Long-Term Clinical Outcomes After Drug-Eluting and Bare-Metal Stenting in Massachusetts
Background— Drug-eluting stents (DES) reduce the need for repeat revascularization, but their long-term safety relative to that of bare-metal stents (BMS) in general use remains uncertain. We sought to compare the clinical outcome of patients treated with DES with that of BMS.
Methods and Results— All adults undergoing percutaneous coronary intervention with stenting between April 1, 2003, and September 30, 2004, at non–US government hospitals in Massachusetts were identified from a mandatory state database. Patients were classified from the index admission according to stent types used. Clinical and procedural risk factors were collected prospectively. Risk-adjusted mortality, myocardial infarction, and revascularization rate differences (DES−BMS) were estimated through propensity score matching without replacement. A total of 11 556 patients were treated with DES, and 6237 were treated with BMS, with unadjusted 2-year mortality rates of 7.0% and 12.6%, respectively (P<0.0001). In 5549 DES patients matched to 5549 BMS patients, 2-year risk-adjusted mortality rates were 9.8% and 12.0%, respectively (P=0.0002), whereas the respective rates for myocardial infarction and target-vessel revascularization were 8.3% versus 10.3% (P=0.0005) and 11.0% versus 16.8% (P<0.0001).
Conclusions— DES treatment was associated with lower rates of mortality, myocardial infarction, and target-vessel revascularization than BMS treatment in similar patients in a matched population-based study. Comprehensive follow-up in this inclusive population is warranted to identify whether similar safety and efficacy remain beyond 2 years.
Received March 20, 2008; accepted August 19, 2008.
The adoption of drug-eluting stents (DES) for percutaneous coronary intervention (PCI) has been based on randomized trials that have demonstrated significantly lower rates of recurrent stenosis than with uncoated or “bare-metal” stents (BMS).1,2 Pooled data from randomized trials have shown similar rates of myocardial infarction (MI) and mortality between the treatments in extended follow-up,3 but some observational studies have raised the concern that beyond the first year of treatment, drug-eluting stenting may be associated with higher rates of thrombosis4 and mortality.5 Randomized studies designed to evaluate DES have had limited power to detect small differences in mortality6 and have been limited to a less complex patient population than those currently treated in the general population.7,8 In contrast, observational studies have been larger and more inclusive but may have been limited by completeness of follow-up and control of selection bias.
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We have recently described lower rates of recurrent MI and mortality associated with DES in the setting of stenting for MI in a regional population-based study.9 We sought to evaluate the complete patient population treated in Massachusetts with PCI to determine whether stent choice was associated with MI and mortality overall. Because stent choice was not randomized, we used a propensity score–matched analysis to minimize bias.
All adults (18 years of age or older) undergoing PCI with stenting for any indication between April 1, 2003, and September 30, 2004, at all acute-care, non–US government hospitals in Massachusetts were included. Because data are used to assess the quality of all cardiac surgeries and coronary procedures as required by the Massachusetts Department of Public Health, no patient consent was required. Study procedures, study investigators, and data security procedures are reviewed annually by the Harvard Medical School Internal Review Board. Subjects were excluded if they were not Massachusetts residents at the time of the procedure or if they could not be linked to hospital discharge billing data (see below).
We used clinical data submitted to a data coordinating center (Mass-DAC) located in Harvard Medical School. Data are collected prospectively by trained hospital personnel who use the American College of Cardiology’s National Cardiovascular Data Registry’s instrument (http://www.accncdr.com/WebNCDR/Common) for PCI and the Society of Thoracic Surgeons’ National Adult Cardiac Database instrument (www.sts.org/sections/stsnationaldatabase) for cardiac surgery, with detailed supplemental patient and operator identifying information collected for quality assessment.10 We linked data from the Massachusetts Registry of Vital Records and Statistics, the Social Security Death Index Interactive Search Web site (http://ssdi.rootsweb.com/cgi-bin/ssdi.cgi), and hospital discharge billing data collected by the Massachusetts Division of Health Care Finance and Policy to the Mass-DAC registry.9
According to the stent types used from the index admission, defined as the first admission during the present observational period, patients were assigned to 1 of 3 groups: (1) DES if all stents used during the index admission were drug eluting; (2) BMS if all stents were bare metal; and (3) “both” if both types of stents were used.
We defined death from any cause within 2 years of the index procedure as the primary outcome. The Massachusetts Registry of Vital Records and Statistics included 2-year mortality data for all study participants at the time of analysis. We used the Social Security Death Index Interactive Search to confirm death dates and mortality status.
MI was determined from the mandatory recording of in-hospital events in the Mass-DAC database (admission or postprocedure) or from the occurrence of any subsequent hospital admission with an International Classification of Diseases, 9th Revision principal diagnosis code of 410.x1 in the hospital discharge billing data. Target-vessel revascularization was defined as PCI performed in a vessel treated during the index procedure or any CABG procedure performed after the index procedure.
We first developed a list of confounders that included patient demographic factors, insurance status, history and risk factors, cardiac status of the patient, catheterization laboratory medications, and diagnostic findings, as well as lesion characteristics and patient-specific lesion-based variables: maximum percent diameter stenosis, any high-risk lesion, any restenotic lesion, and any use of embolectomy or atherectomy. Because some hospitals in Massachusetts are pilot programs that perform only primary angioplasty, without surgery on site, we also included a variable that indicated whether the patient underwent the PCI in a pilot program. Some confounders (neoplasm, gastrointestinal bleeding) that were not collected in the National Cardiovascular Data Registry instrument were created by linking patients to the hospital discharge billing data and identifying relevant International Classification of Diseases, 9th Revision, Clinical Modification codes in the index admission.9
Creation of Treatment Groups
Propensity score matching is a method of adjusting for observed characteristics of patients nonrandomly assigned to differing treatments.11 Because patients were not randomized to receive a DES, we performed a 1-to-1 matched analysis without replacement on the basis of the estimated propensity score of each patient. The log-odds of the probability that a patient received a DES was modeled as a function of the confounders we identified. Using the estimated logits, we first randomly selected a DES patient and then matched the DES patient to the “closest” BMS patient. BMS patients who had an estimated logit within 0.6 SDs of the selected DES patients were eligible for matching. We selected 0.6 because this value has been shown to eliminate ≈90% of the bias in observed confounders.12 We assessed the success of the matches by examining standardized differences in the observed confounders between the matched DES and BMS groups. Small (<10%) differences support the assumption of balance between treatment groups.13
Analysis of Primary Outcome
Using the matched pairs, we conducted paired t tests to determine whether mortality, MI, and revascularization were different between DES and BMS patients. Estimates of the adjusted differences in risks are presented with 95% CIs of the difference. All probability values presented are 2-sided.
Because matching on the propensity score cannot be expected to balance unobserved confounders that are not related to observed confounders, we undertook several sensitivity analyses. First, we examined differences in mortality between DES and BMS patients 2 days after stent placement. If this difference was clinically large, it would indicate the presence of unmeasured confounders, because such an early benefit would be unlikely. Second, we compared DES and BMS outcomes after adjusting for changes in selection over time (online-only Data Supplement). Third, we performed an analysis of patients matched after excluding those who presented with acute MI. Finally, we estimated the degree of residual confounding that would alter the conclusions of the present study (online-only Data Supplement).
Dr Normand had full access to the data; Drs Mauri and Normand take full responsibility for the integrity of the data analysis. All authors have read and agree to the manuscript as written.
Characteristics of the Patients and Lesions
Between April 1, 2003, and September 30, 2004, 21 045 patients received PCI with stenting in Massachusetts performed by 138 operators at 21 hospitals (Figure 1). We excluded from the primary analysis patients who were not residents of Massachusetts or were not linkable to hospital discharge data and Mass-DAC data, as well as patients who were treated with a combination of DES and BMS. This yielded a cohort of 17 793 adults, 11 556 (65%) of whom were treated with DES and 6237 (35%) of whom were treated with BMS. Of patients treated with DES, 8403 (72.7%) received sirolimus-eluting stents only, 2961 (25.6%) received paclitaxel-eluting stents only, and 192 (1.7%) received both types. Rates of DES use increased over the course of the study from 17% to 92% (Figure 2).
Clinical and procedural characteristics differed significantly between patients treated with DES and BMS (Tables 1 and 2⇓). Patients with diabetes mellitus, hyperlipidemia, or hypertension and those with a history of prior PCI were more likely to be treated with DES. In contrast, older patients, smokers, and patients with MI, a history of chronic lung disease, chronic renal insufficiency, cerebrovascular or peripheral vascular disease, neoplasm, or gastrointestinal bleeding were more likely to be treated with BMS. Overall, patients treated with DES received more stents and had more lesions treated than patients with BMS. Patients treated with both BMS and DES were not included in the BMS or DES groups and had more complex procedures than those treated with DES or BMS, with an overall greater number of lesions and vessels treated.
Unadjusted Clinical Outcomes
Unadjusted mortality, MI, and target-vessel revascularization rates were higher for BMS than for DES at 2 years (online-only Data Supplement Table I). The unadjusted rates of adverse events for patients treated with a combination of BMS and DES were intermediate between results for either stent type alone for mortality and MI at 2 years (10.8% and 8.7%) and were higher for target-vessel revascularization (34.6%).
Propensity Score Model
The propensity score model included 63 variables and had an area under the receiver operating characteristic curve of 0.67. Matching by propensity score yielded 5549 DES-treated patients matched to 5549 BMS-treated patients. Standardized differences were less than 10% (Tables 3 and 4⇓⇓; Figure 3), with the exception of acute coronary syndrome within 6 hours of hospital arrival (percent standardized difference 11.7%), emergency or salvage procedure indication (percent standardized difference 10.9%), and glycoprotein IIb/IIIa pretreatment (percent standardized difference 10.5%), all of which were slightly more common in the DES group, and an elective procedure indication (percent standardized difference −12.1%), which was slightly more common in the BMS group.
Mortality Rate Differences Between DES and BMS
MI Rate Differences Between DES and BMS
Revascularization Rate Differences Between DES and BMS
In the propensity-matched sample, rates of revascularization were lower for DES use at 1 year than for BMS use (−6.2% [−7.4% to −5.1%], P<0.0001; Table 5; Figure 4C). A similar absolute difference was preserved at 2 years.
Examination of the magnitude of difference in mortality 2 days after stent placement between the matched pairs showed a small absolute difference of 0.23% (0.45% versus 0.68%, respectively, DES versus BMS; P=0.10). Diffusion of DES was rapid in Massachusetts (Figure 2). Analysis that adjusted for the interaction between time and selection of stent type gave results comparing DES and BMS that were consistent with the primary analysis (online-only Data Supplement Table II). When patients presenting with MI were excluded, and the remaining DES and BMS patients were matched (2947 matched pairs), observed differences in 2-year clinical outcome were consistent with the overall cohort (mortality −1.8% [−3.3% to −0.3%], P=0.0174; MI −1.2% [−2.7% to 0.2%], P=0.0982; target-vessel revascularization −6.8% [−8.7% to −5.0%], P<0.0001), although with the smaller cohort, the difference in MI rate at 2 years was no longer significant.
We examined patients from a regional contemporary US practice with mandatory reporting to compare long-term outcomes after DES or BMS placement. Our primary goal was to evaluate whether DES were associated with increased rates of MI and mortality in long-term follow-up; however, we observed small absolute differences in MI and mortality in favor of DES. Repeat revascularization procedures were also lower.
To date, randomized, controlled trials of approved DES versus BMS have not shown significant differences in death or MI in long-term follow-up.3 Although the chief strength of such randomized comparisons is elimination of selection bias, these studies have been limited by power and generalizability to everyday practice.7,8 Some pooled randomized trials have shown a lower rate of recurrent MI for a certain DES versus BMS.14 Observational studies have had contradictory findings to date;5,15 such studies require more sophisticated methods than randomized studies to minimize bias but may offer improved power and greater generalizability.16 We captured all PCIs performed in Massachusetts over an 18-month period and included a wide range of hospitals and operators (academic, nonacademic, with and without surgical backup, lower- and higher-volume centers) and a wide variety of procedure types (elective and emergent procedures, low and high lesion complexity). Because all PCI procedures in Massachusetts are subject to prospective mandatory reporting of patient and procedural characteristics and outcomes, this is a powerful and reliable cohort.
The present study differed in several important ways from other population-based comparisons of DES and BMS. In contrast to populations in which DES use may be restricted geographically, financially, or according to patient risk,5,15 the present US study reflected a majority of DES use overall (65%). As a result, the present DES sample represents a broader patient population.
To avoid bias due to differential follow-up, we restricted the present analysis to those patients who had complete follow-up at a fixed time point (2 years). Although we had substantially longer follow-up in a subset of patients, we limited the present analysis to a fixed time point to avoid inference on an incomplete sample and to avoid changing conclusions as greater follow-up accrues.17
One mechanism to explain the reductions in MI and mortality that we observed in patients treated with DES may be that prevention of repeat revascularization in a patient population of higher complexity resulted in a reduction in clinical complications of these procedures.19,20 This result was observed despite an absolute difference in target-vessel revascularization lower than reported in randomized controlled trials, in which surveillance angiography was frequent,1,2 but similar to rates recently reported in other US registries.18 With respect to MI, we observed somewhat higher rates than other studies5,15 because we included periprocedural MI.
Late stent thrombosis has been considered a potential mechanism for the increase in mortality in some studies of DES.21 We did not have sufficient data to accurately estimate rates of late stent thrombosis. The present well-powered observational study would suggest that if a small difference in late stent thrombosis was present between DES and BMS, it was not readily detectable in a clinical end point (death or MI) because it represented a small proportion of these events. Given the relatively rare occurrence of stent thrombosis (<1% in the first year and rarer in later follow-up),6 it would seem unlikely that these events would overtake the constant hazard of adverse events related to disease progression22 beyond 2 years.
Because the choice of stent was not assigned randomly, we used propensity score matching to select a group of patients who were essentially similar according to all measured baseline variables. Compared with other methods that use a propensity model to adjust for selection bias, a matched analysis is more likely to reduce power (by restricting the sample to closely matched patients) but has the advantage of more reliably reducing selection bias (compared with regression-based propensity analysis). We were afforded this opportunity because the density of DES and BMS procedures performed in Massachusetts was high (>14 000 PCI procedures per year per 6 million adults) and because the patterns of use of DES and BMS in the present study spanned both low- and high-risk patients. We confirmed that the matched patients were similar with regard to each of 63 baseline variables, and with this degree of similarity, matching of unmeasured confounders is expected23; however, we acknowledge the possibility of residual confounding. This was estimated to be small, as measured by the 2-day mortality difference. Some sources of residual bias include varying completion of revascularization, limited ability to adjust for angiographic characteristics (lesion length and vessel diameter were not available), and concomitant medical therapy.
We collected information on use of and contraindications to dual-antiplatelet therapy with aspirin and thienopyridine because of its known relationships to mortality, MI, and stent thrombosis.24–26 Although we did not have pharmacy data to compare the duration of therapy and compliance in patients treated with DES and BMS, during the period under study, the existing cardiology society guidelines recommended a longer duration of thienopyridine therapy in patients with DES (3 to 6 months minimum) than in those with BMS (1 month minimum).27 We cannot exclude the possibility that the longer use of thienopyridine treatment that is recommended with DES selection could have contributed to a mortality and MI benefit in favor of DES over BMS. Because the most recent national society recommendation is for 12 months of dual-antiplatelet therapy for DES,28 the associated effect of dual-antiplatelet therapy with DES selection compared with BMS may increase in future studies.
We combined patients treated with paclitaxel-eluting and sirolimus-eluting stents within the DES group. Differences in safety between DES remain controversial, and other population-based studies have not shown significant differences in mortality between these 2 stents.29
In conclusion, in a large population-based study reflecting primarily DES use across a cohort with comprehensive follow-up after PCI, we found that DES were associated with lower mortality, MI, and target-vessel revascularization than BMS at 2 years of follow-up. Longer-term follow-up will be required to provide further reassurance of preserved safety in the broad patient population currently treated with these coronary devices.
The authors wish to acknowledge Paul Dreyer, PhD, of the Massachusetts Department of Public Health and the members of the Mass-DAC PCI Data Adjudication Committee: Kurt Barringhaus, MD; Clifford J. Berger, MD; David Cohen, MD; Angela Corey; Jean Crossman, RN; Daniel Fisher, MD; Joseph Garasic, MD; Jean-Pierre Geagea, MD; Gregory Giugliano, MD; Kalon Ho, MD; Alice Jacobs, MD; James Kirshenbaum, MD; Josh Krasnow, MD; Anthony Marks, MD; Theo E. Meyer, MD, PhD; Kathy Minahan, RN; Zoran Nedelijkovic, MD; Barbara Oxley, RN; Thomas C. Piemonte, MD; Kenneth Rosenfield, MD; Pinak B. Shah, MD; Samuel J. Shubrooks, Jr, MD; James Waters, MD; and Bonnie Weiner, MD. The authors also wish to thank Manu Varma for assistance with preparation of tables and figures.
Sources of Funding
This study was funded by Massachusetts Department of Public Health contract No. 620022A4PRE (Dr Normand, A. Lovett, K. Zelevinsky, T.S. Silbaugh, and R.E. Wolf). The study sponsor did not influence the study design, collection, or analysis or interpretation of data, the writing of the report, or the decision to submit the article for publication.
Dr Mauri has received honoraria from Abbott Vascular, Boston Scientific, Cordis, and Medtronic Vascular. Dr Zhou completed employment by Boston Scientific 1 year before this work was begun. Dr Resnic has consulted for or received honoraria from Abbott Vascular and Cordis Corp. The remaining authors report no conflicts.
Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003; 349: 1315–1323.
Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation. 2004; 109: 1942–1947.
Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, Kukreja N, Juni P, Sianos G, Hellige G, van Domburg RT, Hess OM, Boersma E, Meier B, Windecker S, Serruys PW. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007; 369: 667–678.
Shahian DM, Silverstein T, Lovett AF, Wolf RE, Normand SL. Comparison of clinical and administrative data sources for hospital coronary artery bypass graft surgery report cards. Circulation. 2007; 115: 1518–1527.
Cohen J. The t test for means. In: Cohen J, ed. Statistical Power Analysis for the Behavioral Sciences. Toronto, Canada: Academic Press Inc; 1977. Chapter 2.
Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schomig A, Pfisterer ME, Stone GW, Leon MB, de Lezo JS, Goy J-J, Park S-J, Sabate M, Suttorp MJ, Kelbaek H, Spaulding C, Menichelli M, Vermeersch P, Dirksen MT, Cervinka P, Petronio AS, Nordmann AJ, Diem P, Meier B, Zwahlen M, Reichenbach S, Trelle S, Windecker S, Juni P. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet. 2007; 370: 937–948.
Mauri L, Normand SL. Studies of drug-eluting stents: to each his own? Circulation. 2008; 117: 2047–2050.
James S, Carlsson J, Lindback J, Nilsson T, Stenestrand U, Wallentin L, Lagerqvist B; Swedish Coronary Angiography and Angioplasty Registry (SCAAR) Group. Long-term outcomes with drug-eluting stents vs. bare-metal stents in Sweden: one additional year of follow-up. Presented at: European Society of Cardiology Congress; September 1–7, 2007; Vienna, Austria.
Abbott JD, Voss MR, Nakamura M, Cohen HA, Selzer F, Kip KE, Vlachos HA, Wilensky RL, Williams DO. Unrestricted use of drug-eluting stents compared with bare-metal stents in routine clinical practice: findings from the National Heart, Lung, and Blood Institute Dynamic Registry. J Am Coll Cardiol. 2007; 50: 2029–2036.
Doyle B, Rihal CS, O'Sullivan CJ, Lennon RJ, Wiste HJ, Bell M, Bresnahan J, Holmes DR Jr. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation. 2007; 116: 2391–2398.
Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006; 48: 2584–2591.
Cutlip DE, Chhabra AG, Baim DS, Chauhan MS, Marulkar S, Massaro J, Bakhai A, Cohen DJ, Kuntz RE, Ho KK. Beyond restenosis: five-year clinical outcomes from second-generation coronary stent trials. Circulation. 2004; 110: 1226–1230.
Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005; 293: 2126–2130.
Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation. 2006; 113: 2803–2809.
Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kern MJ, King SB III, Morrison DA, O'Neill WW, Schaff HV, Whitlow PL, Williams DO. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006; 47: 216–235.
Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O'Gara P, Whitlow P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007; 49: 734–739.
The late safety of drug-eluting stents (DES) has been a matter of recent controversy. Randomized trials have not been powered to detect differences in mortality compared with bare-metal stents (BMS) and have been limited to lower-risk patients. This population-based study collected prospective clinical and procedural data on all patients who underwent percutaneous coronary intervention with stents from April 1, 2003, through September 30, 2004, at nongovernment hospitals in Massachusetts. Rates of mortality, myocardial infarction, and repeat revascularization procedures on the treated vessel were ascertained over the 2 years after stent placement. The goal of the study was to determine long-term patient outcomes by stent type in a population representative of current US medical practice. Because the choice of stent was not assigned randomly, a propensity score–matched analysis was performed to compare DES- and BMS-treated patients with similar characteristics. One-to-one matching was performed with a logistic regression model created from 63 variables to identify unique pairs of DES and BMS patients with similar baseline characteristics. A total of 17 793 patients who underwent placement of DES or BMS were identified; patients who received both stent types were excluded. Sixty-five percent of patients (11 556) received DES compared with 35% (6237) who received BMS. A total of 5549 DES patients matched to 5549 BMS patients were analyzed for each of the 2-year outcomes. The 2-year risk-adjusted mortality, myocardial infarction, and target-vessel revascularization rates each were lower for patients treated with DES than for those treated with BMS.
Guest Editor for this article was Eric R. Bates, MD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.781377/DC1.