EDITORIAL COMMENT
The Evolution of Thienopyridine TherapyClopidogrel Duration, Diabetes, and Drug-Eluting Stents*
Seung-Hyuk Choi, MD*, ,
Anand Prasad, MD*, and
Sotirios Tsimikas, MD, FACC*,,*
* Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Division of Cardiology, University of California San Diego, San Diego, California.
* Reprint requests and correspondence: Dr. Sotirios Tsimikas, Vascular Medicine Program, University of California San Diego, 9500 Gilman Drive, BSB 1080, La Jolla, California 92093-0682. (Email: stsimikas{at}ucsd.edu).
The widespread clinical application of coronary stents was paralleled by another fundamental advance in adjunctive medical therapy, namely the recognition of the critical role of the platelet in stent thrombosis. During the early development of bare-metal stents (BMS), the use of prolonged heparin infusion, dextran, aspirin, dipyridamole, and warfarin remained suboptimal in preventing acute and subacute stent thrombosis. The addition of thienopyridines to aspirin, along with optimal stent deployment techniques, had reduced the incidence of stent thrombosis to an acceptably low level (1% to 2%).
The introduction of drug-eluting stents (DES) was heralded by euphoria when early reports suggested near zero percent restenosis. However, pre-clinical DES studies had suggested less-complete vessel healing, and the initial recommendation was to increase the use of dual antiplatelet therapy to 3 to 6 months. This initial excitement was significantly tempered by the realization of late (>1 year) stent thrombosis and potentially of death and myocardial infarction (MI). This was documented by a variety or sources, including the Food and Drug Administration (FDA); case reports (1); and clinical studies and registries such as BASKET-LATE (Basel Stent Cost-Effectiveness Trial—Late Thrombotic Events) (2), SCAAR (Swedish Coronary Angiography and Angioplasty Registry) (3), and the Denmark registries (4). Subgroup analyses demonstrated that stent thrombosis was more prevalent in several clinical (diabetes, older age, renal failure) and angiographic subsets (ostial, bifurcation, overlapping stents, prior brachytherapy) and was particularly potentiated by clopidogrel withdrawal (5). For example, Airoldi et al. (6) showed that stent thrombosis occurred on average after 13 days if clopidogrel was discontinued within the first 6 months of stent placement. However, if clopidogrel was discontinued after 6 months of stent placement, stent thrombosis occurred on average 90 days later, suggesting different pathophysiological mechanisms of subacute and late stent thrombosis.
The rapid penetration of DES use (near 90%) resulted in significant application in "off-label" indications, which are associated with increased adverse events for both DES and BMS (7). Interestingly, long-term follow-up of patients in randomized trials has not shown an increased cumulative risk of death/MI, but some landmark analyses censoring events before 6 months have shown an additional 0.1% to 0.5% risk of DES thrombosis starting at 6 months after stent deployment (8,9). These findings led to major debate regarding the clinical usefulness of DES in scientific circles, regulatory agencies, and the public, leading to a reassessment of the appropriate indications for DES, which hitherto had only shown a decrease in target vessel revascularization (TVR) but not death and MI (10). In a case of the perfect storm, concurrent publication of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial intensified the debate of the role of percutaneous coronary intervention (PCI) in stable angina, leading to a downward re-equilibration of DES use (11).
Compared with BMS, DES resulted in markedly reduced neointima formation but also in delayed endothelialization, more inflammation, hypersensitivity, thrombus formation, and outward remodeling, which might prolong the window of vulnerability to stent thrombosis (12). With increasing concern about late stent thrombosis, the FDA along with the American Heart Association/American College of Cardiology (AHA/ACC) and recently updated PCI guidelines (13) have empirically suggested at least 1 year of clopidogrel in patients not at high risk for bleeding, making this a Class I, Level of Evidence: B indication. Clopidogrel use beyond 1 year was designated a Class IIb, Level of Evidence: C indication.
In this issue of the Journal, Brar et al. (14) provide valuable information regarding the duration of clopidogrel therapy after DES. They evaluated a consecutive series of 749 diabetic patients for 18 months who underwent first-time PCI with either DES or BMS at a pre-paid system with near complete access to the number of clopidogrel prescriptions filled, dose, and number of pills dispensed. Increased duration of clopidogrel use was associated with a significantly lower incidence of death and MI (3.2%, 9.4%, and 16.5% for clopidogrel duration >9 months, 6 to 9 months, and <6 months, respectively) in both the DES and BMS groups. Furthermore, this finding persisted even when data in the first 6 months were censored, consistent with a durable effect. In a secondary analysis, the incidence of death and MI did not differ by stent type, but this analysis is likely underpowered. This study also lacks data on nondiabetic patients, and this system of health care delivery is not representative of that for most patients who are receiving DES in the U.S. Nonetheless, it provides important data in a patient subgroup that is at highest risk of stent thrombosis, restenosis, progression of atherosclerosis, and new thrombotic events (15).
These data are consistent with and extend the findings of Eisenstein et al. (16), who also showed that extended clopidogrel use was associated with lower adjusted rates of death and MI. In that study, adjudication of clopidogrel use was less reliable, because it was based on patient self-report and the incidence and outcomes in diabetic patients was not reported. These 2 studies in composite provide reassuring data that extended clopidogrel use is associated with improved outcomes and substantiate the AHA/ACC recommendation for 1 year of clopidogrel in patients receiving DES. Both of these studies are limited by the observational nature, the presence of several important baseline differences in groups, lack of reporting on rates of major bleeding, and undeniable physician selection bias in choosing the duration of clopidogrel. Therefore, these findings need to be validated in randomized clinical trials.
The initial reports of increased death and MI in DES registries have recently been counterbalanced by several new analyses (Ontario, Massachusetts, and New York registries) showing at least similar if not better overall clinical outcomes of DES versus BMS with continued reduction in TVR (17). Furthermore, the initial worse outcomes in patients receiving DES in the SCAAR registry have not been confirmed in longer-term follow-up. Finally, data from a Medicare database of over 75,000 patients suggest a mortality benefit of DES compared with BMS (18). The reasons for these disparate results are not yet clear but might reflect better patient selection, increased use of BMS in patients who cannot sustain prolonged clopidogrel treatment, and increasing duration of clopidogrel therapy. However, it is evident that significant improvements must be made in reducing restenosis in a safer manner and in a manner that does not hold patients and physicians captive to long-term thienopyridine use. These include newer generation of stents with low risk of thrombogenesis, novel pharmacologic therapies, and identification of factors mediating platelet resistance, particularly in diabetic patients (19). The continued evolution of thienopyridine therapy for stent thrombosis has reached a crescendo of "treat as long as the patient can tolerate it," and it will likely change again as new data are published, particularly with evolving data on the risk of bleeding with long-term thienopyridine use. In the meantime, in patients who have already received DES and who are not at high risk of bleeding, it seems prudent to continue dual antiplatelet therapy indefinitely until new data emerge demonstrating otherwise.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy Lancet 2004;364:1519-1521.[CrossRef][Web of Science][Medline]2. 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;48:2584-2591.[Abstract/Free Full Text] 3. Lagerqvist B, James SK, Stenestrand U, Lindback J, Nilsson T, Wallentin L. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[CrossRef][Medline] 4. Jensen LO, Maeng M, Kaltoft A, et al. Stent thrombosis, myocardial infarction, and death after drug-eluting and bare-metal stent coronary interventions J Am Coll Cardiol 2007;50:463-470.[Abstract/Free Full Text] 5. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents JAMA 2005;293:2126-2130.[Abstract/Free Full Text] 6. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment Circulation 2007;116:745-754.[Abstract/Free Full Text] 7. Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off-label and untested use of drug-eluting stents JAMA 2007;297:1992-2000.[Abstract/Free Full Text] 8. Mauri L, Hsieh WH, Massaro JM, Ho KKL, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents N Engl J Med 2007;356:1020-1029.[CrossRef][Medline] 9. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation Circulation 2007;115:2842-2847.[Abstract/Free Full Text] 10. 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 J Am Coll Cardiol 2007;49:734-739.[Abstract/Free Full Text] 11. Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and consequences of the COURAGE trial J Am Coll Cardiol 2007;50:1598-1603.[Abstract/Free Full Text] 12. 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;48:193-202.[Abstract/Free Full Text] 13. King III SB, Smith Jr. SC, Hirshfeld Jr. JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (2007 Writing Group to Review New Evidence and Update the 2005 ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention) J Am Coll Cardiol 2008;51:172-209.[Free Full Text] 14. Brar SS, Kim J, Brar SK, et al. Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions J Am Coll Cardiol 2008;51:2220-2227.[Abstract/Free Full Text] 15. Machecourt J, Danchin N, Lablanche JM, et al. Risk factors for stent thrombosis after implantation of sirolimus-eluting stents in diabetic and nondiabetic patients: The EVASTENT matched-cohort registry J Am Coll Cardiol 2007;50:501-508.[Abstract/Free Full Text] 16. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation JAMA 2007;297:159-168.[Abstract/Free Full Text] 17. Tu JV, Bowen J, Chiu M, et al. Effectiveness and safety of drug-eluting stents in Ontario N Engl J Med 2007;357:1393-1402.[CrossRef][Web of Science][Medline] 18. Groeneveld PW, Matta MA, Greenhut AP, Yanf F. Drug-eluting compared with bare-metal coronary stents among elderly patients J Am Coll Cardiol 2008;51:2017-2024.[Abstract/Free Full Text] 19. Angiolillo DJ, Bernardo E, Sabate M, et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease J Am Coll Cardiol 2007;50:1541-1547.[Abstract/Free Full Text]
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