Clopidogrel and long-term outcomes after stent implantation for acute coronary syndrome

Transcription

1 Clinical Investigations Acute Ischemic Heart Disease Clopidogrel and long-term outcomes after stent implantation for acute coronary syndrome P. Michael Ho, MD, PhD, FACC, a,b Stephan D. Fihn, MD, MPH, c,d,e Li Wang, MS, c,d Chris L. Bryson, MD, MS, d,e Elliott Lowy, PhD, c,d,e Charles Maynard, PhD, c,d,e David J. Magid, MD, MPH, b,f Eric D. Peterson, MD, MPH, FACC, g Robert L. Jesse, MD, PhD, FACC, h and John S. Rumsfeld, MD, PhD, FACC a,b Denver and Aurora, CO; Seattle, WA; Durham, NC; and Richmond, VA Background Little is known about the association between clopidogrel use and long-term outcomes after stent implantation for acute coronary syndromes (ACS) in clinical practice. Methods This retrospective cohort study included patients with ACS receiving drug-eluting stent (DES) or bare-metal stent (BMS) and discharged from all Veterans Health Administration hospitals from 2003 to Clopidogrel use was assessed by pharmacy dispensing data. Multivariable Cox regression assessed the association between clopidogrel discontinuation and outcomes with clopidogrel use as a time-varying covariate and adjusting for demographics, comorbidities, hospital presentation, and treatment variables. Median follow-up was 538 days. Results Of 1455 patients with ACS, 65.8% received BMS and 34.2% received DES. The median number of days of clopidogrel use was 299. In multivariable analysis, clopidogrel discontinuation was associated with higher all-cause mortality (hazard ratio [HR] 2.40, 95% confidence interval [CI] ). The findings were consistent for patients receiving BMS (HR 2.65, 95% CI ) or DES (HR 2.00, 95% CI ) and for the outcomes of acute myocardial infarction (AMI) and AMI or mortality. When follow-up was divided into 6-month intervals, the association between clopidogrel discontinuation and higher mortality remained consistent up to 18 months after hospital discharge. In secondary analysis of patients who were event-free at 6 months, clopidogrel discontinuation was associated with higher risk for AMI among patients receiving DES (HR 3.57, 95% CI ) compared with BMS (HR 1.26, 95% CI ). Conclusion Clopidogrel discontinuation after extended use was still associated with increased mortality risk. Clinical trials are urgently needed to define the optimal duration of clopidogrel therapy after stent implantation for ACS. (Am Heart J 2007;154: ) Drug-eluting stents (DESs) are used in most percutaneous coronary interventions (PCIs) in the acute coronary syndrome (ACS) setting, although DES are not currently approved by the Food and Drug Administration for this indication. 1,2 Clinical trials have demonstrated the From the a Denver VA Medical Center, Denver, CO, b University of Colorado Health Sciences Center, Denver, CO, c Ischemic Heart Disease Quality Enhancement Research Initiative, Seattle, WA, d VA Puget Sound Health Care System, Seattle, WA, e University of Washington, Seattle, WA, f Clinical Research Unit, Kaiser Permanente of Colorado, Aurora, CO, g Duke Clinical Research Institute, Durham, NC, and h Richmond VA Medical Center, Richmond, VA. Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. This study was supported by a grant from the Ischemic Heart Disease Quality Enhancement Research Initiative of the US Department of Veterans Affairs. Dr Ho and Dr Bryson are supported by VA Research & Development Career Development Awards. Submitted July 6, 2007; accepted August 28, Reprint requests: P. Michael Ho, MD, PhD, Denver VA Medical Cdenter, 1055 Clermont St., Cardiology (111B), Denver, CO michael.ho@uchsc.edu /$ - see front matter 2007, Mosby, Inc. All rights reserved. doi: /j.ahj benefit of clopidogrel use for 9 to 12 months after baremetal stent (BMS) implantation in the ACS setting. 3,4 In contrast, clinical trials assessing the efficacy of DES have prespecified the duration of clopidogrel treatment after stent placement, and there are few data available regarding the association between length of clopidogrel use and outcomes after DES placement for ACS. 5,6 Two recent studies provide data relevant to this issue. A single-center study demonstrated patients' report of clopidogrel use at 6 and 12 months after DES was associated with a reduction in death and/or myocardial infarction (MI) events at 24 months. 7 In the BASKET-LATE trial, there were no differences in event rates between DES versus BMS at 18 months of follow-up. 8 However, following clopidogrel discontinuation after 6 months of treatment, there was significantly increased risk of cardiac death or MI in the DES group compared with BMS (4.9% vs 1.3%). These findings along with other recent studies demonstrating increased stent thrombosis risk with DES highlight an urgent need to evaluate clopidogrel use and patients outcomes after stent implantation in the setting of ACS. 9-18

2 American Heart Journal Volume 154, Number 5 Ho et al 847 Accordingly, the objectives of this study were to assess the association between clopidogrel use and outcomes in a national cohort of veterans with ACS undergoing stent implantation. Specifically, we evaluated the association between clopidogrel use after stent implantation with allcause mortality and recurrent acute myocardial infarction (AMI). Second, we assessed the association between clopidogrel use and outcomes stratified by stent type, BMS versus DES. Third, we evaluated the association between clopidogrel use and outcomes, accounting for patient adherence to statin medications as a proxy of overall medication adherence. Methods Data for this study were collected as part of the Cardiac Care Follow-up Clinical Study, which uses national data from the Veterans Health Administration (VHA) External Peer Review Program for quality monitoring and improvement for a variety of medical conditions and procedures, including AMI and unstable angina (UA). Starting in 2003, the records of all patients with AMI or UA discharged from a VHA hospital were abstracted, as part of a national Veterans Affairs (VA) cardiac care initiative. All patients with International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes 410.xx and 411.xx were identified from the VA Patient Treatment File, and their records were manually abstracted by trained abstractors using standard reporting forms. Percutaneous coronary intervention procedural details were also collected including whether a DES versus a BMS was used. Additional details of the study methods have been published. 19 Patient population All patients with acute MI or UA as documented by standard electrocardiographic criteria, elevated troponin levels, and/or other clinical evidence underwent PCI with either a BMS or DES, prescribed clopidogrel at hospital discharge, and discharged from any 1 of 127 VHA medical centers between October 1, 2003, and September 30, 2004, were included. Patients admitted with other primary medical conditions but developed AMI during the hospitalization or as a postoperative complication were also included if they underwent a PCI procedure with either a BMS or DES and survived to hospital discharge. Patients who were transferred into VHA hospitals from other medical facilities for ACS were excluded because PCI procedural details were not available. The final analytic cohort for this study was composed of 1455 patients. Clopidogrel use The primary independent variable of interest was clopidogrel use based on the Pharmacy Benefits Management data. Because of the VA's prescription benefits, most veterans who undergo PCI in the VA use the VA pharmacy for clopidogrel because of the low cost. 20 Clopidogrel use started on the day of hospital discharge and was considered available and taken if there was a prescription for clopidogrel that covered the date of follow-up based on the dispense date and number of days supplied. When there was a gap of more than 1 day between prescription refills, patients were considered to have discontinued the medication. If a patient refilled their clopidogrel prescription at some point later in time, they were considered to be taking the medication again. In secondary analysis, we increased the gap to 7 days between prescription refills to categorize a patient as discontinuing clopidogrel, and the findings were consistent with the primary results. The last day of clopidogrel use was based on the date of the last prescription refill plus the number of days supplied for that refill. Therefore, the total number of clopidogrel-covered days was calculated from the day of discharge to the last clopidogrel refill date plus the number of days supplied for that last refill. Outcomes The primary outcome was all-cause mortality after PCI for the index ACS hospitalization. The new VA vital status file was used to determine vital status after hospital discharge. 21,22 Secondary outcomes were rehospitalization for AMI after the index hospitalization and the combined end point of all-cause mortality and AMI rehospitalization. Acute myocardial infarction was based on a primary discharge International Classification of Diseases, Ninth Revision, diagnosis code of 410.xx for any hospitalization after the index ACS hospitalization. The median follow-up was 538 days. Statistical methods Unadjusted cumulative mortality was compared between patients continuing and discontinuing clopidogrel using the Nelson Aalen cumulative hazard method. 23 Survival was measured beginning at hospital discharge and censored at the end of follow-up. In multivariable analysis, Cox proportional hazards models with a time-varying covariate for clopidogrel use were constructed to evaluate the association between clopidogrel discontinuation and time to death. These models adjusted for patient demographics (age, race), comorbidities (heart failure, diabetes, MI, PCI, coronary artery bypass graft cerebrovascular disease, renal disease, chronic obstructive pulmonary disease (COPD), and prior clopidogrel use), hospital presentation factors thrombolysis in myocardial infarction risk score for ST-elevation MI or non ST-elevation MI, left ventricular systolic dysfunction, MI vs UA as the final discharge diagnosis and glycoprotein IIb/IIIa use. The same analyses were repeated for the secondary outcomes of recurrent hospitalization for AMI and the combined end point of mortality and AMI. Next, we performed a series of sensitivity analyses to further assess the robustness of our primary analyses. First, we stratified our cohort by whether patients received BMS versus DES and assessed the association between clopidogrel discontinuation and outcomes. Second, we divided the follow-up into 6-month intervals and assessed the association between clopidogrel discontinuation and mortality during each of the 6-month intervals, up to 18 months after hospital discharge. Third, we excluded patients receiving BMS after July 1, 2004, out of concern that, given the wide adoption of DES after its introduction, BMS may only be placed in particularly high-risk patients. The increased risk associated with clopidogrel discontinuation was consistent when patients receiving BMS after July 1 were excluded, and therefore, the results are not further reported. Fourth, we performed a landmark analysis and defined the landmark as 6 months after the index PCI procedure due to concern that patients experiencing an early event after

3 848 Ho et al American Heart Journal November 2007 Table I. Baseline characteristics of patients receiving stents in fiscal year 2004 Figure 1 Variables Overall cohort (N = 1455) Demographics Age, mean (SD) 64.0 (11.2) Male 1427 (98.1%) White 790 (54.3%) Comorbidities Heart failure 218 (15.0%) Diabetes 276 (19.0%) Prior MI 308 (21.2%) Prior PCI within the last 6 months 172 (11.8%) Prior CABG 254 (17.5%) Cerebrovascular disease 75 (5.2%) Renal disease 176 (12.1%) Chronic obstructive pulmonary 185 (12.7%) disease Prior clopidogrel use 167 (11.5%) ACS presentation factors TIMI risk score 3.24 (1.29) Left ventricular ejection fraction b 40% 326 (23.7%) ACS treatment Glycoprotein IIb/IIIa inhibitor use 943 (64.8%) Final diagnosis AMI 1387 (95.3%) UA 68 (4.7%) Use of BMS and DES for each month from October 1, 2003, to September 30, Figure 2 CABG, Coronary artery bypass graft; TIMI, thrombolysis in myocardial infarction. PCI may be a particularly high-risk group. Because we were interested in assessing long-term outcomes after stent implantation, we evaluated the association between clopidogrel discontinuation and outcomes among patients who were eventfree at 6 months, including comparison of DES versus BMS. Fifth, we quantified the proportion of patients discontinuing clopidogrel therapy early (ie, within 6 months of hospital discharge) and assessed the patient factors associated with early discontinuation of clopidogrel using logistic regression models. Finally, we assessed the association between clopidogrel discontinuation and mortality according to different levels of patient adherence to statin medications to further assess whether adherence behavior had an impact on clopidogrel discontinuation and outcomes. All patients in the cohort were prescribed statin medications at hospital discharge, and statin adherence was calculated using the proportion of days covered method, number of days supplied over the follow-up period. Based on this method, patients were categorized into low (b 60%), intermediate (60%-79%), or high ( 80%) levels of statin adherence. Then, within each stratum of adherence, the association between clopidogrel discontinuation and mortality was assessed. These secondary analyses used the same multivariable modeling techniques as the primary analyses. Analyses were conducted using STATA v9.0 (Chicago, IL). The Cardiac Care Follow-up Clinical Study is approved by University of Washington Institutional Review Board, and waiver of informed consent has been granted. Results Baseline characteristics of the study population are presented in Table I. The average age was 64.0 ± 11.2 years. Patients in the cohort had multiple comorbid Unadjusted cumulative all-cause mortality rates between patients discontinuing and continuing clopidogrel. conditions including diabetes (19.0%), prior MI (21.2%), PCI within the last 6 months (11.8%), and COPD (12.7%). Almost one quarter of the patients had left ventricular systolic dysfunction, and almost two thirds received glycoprotein IIb/IIIa inhibitors during the hospitalization. The monthly rates of stent use, BMS versus DES, from October 2003 through September 2004 are shown in Figure 1. Toward the end of the fiscal year, DESs were implanted in most of the cases for patients with ACS in the VHA. Overall, 957 (65.8%) of the patients received BMSs and 34.2% received DESs. The median number of clopidogrel-covered days was 299 days with an interquartile range of 180 to 384 days. There were no significant differences in the number of clopidogrel-covered days between patients receiving BMS and patients receiving DES (median 297 days,

4 American Heart Journal Volume 154, Number 5 Ho et al 849 interquartile range 171 to 395 vs 300 days, interquartile range , P =.99). Approximately 20% (20.4%) of patients discontinued clopidogrel therapy within 6 months of ACS hospital discharge. Patient factors associated with early clopidogrel discontinuation included COPD (odds ratio [OR] 1.58, 95% confidence interval [CI] ) and left ventricular systolic dysfunction (OR 1.42, 95% CI ), whereas patients on clopidogrel before the index ACS hospital admission were more likely to continue the medication afterward (OR 0.51, 95% CI ). The median follow-up was 538 days. Patients discontinuing clopidogrel had higher mortality compared with patients continuing clopidogrel (19.9% vs 6.9%, P b.001) (Figure 2). In multivariable analyses, clopidogrel discontinuation remained significantly associated with higher mortality risk (hazard ratio [HR] 2.40, 95% CI ). The findings were consistent among patients receiving BMS (HR 2.65, 95% CI ) or DES (HR 2.00, 95% CI ). For the secondary outcomes, clopidogrel discontinuation was also associated with higher risk of rehospitalization for AMI (HR 1.78, 95% CI ) and the combined outcome of mortality and AMI (HR 1.90, 95% CI ). In addition, the mortality risk associated with clopidogrel discontinuation was consistent throughout the follow-up period, including 0 to 6 months (HR 2.67, 95% CI ), 7 to 12 months (HR 2.26, 95% CI ), and 13 to 18 months (HR 2.85, 95% CI ). The CIs were wider in the 13- to 18-month period because of a small number of events, but the magnitude of the HR was consistent with the earlier periods. Among patients who were event-free at 6 months, the association between clopidogrel discontinuation and allcause mortality was consistent with the primary results, and there was no significant difference between BMS and DES. However, clopidogrel discontinuation was associated with higher risk for subsequent AMI among patients receiving DES (HR 3.57, 95% CI ) compared with BMS (HR 1.26, 95% CI ). Next, clopidogrel discontinuation was associated with increased mortality risk regardless of the level of statin adherence, although the magnitude of association was stronger among patients with reduced adherence: high adherence (HR 1.93, 95% CI ), intermediate adherence (HR 8.05, 95% CI ), or low adherence (HR 5.59, 95% CI ). Discussion The primary objective of this analysis was to assess the association between clopidogrel discontinuation and outcomes after stent implantation for ACS. With a median follow-up of 538 days, clopidogrel discontinuation was associated with significantly higher risk for all-cause mortality, recurrent AMI, and the combined end point of mortality and AMI. The increased risk associated with clopidogrel discontinuation was consistent through 18 months of follow-up, for patients receiving BMSs or DESs, and even after accounting for adherence to statin medications as a proxy for overall patient medication adherence. To date, there has been little data regarding the benefit of extended clopidogrel use for patients undergoing DES implantation for ACS. Prior studies have demonstrated the benefit of extended clopidogrel use after BMS implantation in the setting of ACS. 3,4,24 In the PCI-CURE and CREDO trials, where approximately 80% to 90% of patients received BMS (the others had balloon angioplasty), there was an approximate 30% relative risk reduction of events among patients receiving clopidogrel for 9 to 12 months after PCI. The few DES trials that have enrolled patients with ACS have focused only on patients with ST-segment elevation and prespecified the duration of clopidogrel therapy at either 6 or 12 months, leaving unanswered the question of optimal duration of clopidogrel therapy Moreover, data on clopidogrel use and patient outcomes after stent implantation for ACS in real world clinical settings have been lacking, and there has been little data on clopidogrel use beyond 12 months after stent implantation. Our findings support the effectiveness of extended clopidogrel use among patients with ACS receiving BMS in clinical practice and suggest the hypothesis that clopidogrel use for at least 18 months after DES implantation in the ACS setting may confer a benefit. Our study highlights the urgent need for clinical trials to test the efficacy of extended clopidogrel treatment after stent implantation in the setting of ACS, especially for patients receiving DES. In contrast to prior studies that have relied primarily on patient self-report, we used detailed pharmacy dispensing data to assess clopidogrel use. 7,28,29 This method has been shown to be more accurate than patient self-report, and medication use based on pharmacy records has been correlated with a broad range of patient outcomes In addition, our assessment of clopidogrel use with a timevarying method does not assume that once a patients starts the medication it is continued indefinitely and accounts for stops and restarts of the medication which reduces the likelihood of survival bias. 33,34 Finally, we accounted for patient adherence behavior by performing a stratified analysis of the association between clopidogrel discontinuation and outcomes according to different levels of statin adherence. The association between clopidogrel discontinuation and adverse outcomes persisted across the varying levels of adherence. The magnitude of association was higher among patients with lower adherence, emphasizing the importance of medication adherence as an important cofactor to measure in effectiveness studies and as a target for improved patient outcomes in clinical practice. However, there was still

5 850 Ho et al American Heart Journal November 2007 significantly increased risk of mortality associated with clopidogrel discontinuation among patients with the highest level of statin adherence ( 80%), reinforcing the primary study conclusion of an association between extended clopidogrel use and better outcomes after stent implantation in the setting of ACS. Our findings expand the literature for several reasons. First, among patients who were event-free at 6 months, there was a suggestion of higher AMI hospitalization risk associated with clopidogrel discontinuation among patients receiving DES compared with BMS. In contrast to prior studies, we use detailed pharmacy data to assess clopidogrel use, and these findings add further evidence to recent concerns of increased stent thrombosis risk associated with DES. 7 Second, we identified several additional patient factors associated with early clopidogrel discontinuation including patients with COPD and left ventricular systolic dysfunction. This adds to the list of factors that have been previously associated with clopidogrel discontinuation including patients who are older, have less than a high school education, are unmarried, avoid healthcare due to cost, and have preexisting cardiovascular disease before presentation with AMI. 28 These factors may be helpful to identify patients for future interventions to improve clopidogrel use. Third, we recognize that the magnitude of clopidogrel effect found in this observational study was larger than found in the randomized trials. However, in contrast to the randomized trials where patients are assigned to a treatment group and assumed to take the medication as directed, we accounted for patients being on and off clopidogrel and compared the risk of death/ami between when patients were on the drug and when patients were off the drug. This design contributes to an observed larger magnitude of benefit compared with a randomized trial design where intention-to-treat analysis does not account for any medication nonadherence. Moreover, to address potential confounding as a contributor to the magnitude of association found, we adjusted for a number of covariates as well as adherence to statin medications. Although we cannot exclude the possibility of residual confounding, this limitation is inherent in any observational effectiveness study and underscores that a randomized efficacy study is needed to further address this question. There are several limitations of our study that should be acknowledged. We did not have data on aspirin use after hospital discharge because most patients receiving care in the VHA obtain aspirin over the counter. Prior reports have shown that N95% of VHA patients without contraindications are prescribed aspirin at ACS hospital discharge, and we presumed that all patients were prescribed aspirin in addition to clopidogrel after stent implantation. 35 Second, we did not have data on recurrent AMI events outside the VHA. However, we had complete ascertainment of vital status, and the association between clopidogrel and AMI outcome was consistent with our mortality findings. Further minimizing the potential effect of this bias, we would expect that recurrent AMI hospitalizations outside the VHA would tend to bias the results toward the null. Third, we did not have causespecific mortality because this is not currently captured in the VA vital status file. Fourth, we did not have detailed data on coronary anatomy or the brands of DES used. The primary objective of the study was focused on long-term outcomes associated with clopidogrel use after stent implantation during ACS hospitalization. Future studies should address whether there are any potential adverse risks related to extended clopidogrel use and whether the increased risk associated with clopidogrel discontinuation varies according to specific coronary lesion risk, procedural characteristics, or type of DES. Finally, we do not know the reason(s) for clopidogrel discontinuation. For example, if the medication was stopped because of overall clinical deterioration, the association between clopidogrel discontinuation and adverse events may not be causal. Future studies should explore the specific reasons for clopidogrel discontinuation. In conclusion, we found that clopidogrel discontinuation after stent implantation for ACS was associated with adverse outcomes. Clopidogrel discontinuation was associated with higher mortality risk up to 18 months after ACS hospital discharge, suggesting that extended clopidogrel therapy after stent implantation in the setting of ACS may be warranted. Randomized controlled clinical trials are urgently needed to address this important issue of optimal duration of clopidogrel treatment after stent implantation in the DES era. References 1. Rao SV, Shaw RE, Brindis RG, et al. Patterns and outcomes of drug-eluting coronary stent use in clinical practice. Am Heart J 2006;152: FDA Statement on Coronary Drug-Eluting Stents (September 14, 2006) website. Accessed February 6, Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358: Steinhubl SR, Berger PB, Mann III JT, et al. Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288: Morice MC, Serruys PW, Sousa JE, et al, RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and twelvemonth results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38-42.

6 American Heart Journal Volume 154, Number 5 Ho et al Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and longterm clinical outcomes after drug-eluting stent implantation. JAMA 2007;297: [Epub 2006 Dec 5]. 8. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. 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: [Epub 2006 Nov 2]. 9. Grines CL, Bonow RO, Casey Jr DE, et al. 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. Circulation 2007 [Epub ahead of print]. 10. Harrington RA, Califf RM. Late ischemic events after clopidogrel cessation following drug-eluting stenting: should we be worried? J Am Coll Cardiol 2006;48: [Epub 2006 Oct 31]. 11. Bavry AA, Kumbhani DJ, Helton TJ, et al. Late thrombosis of drugeluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006;119: Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during longterm follow-up. Am J Cardiol 2006;98:352-6 [Epub 2006 Jun 12]. 13. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48: [Epub 2006 May 5]. 14. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and longterm outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113: [Epub 2006 Feb 20]. 15. Ong AT, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45: Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drugeluting stents. JAMA 2005;293: Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007;356: [Epub 2007 Feb 12]. 18. Lagerqvist B, James SK, Stenestrand U, et al, SCAAR Study Group. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356: [Epub 2007 Feb 12]. 19. Maynard C, Lowy E, Rumsfeld J, et al. The prevalence and outcomes of in-hospital acute myocardial infarction in the Department of Veterans Affairs Health System. Arch Intern Med 2006;166: Piette JD, Heisler M. Problems due to medication costs among VA and non-va patients with chronic illnesses. Am J Manag Care 2004;10: Cowper DC, Kubal JD, Maynard C, et al. A primer and comparative review of major US mortality databases. Ann Epidemiol 2002;12: Sohn MW, Arnold N, Maynard C, et al. Accuracy and completeness of mortality data in the Department of Veterans Affairs. Popul Health Metr 2006;4: Aalen O. Nonparametric estimation of partial transition probabilities in multiple decrement models. Ann Stat 1978;6: Bernardi V, Szarfer J, Summay G, et al. Long-term versus short-term clopidogrel therapy in patients undergoing coronary stenting (from the Randomized Argentine Clopidogrel Stent [RACS] trial). Am J Cardiol 2007;99: [Epub 2006 Dec 1]. 25. Laarman GJ, Suttorp MJ, Dirksen MT, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention. N Engl J Med 2006;355: Spaulding C, Henry P, Teiger E, et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006; 355: Menichelli M, Parma A, Pucci E, et al. Randomized trial of Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction (SESAMI). J Am Coll Cardiol 2007;49: [Epub 2007 Apr 30]. 28. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006;113: [Epub 2006 Jun 12]. 29. Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents. JAMA 2007; 297: Wang PS, Benner JS, Glynn RJ. How well do patients report noncompliance with antihypertensive medications? A comparison of self-report versus filled prescriptions. Pharmacoepidemiol Drug Saf 2004;13: Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353: Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med 2006;166: Zhou Z, Rahme E, Abrahamowicz M, et al. Survival bias associated with time-to-treatment initiation in drug effectiveness evaluation: a comparison of methods. Am J Epidemiol 2005;162: [Epub 2005 Sep 28]. 34. Schneeweiss S. Methods in pharmacoepidemiology: time-varying drug effects revisited. Pharmacoepidemiol Drug Saf 2006;15: Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics-2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69-e171 [Epub 2006 Dec 28]. Correction The article Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score accurately predicts longterm mortality post acute coronary syndrome (Am Heart J 2007;153:29-35) was published with an error in Table 1: Under the In-hospital coronary revascularization the value of PCI should be 377 (35.7%).