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Acute coronary syndromes (ACS) are a set of ischemic cardiac conditions caused by stenosed coronary arteries, including unstable angina and myocardial infarctions (Table 1). Recently, controversy surrounding the advantages and disadvantages of drug-eluting stents (DES), compared with bare-metal stents (BMS), in ACS has filled the editorial pages of clinical journals.1-4
Stents reduce the risk of restenosis after percutaneous coronary interventions (PCI; previously called angioplasty, percutaneous transluminal coronary, or balloon angioplasty). Therefore, stent placement has replaced balloon angioplasty as the treatment of choice.5 Although both types of stents, drug-eluting or not, can reduce restenosis risk and subsequent revascularization, DES prevent restenosis more effectively. DES have reduced the occurrence of repeat revascularization procedures by 50% to 75%.6,7 Consequently, since their introduction to the US market in 2003 and 2004, DES have captured the lion?s share of the coronary intervention market (78%).8
BMS and DES are small metal devices that hold stenosed arteries open after PCI. Unlike BMS, which do not release medicine at the site of placement, DES release agents that inhibit smooth muscle cell proliferation and migration, directly inhibiting the sequence of events that results in restenosis. Cordis? Cypher releases sirolimus, an immune-suppressing agent, and Boston Scientific?s Taxus releases paclitaxel, an antineoplastic agent that inhibits cell mitosis. Both agents are highly lipophilic and are maintained in the artery wall long after the drug is completely released.9 Clinical trials and postmarket evaluation studies have shown that DES reduce restenosis and the need for revascularization, compared with BMS, for as long as 4 years.6,7
What Is the Controversy?
A relatively uncommon adverse event, stent thrombosis, occurs in about 0.6% of patients per year.6 Stent thrombosis is the formation of a clot at the site of stent placement. When it occurs, it may occlude the artery and cause death in as many as 45% of patients.10 Stent thrombosis usually occurs early (within 30 days of stent placement) or late (more than 1 year after stent placement).
When the FDA first approved DES on the basis of 9-month clinical trials, the risk of stent thrombosis did not appear to be increased, compared with the risk with BMS.6,7 Recent postmarket surveillance studies, however, suggest that the risk of late stent thrombosis with DES is increased, compared with that of BMS.6 In fact, after 4 years, patients with DES have similar death rates, compared with patients with BMS, despite DES? superior ability to prevent restenosis over the entire 4 years.6
Late Stent Thrombosis Causes
One proposed mechanism for the increased late stent thrombosis with DES is that the sirolimus or paclitaxel prevents the DES from becoming endothelialized, or covered with endothelial cells, soon after placement.11 BMS becomes encased in endothelial tissue within a month of placement.5 It is currently unclear when and if endothelialization ever occurs with DES. Nonendothelialized stents? greater direct contact with blood may increase the risk of clot formation. So, whereas the risk of stent thrombosis with BMS decreases after 30 days, the risk remains high with DES.
Identifying Higher Risk
Any patient who receives a DES instead of a BMS is at a higher risk for late stent thrombosis (albeit at a lower risk for restenosis). Among patients who receive DES, however, 2 types of patients have a much higher risk: (1) patients who receive DES for so-called off-label indications, and (2) patients who discontinue dual antiplatelet therapy prematurely.
The first risk factor, off-label use of DES, is relatively common?occurring in as many as 60% of patients receiving them.12 The FDA-approved criteria for DES use include only the types of lesions that were studied in clinical trials: new coronary artery lesions no longer than 28 to 30 mm.13,14 Yet, as many as 50% to 60% of patients receive DES for multiple lesions or lesions longer than 36 mm?in addition to other characteristics that complicate their disease and that were not studied in clinical trials.12 Recent studies have shown that patients with off-label indications have more than double the risk of early and late stent thrombosis, compared with patients with less complex disease.12
The other substantial risk factor is early discontinuation of thienopyridine therapy (ie, the use of ticlopidine or clopidogrel). More than 16% of patients discontinue thienopyridines less than 1 month after DES placement.15 Recent analyses indicate that 29% of patients who discontinue thienopyridine therapy prematurely experience stent thrombosis, and early discontinuers have 9 times the risk of death in the first year following stent placement.15,16 The College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons, the American Dental Association, and the American College of Physicians outline some steps that health care professionals should take to minimize early discontinuation of thienopyridine therapy (Table 2).16
Summary and Conclusion
Stent placement for ACS can be a lifesaving intervention for many patients. Careful consideration must be given to stent selection and to ensuring appropriate drug therapy after the intervention. This controversy illustrates the importance of continuing to monitor patients for adverse events after market approval of drugs and devices. Additionally, the need for continued thienopyridine therapy after stent placement highlights the critical role of the pharmacist in managing patients with ACS.
1. Curfman GD, Morrissey S, Jarcho JA, Drazen JM. Drug-eluting coronary stents?promise and uncertainty. N Engl J Med. 2007;356(10):1059-1060.
2. Harrington RA, Ohman EM. The enigma of drug-eluting stents: hope, hype, humility, and advancing patient care. JAMA. 2007;297(18):2028-2030.
3. Maisel WH. Unanswered questions?drug-eluting stents and the risk of late thrombosis. N Engl J Med. 2007;356(10):981-984.
4. Spinler SA, Wilensky RL. Duration of clopidogrel therapy after placement of drug-eluting intracoronary stent. Am J Health-Syst Pharm. 2007;64:1432-1434.
5. Smith SCJ, Feldman TE, Hirschfeld JWJ, et al. 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. Circulation. 2006;113:e166-286.
6. Stone GW, Ellis SG, Cox DA, et al. Sirolimus-eluting stents versus standard stents in patients with coronary artery disease. N Engl J Med. 2004;350:221-231.
7. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323.
8. Rao SV, Shaw RE, Brindis RG, et al. Patterns and outcomes of drug-eluting coronary stent use in clinical practice. Am Heart J. 2006;152:321-326.
9. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 2007;115:1051-1058.
10. 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.
11. Joner F, 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.
12. Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents. JAMA. 2007;297(18):2001-2009.
13. Director of Device Evaluation in the Center for Devices and Radiologic Health to Mirjam van Werven 24 April 2003. Rockville, Md. Cypher sirolimus-eluting coronary stents on RAPTOR Rapid Exchange Deliver System. Available at: www.fda.gov/cdrh/pdf2/P020026A.PDF. Accessed June 9, 2007.
14. Director of Device Evaluation in the Center for Devices and Radiologic Health to Douglas E. Ferguson 4 March 2004. Rockville, Md. TAXUS Express2 paclitaxel-eluting coronary stent system. Available at: www.fda.gov/cdrh/pdf3/p030025a.pdf. Accessed June 9, 2007.
15. 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(24):2803-2809.
16. Grines CL, Bonow RO, Casey DE, Jr., 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;115(6):813-818.