 2008.
- Accepted June 3, 2008.
- American College of Cardiology Foundation
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