More than 1 million percutaneous coronary intervention

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1 n report n Percutaneous Coronary Intervention: Assessing Coronary Vascular Risk Associated With Bare-Metal and Drug-Eluting Stents Sarah A. Spinler, PharmD, FCCP, BCPS (AQ Cardiology) Abstract Percutaneous coronary intervention (PCI) with stenting is increasingly being utilized for acute coronary syndromes (ACS), and the debate over the safety and efficacy of drug-eluting stents (DESs) versus bare-metal stents (BMSs) has intensified. The difficulty in consistently assessing stent safety is because of the widespread off-label use in patients with clinical features and coronary anatomy inconsistent with the approved use in stable patients with relatively noncomplex coronary stenosis, short-term follow-up of only 1 year in pivotal clinical trials that leads to approval, and inconsistency in the nature and duration of adjunctive antiplatelet therapy. Of concern are the high recurrence rates after the first episode of stent thrombosis, as demonstrated by the Dutch Stent Thrombosis Study. However, more recent analyses using better statistical models favor DESs versus BMSs, both for survival and repeat revascularizations. Recommendations from updated guidelines from the American College of Cardiology/American Heart Association/ Society for Cardiovascular Angiography and Interventions are summarized for oral antiplatelet therapy with DESs and BMSs in the management of ACS. For patients undergoing elective PCI, dual antiplatelet therapy with aspirin and clopidogrel is recommended for at least 4 weeks for a BMS and 12 months for a DES, with aspirin continued indefinitely. For patients with non ST-segment elevation ACS or ST-segment elevation myocardial infarction, dual antiplatelet therapy is recommended for at least 12 months. In summary, more recent data suggest that the benefits outweigh the risks of DESs compared with BMSs, and that the rate of DES placement will continue to rise. It is important that clinicians be aware of the indications for dual antiplatelet therapy and the appropriate durations of dual antiplatelet therapy in patients undergoing PCI. (Am J Manag Care. 2009;15:S42-S47) More than 1 million percutaneous coronary intervention (PCI) procedures are performed in the United States each year. Patients with significant lesions (>50%) in 1 or more coronary arteries are suitable for PCI and fall into 4 major categories 1 : 1) Elective PCI: asymptomatic ischemia or Canadian Cardiovascular Society class I or II angina (mild); 2) Urgent PCI: class III angina but no acute coronary syndromes (ACS) (symptoms limit physical activity); 3) Emergent or primary PCI for ST-segment elevation myocardial infarction (STEMI): acute thrombus obstructing a coronary artery; and 4) Non ST-segment elevation ACS with acute thrombus occluding or partially occluding coronary artery. May be urgent or emergent depending on symptoms and electrocardiogram findings or diagnosis of myocardial infarction (MI). 1 Originally, PCI was performed without stenting via balloon angioplasty in 1977 that reduced stenosis and relieved ischemic symptoms as well as decreased the frequency of major adverse cardiac events such as reinfarction and the need for urgent target vessel revascularization. 2 However, it was associated with elastic recoil and acute occlusion (leading to MI) as well as neointimal hyperplasia (leading to restenosis and rehospitalization). Introduced in 1994, and accounting for more than 70% of PCI by the late 1990s, bare-metal stents (BMSs) reduced the risk of acute closure, thrombosis, and restenosis. 3 Drug-eluting stents (DESs), containing antiproliferative agents, were introduced in 2003 and further reduced the rates of restenosis and early thrombosis to less than 1%. 3 Restenosis and Late Stent Thrombosis It is believed that the most prominent complication of BMSs placement is restenosis, Managed whereas that Care of DESs & is late thrombosis. However, Healthcare several contradictory Communications, reports have been published, LLC both in support of and against these observations. The difficulty in consistently assessing stent safety is because of the widespread off-label use in patients with clinical features and coronary anatomy inconsistent with the approved use in stable patients with relatively noncomplex S42 n n March 2009

2 Assessing Coronary Vascular Risk Associated With Bare-Metal and Drug-Eluting Stents coronary stenosis, short-term follow-up of only 1 year in pivotal clinical trials that leads to approval, and inconsistency in the nature and duration of adjunctive antiplatelet therapy. 4 Late stent thrombosis can occur months or even years after DES implantation and may result in catastrophic events with life-threatening complications. In addition, the high recurrence rates after the first episode of stent thrombosis are of major concern. 5 The Dutch Stent Thrombosis Study of recurrent stent thrombosis was a multicenter observational study of 431 patients who have experienced an initial thrombotic event after stent implantation. 5 Approximately 75% of the patients had ACS, and 60% received BMSs and 35% received DESs. The patients enrolled in this study had definite stent thrombosis, which was characterized as follows: acute stent thrombosis (<24 hours; 32%), subacute thrombosis, (1-30 days; 41%), late (30 days-1 year; 13%) or very late stent thrombosis (>1 year; 13%). 5 A high recurrence rate of 18.8% after the first episode of stent thrombosis was observed during a median follow-up of 27 months, contributing to all-cause mortality of 15.4%. The study showed that although a thrombotic event is not necessarily fatal, the population is at high risk for recurrent stent thrombosis and a high mortality rate, regardless of the type of stent used. Therapeutic Benefits and Risks Associated With BMSs and DESs The concerns regarding the safety and efficacy of DESs versus BMSs have intensified and are at the center of much recent debate. 6 Several recent studies have attempted to evaluate the relative therapeutic benefits and risks associated with BMSs and DESs. The propensity for off-label use and the inconsistency in adjunctive antiplatelet therapy have made the evaluation of relative risks and benefits more difficult, especially considering the uncommon but potentially serious complication of stent thrombosis. 7 Early analyses favored BMSs versus DESs, but more recent data and better statistical analyses increasingly favor DESs. 8 A recent analysis of 14 clinical trials comparing sirolimus-eluting stents (SESs) with BMSs (4958 patients and mean follow-up interval, months) concluded that the survival and risk of stent thrombosis were similar (risk of death: hazard ratio [HR], 1.03; 95% confidence interval [CI], ; stent thrombosis: HR, 1.09; 95% CI, ). 9 A more recent study of 7217 patients treated for acute MI found that the 2-year risk-adjusted mortality and repeat revascularization rates were significantly lower in DES-treated patients compared with those treated with BMSs, for both STEMI and non ST-segment elevation myocardial infarction (NSTEMI) (STEMI: mortality, 8.5% DESs vs 11.6% BMSs, P =.008; repeat revascularization, 10.2% DESs vs 13.9% BMSs, P =.003; NSTEMI: mortality, 12.8% DESs vs 15.6% BMSs, P =.04; repeat revascularization, 9.8% DESs vs 15.2% BMSs, P <.001). 10 Repeat revascularization is an important end point from a managed care perspective. In an observational study with 2-year follow-up, Malenka et al compared the outcomes of 38,917 Medicare patients undergoing nonemergent coronary stenting from October 2002 to March 2003 (BMS era) with 28,086 similar patients from September through December 2003 (DES era; 61.5% DESs and 38.5% BMSs). 11 Rates of repeat revascularization were significantly lower in the DES era versus the BMS era (PCI, 17.1% vs 20.0%, P <.001; coronary artery bypass graft [CABG], 2.7% vs 4.2%, P <.01), whereas the adjusted risk of 2-year mortality or STEMI was similar (HR, 0.96; 95% CI, ). The concern regarding off-label versus on-label stenting, for both DESs and BMSs, was addressed by a 2-year outcomes study of 1285 consecutive patients with the routine use of DESs and a comparable group of 1164 consecutive patients treated with BMSs. 12 In general, off-label use was associated with a higher incidence of nonfatal MI or death versus on-label use of DESs and BMSs (Figure). For either off-label or on-label use, DESs showed favorable end points compared with BMSs at 2 years with HRs for DESs versus BMSs for nonfatal MI or death (off-label: HR, 0.78, 95% CI, ; on-label: HR, 0.47, 95% CI, ), all-cause mortality (off-label: HR, 0.72, 95% CI, ; on-label: HR, 0.42, 95% CI, ), and target vessel revascularization (off-label: HR, 0.67, 95% CI, ; on-label: HR, 0.43, 95% CI, ). 12 Interestingly, no stent thrombosis was found in the on-label use of either BMSs or DESs, whereas the incidence of stent thrombosis was similar in the off-label use of both BMSs and VOL. 15, No. 2 n The American Journal of Managed Care n S43

3 Report DESs. Conversely, late stent thrombosis occurred only in off-label DES use, not in off-label BMS use. Note that there are limitations to observational studies that are nonrandomized with respect to potential confounding patient factors which may affect the risk of recurrent clinical events. In another study that analyzed data from 6551 patients in the National Heart, Lung, and Blood Institute Dynamic Registry, off-label use occurred in 54.7% of patients with BMSs and in 48.7% of patients with DESs. 13 At 1-year follow-up, significantly lower rates of death or MI were found for off-label use of DESs compared with off-label use of BMSs (7.5% vs 11.6%; P <.001), but no significant difference was found when comparing the standard use of DESs with BMSs. However, DESs were found to be superior to BMSs in lowering the rates of repeat revascularization for both standard use as well as offlabel use (standard use: 7.7% vs 13.4%, P <.001; offlabel: 12.7% vs 17.5%, P <.001). 13 It may be noted that in this study, patients in the DES group had a significantly higher prevalence of diabetes, hypertension, renal disease, and previous PCI (all P <.001). 13 Although DES studies are frequently grouped together for comparing outcomes with BMSs, considerable differences are observed in DESs containing different agents. A comparison of early (0-30 days) and late (<30 days) stent thrombosis rates between SESs and paclitaxel-eluting stents (PESs) documented a 2.9% cumulative incidence of angiographically proven stent thrombosis that occurred at 3 years, with late stent thrombosis occurring steadily during the 3-year period. 14 Similar incidence of early stent thrombosis was observed for SESs and PESs, whereas late stent thrombosis occurred more frequently in the PES group compared with the SES group (1.8% and 1.4%, respectively; P =.031). 14 Not surprisingly, ACS and diabetes at presentation were also independent predictors of stent thrombosis. Guidelines and Recommendations for Improving Coronary Vascular Outcomes Class I recommendations for PCI provided by the American College of Cardiology (ACC)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions favor DESs as an alternative to BMSs in patients with a favorable effectiveness/safety profile (Table). 15 However, prior confirmation of the ability to comply with the recommended duration of dual antiplatelet therapy (aspirin n Figure. Off-Label Versus On-Label Stenting: Kaplan-Meier Plots of Cumulative Events Up to 2 Years Nonfatal MI or Death No. at Risk Cummulative Incidence, % Off-label use vs On-label use HR: 2.53 ( ) On-label BMS On-label DES Log-rank P value < Time, days Off-label BMS Off-label DES Off-label DES Off-label BMS On-label DES On-label BMS Off-label DES vs Off-label BMS HR: 0.78 ( ) On-label DES vs On-label BMS HR: 0.47 ( ) BMS indicates bare-metal stent; DES, drug-eluting stent; HR, hazard ratio; MI, myocardial infarction. Reprinted with permission from Applegate RJ, et al. J Am Coll Cardiol. 2008;51(6): S44 n n March 2009

4 Assessing Coronary Vascular Risk Associated With Bare-Metal and Drug-Eluting Stents n Table. Key Guideline Recommendations for Improving Coronary Vascular Outcomes Post PCI (A) ACC/AHA/SCAI Updated PCI Guidelines: DES and BMS 15 Class I Recommendations A DES should be considered as an alternative to a BMS in patients for whom clinical trials indicate a favorable effectiveness/safety profile Before implanting a DES, the cardiologist should discuss with the patient the need for and duration of dual antiplatelet therapy and confirm the patient s ability to comply with the recommended therapy for DESs In patients undergoing preparation for PCI who are likely to require invasive or surgical procedures for which dual antiplatelet therapy must be interrupted during the next 12 months, consideration should be given to the use of a BMS or the performance of balloon angioplasty with provisional stent implantation Class IIb Recommendations A DES may be considered for clinical and anatomic settings in which the effectiveness/safety profile appears favorable but has not been fully confirmed by clinical trials (B) ACC/AHA/SCAI Updated PCI Guidelines: Oral Antiplatelet Therapy for Elective PCI 15 Class I Recommendations: Aspirin Patients already taking daily long-term aspirin should take mg before PCI Patients not already taking daily aspirin should be given mg of aspirin at least 2 hours and preferably 24 hours before PCI After PCI, in patients without allergy or increased risk of bleeding, aspirin mg daily should be given for at least: 1 month after BMS implantation 3 months after sirolimus-eluting stent implantation 6 months after paclitaxel-eluting stent implantation Subsequently, the recommended aspirin dose is 75 a -162 mg daily indefinitely Class I Recommendations: Clopidogrel A loading dose of clopidogrel, generally 600 mg, should be administered before or when PCI is performed In patients undergoing PCI within hours of receiving fibrinolytic therapy, a clopidogrel oral loading dose of 300 mg may be considered For all post-pci stented patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months if the patient is not at high risk of bleeding For patients receiving a BMS, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless patient is at increased risk of bleeding, then it should be given for a minimum of 2 weeks) Class IIa Recommendations: Clopidogrel and Aspirin If clopidogrel is given at the time of procedure, supplementation with Gp IIb/IIIa receptor antagonists can be beneficial For patients with an absolute contraindication to aspirin, it is reasonable to give a 300- to 600-mg loading dose of clopidogrel, administered at least 6 hours before PCI, and/or Gp IIb/IIIa antagonists at the time of PCI In patients with increased risk of bleeding, a lower dose of mg of aspirin is reasonable during the initial period after stent implantation Class IIb Recommendations: Clopidogrel and Aspirin Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement (C) ACC/AHA Updated ACS Guidelines: Aspirin and Clopidogrel 16,17 STEMI Management Class I Recommendations Aspirin mg immediately and continued indefinitely Dose reduced to 75 a -162 mg daily for long-term secondary prevention Clopidogrel 75 mg daily should be added to aspirin in patients with STEMI regardless of the reperfusion strategy Continue clopidogrel for at least 14 days If PCI performed, clopidogrel continued for BMS: minimum of 1 month and ideally up to 1 year DES: at least 1 year In patients not at high risk of bleeding Discontinue clopidogrel for 5-7 days before elective CABG surgery UA/NSTEMI Management Class I Recommendations Aspirin mg immediately and continued indefinitely Dose reduced to 75 a -162 mg daily for chronic secondary prevention Clopidogrel loading dose of mg (option of 900 mg) Daily dose 75 mg once daily continued for at least 1 month and ideally 1 year If PCI performed, clopidogrel continued for: BMS: minimum of 1 month and ideally up to 1 year DES: at least 1 year In patients not at high risk of bleeding Discontinue clopidogrel for 5-7 days before elective CABG surgery Class IIa Recommendations In patients aged <75 years who receive a fibrinolytic or no reperfusion therapy, it is reasonable to consider a 300-mg loading dose of clopidogrel Long-term clopidogrel therapy for 1 year can be considered for patients with STEMI regardless of reperfusion strategy ACC indicates American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; BMS, bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; Gp, glycoprotein; NSTEMI, non ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SCAI, Society for Cardiovascular Angiography and Interventions; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina. a Available dose in the United States is 81 mg. 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5 Report and clopidogrel) is critical for DESs, otherwise BMSs should be considered. Patients should continue their daily aspirin regimen before PCI, but patients who do not take aspirin daily should receive an initial dose of 325 mg. Post PCI, aspirin doses of 325 mg daily are recommended for a short period of time (1-6 months, depending on stent type) in patients without the risk of allergy or bleeding, followed by lower maintenance doses indefinitely (Table). For clopidogrel, a higher loading dose of 600 mg is a new recommendation, and 75 mg daily should be given for at least 1 month and ideally up to 1 year post PCI for patients not at high risk of bleeding. 15 The ACC/AHA recommendations for dual antiplatelet therapy in the management of unstable angina/nstemi are similar to those mentioned above, with a caveat that clopidogrel should be discontinued 5 to 7 days before elective CABG surgery, and dual antiplatelet therapy is indicated, regardless of PCI, ideally for 12 months. 16 For STEMI, clopidogrel 75 mg should be added to the aspirin regimen regardless of the reperfusion strategy, and clopidogrel should be continued for at least 2 weeks. 17 For STEMI, once PCI is performed, recommendations on the duration of dual antiplatelet therapy are mandated based on stent type, according to the PCI guidelines. Understanding the Risks and Benefits of Prolonged Antiplatelet Therapy Current guideline recommendations are based on clinical trial durations with an extension of clopidogrel therapy to at least 12 months in patients with DESs. Some cardiologists may elect to continue clopidogrel therapy beyond 1 year in patients with DESs to prevent late stent thrombosis in patients at low risk of bleeding. Some clinical and angiographic predictors of DES thrombosis include advanced age; chronic kidney disease; ACS; diabetes mellitus; multiple lesions; and long, overlapping, or bifurcation lesions. 18 Prevalence of late stent thrombosis may be higher in patients with MI compared with those with stable angina because of delayed vessel healing, greater strut penetration in MI with necrotic core, and greater thrombus burden. 19 Patients who discontinue thienopyridine therapy within 30 days are more likely to die within the following 11 months or be rehospitalized, but adequate data are not available regarding the benefits and risks of continuation of dual antiplatelet therapy beyond 12 months. 20 Consideration of tolerability of dual antiplatelet therapy is important in making decisions for prolonged antiplatelet therapy. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial examined the bleeding events over time. The instantaneous hazard for severe or moderate bleeding was initially higher for the clopidogrel plus aspirin group compared with the aspirin plus placebo group. 21 However, after approximately a 1-year period, there was no difference between the 2 groups, signifying that if the patients can tolerate dual antiplatelet therapy for 1 year, they are more likely to be able to safely continue prolonged therapy. Summary Intracoronary stenting has replaced balloon angioplasty as the PCI procedure of choice because of lower risk of restenosis. In summary, more recent data suggest that the benefits outweigh the risks of DESs compared with BMSs, and that the rate of DES placement will continue to rise. Pharmacists should be aware of the indications for dual antiplatelet therapy and the appropriate duration of dual antiplatelet therapy in patients undergoing PCI. Patients receiving a DES must be carefully selected to ensure long-term adherence to dual antiplatelet therapy in order to minimize the risk of late stent thrombosis. For patients undergoing PCI intracoronary stenting, dual antiplatelet therapy should be continued for at least 1 month in patients receiving a BMS during elective PCI, for 1 year in patients receiving a DES during elective PCI, for 1 year in patients with non ST-segment elevation ACS or STEMI receiving either a BMS or a DES, and possibly longer if the therapy is well tolerated. Author Affiliations: From the Department of Pharmacy Practice/Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, and the Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA. Funding Source: Financial support for this work was provided by Daiichi Sankyo, Inc and Eli Lilly and Company. Author Disclosure: Speakers bureau for Bristol-Myers Squibb and sanofi-aventis, and consultant for sanofi-aventis. Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. S46 n n March 2009

6 Assessing Coronary Vascular Risk Associated With Bare-Metal and Drug-Eluting Stents Address correspondence to: Sarah A. Spinler, PharmD, FCCP, BCPS (AQ Cardiology), Professor of Clinical Pharmacy, University of the Sciences in Philadelphia, Philadelphia College of Pharmacy, Department of Pharmacy Practice/Pharmacy Administration, 600 S 43rd St, Box GRI 108-T, Philadelphia, PA s.spinle@usip.edu. References 1. Smith SC, Feldman TE, Hirshfeld JW Jr, et al. 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(1): Grech ED. ABC of interventional cardiology: percutaneous coronary intervention. I: history and development. BMJ. 2003;326(7398): Dobesh PP, Stacy ZA, Ansara AJ, Enders JM. 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