US Pharm. 2012;37(2):HS-4-HS-7.
Percutaneous coronary intervention (PCI) involves both nonstent and stent procedures. While bare-metal stents (BMS) are still utilized, drug-eluting stents (DES) now offer clinicians the ability to prevent restenosis via a different mechanism. BMS prevent restenosis by attenuating arterial recoil and contraction, which was observed with balloon angioplasty. DES supply an antiproliferative drug to the target lesion that inhibits excessive growth of neointima. DES consist of a standard metallic stent, a polymer coating, and an antirestenotic drug that is mixed within the polymer and released over time. First-generation DES include sirolimus-eluting stents (SES; 2003) and paclitaxel-eluting stents (PES; 2004) (TABLE 1). Second-generation DES, including zotarolimus- and everolimus-eluting stents (ZES, EES), were approved for use in the United States in 2008 (TABLE 1). Although the underlying principle of DES remains constant, each type may offer variations with respect to deliverability (ease of placement), efficacy (preventing restenosis), and safety (thrombosis rates). The use of dual antiplatelet therapy (DAPT) with stents has significantly improved outcomes in patients undergoing PCI.
SES and PES revolutionized rates of restenosis after cardiac procedures. These stents were developed to prevent the proliferation of smooth-muscle cells and other cell types seen with restenosis. The FDA approved SES and PES for use in patients with newly diagnosed, previously untreated single lesions <28 mm to 30 mm in length and a vessel diameter between 2.5 mm and 3.75 mm.
Sirolimus is a macrocytic triene antibiotic that has immunosuppressive and antiproliferative properties and elutes slowly over 4 to 6 weeks.1 The efficacy of SES in preventing restenosis was demonstrated in the RAVEL, SIRIUS, and SCANDSTENT trials and the RESEARCH registry.2-8 RAVEL and SIRIUS, which compared SES with BMS, included stented patients with stable or unstable angina who received DAPT for 6 to 9 months. In the trials, there was a significant reduction of in-stent restenosis, late lumen loss, and target lesion revascularization (TLR) over 1 to 5 years.2-6 In all trials, there was no difference in rates of death or myocardial infarction (MI).7,8
Paclitaxel, an antineoplastic, works by disrupting the function of the microtubules responsible for proper chromosome segregation during cell division, and it is released bimodally over a 2-week period.9 The efficacy of PES was demonstrated in the TAXUS II and TAXUS IV trials, which examined patients with low-risk lesions or previously untreated coronary stenosis who randomly received BMS or PES with either a slow or a moderate drug-release rate. All trials resulted in reduction of in-stent restenosis and TLR.10-12 Furthermore, TAXUS IV demonstrated that these benefits were maintained in subgroups, including patients with vessels <2.5 mm in diameter, those with lesions >20 mm in length, and those with renal insufficiency or diabetes.13 Pooled and long-term analysis also revealed a reduction in cardiovascular (CV) events.14,15 The newest member of the PES series is the TAXUS Liberté, which has thinner struts to improve deliverability and was shown to be noninferior to its prototype in the TAXUS ATLAS trial.16
PES and SES were compared in several clinical trials, most of which concluded that SES were associated with lower rates of clinical restenosis and late lumen loss.17-22 The superiority of SES may be due to differences in mechanism of action, timing of drug delivery, and cellular inflammatory response for SES and PES at sites of overlapping stents.23,24
The newer stents, EES and ZES, are thinner and more flexible and have a cobalt-chromium alloy platform, which makes them more deliverable than the first-generation stents. These stents may also be more biocompatible, thereby generating less inflammatory response and faster vessel endothelialization.
Everolimus, a sirolimus derivative, is a semisynthetic, lipophilic, highly absorbable macrolide immunosuppressant.25 Everolimus elutes over time, with 80% absorbed within the first month and the remainder eluting over a 4-month period.25 EES demonstrated efficacy over BMS in the SPIRIT FIRST trial, with significantly lower in-stent late lumen loss at 6 months.26 EES’ superior performance relative to PES was further shown in a meta-analysis of four trials in which EES reduced the risk of stent thrombosis, MI, ischemic TLR, and death.27 In the SPIRIT II–IV trials, EES and PES were compared in patients with simple and complex coronary disease. EES use resulted in significantly lower rates of in-stent late loss and target-lesion failure (defined by cardiac death, target-vessel MI, ischemic TLR) up to 2 years later.28-33 Although no randomized trials have compared EES and SES, the X-SEARCH registry was used to evaluate the efficacy and safety of EES in higher-risk patients. EES were compared in three historical groups of patients who received BMS, SES, or PES. At 6 months, EES had a significantly lower rate of TLR, compared with BMS, and rates comparable to those with SES and PES.34
Zotarolimus, also a sirolimus derivative, is a lipophilic immunosuppressant. The polymer used in ZES mimics the cell membrane’s phospholipid phosphorylcholine. Ninety-five percent of zotarolimus elutes within the first 2 weeks.35 The efficacy of ZES has been examined in the ENDEAVOR trials. In ENDEAVOR I and II, which compared ZES with BMS, TLR was lower with ZES at up to 2 years.36,37 In ENDEAVOR III and IV, which compared ZES with SES and PES, respectively, angiographic in-segment late lumen loss—a surrogate for restenosis—was higher in the ZES group versus the SES group.38,39 Compared with PES, however, ZES was noninferior for the primary endpoint of target-vessel failure.38,39 The SORT-OUT III trial showed similar results in the primary composite endpoint of cardiac death, MI, and TLR, which occurred significantly more often with ZES than with SES.40 The ZEST trial, which compared ZES, SES, and PES, found no difference in the primary composite endpoint of death, MI, and TLR.41
In a recent trial assessing EES and ZES in complex clinical or lesion characteristics (renal insufficiency, low ejection fraction, recent acute MI, multiple or long bifurcations, bypass grafts, in-stent restenosis, unprotected left main artery, thrombus, or total occlusion), there was no difference in the primary endpoint of target-vessel failure.42,43
Antiplatelet Therapy With Stents
Coronary rethrombosis and coronary restenosis are sequelae of stent placement. Coronary rethrombosis is defined as reocclusion of coronary vessels by thrombin formation, and coronary restenosis is reocclusion of coronary vessels and smooth-muscle endothelial overgrowth.44 These sequelae can lead to devastating events such as MI and death. DES are associated with a reduced risk of restenosis but an increased risk of rethrombosis, specifically with early discontinuation of DAPT.45-48
Predictors of later DES thrombosis have been identified, including patient and angiographic characteristics. Patient characteristics consist of older age, diabetes mellitus, low cardiac ejection fraction, renal failure, and ACS. In addition, early discontinuation of antiplatelet medications has been identified as a risk factor for stent thrombosis. Angiographic characteristics such as long or overlapping stents, stent placement in small vessels, bifurcation lesions, and suboptimal stent results also increase the risk of DES thrombosis.49
The American College of Clinical Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Intervention (ACCF/AHA/SCAI) guideline for PCI, updated in 2011, includes new recommendations for the prevention of stent thrombosis.50 The guideline stresses that PCI with coronary stenting (BMS or DES) should not be performed if the patient is unlikely to tolerate and comply with DAPT for the appropriate treatment duration based on the type of stent implanted.50,51
Antiplatelet Therapy Prior to PCI: Prior to undergoing PCI, patients currently receiving daily aspirin therapy should take 81 mg to 325 mg; those not currently receiving aspirin therapy should be given nonenteric aspirin 325 mg. In addition, a second antiplatelet agent or DAPT is warranted. Patients undergoing PCI with stenting should receive a loading dose of a P2Y12 receptor inhibitor. Options include clopidogrel 600 mg (ACS and non-ACS patients), prasugrel 60 mg (ACS patients), and ticagrelor 180 mg (ACS patients). The loading dose of clopidogrel for patients undergoing PCI after fibrinolytic therapy should be 300 mg <24 hours and 600 mg >24 hours after receiving fibrinolytic therapy.52,53
Antiplatelet Therapy Following PCI: After PCI, the use of aspirin 81 mg should be continued indefinitely. Duration of and agent choice for P2Y12 inhibitor therapy after stent implantation vary according to the indication. In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 inhibitor therapy should be administered for >12 months. Options include clopidogrel 75 mg daily, prasugrel 10 mg daily, and ticagrelor 90 mg twice daily. In patients receiving DES for a non-ACS indication who are not at high risk for bleeding, clopidogrel 75 mg daily should be given for >12 months. Patients receiving BMS for a non-ACS indication should receive clopidogrel for a minimum of 1 month, and ideally up to 12 months (unless patient is at increased risk for bleeding, in which case it should be given for a minimum of 2 weeks). The continuation of clopidogrel, prasugrel, or ticagrelor beyond 12 months may be considered in patients undergoing DES placement.52,53
The guideline states that the daily use of aspirin 81 mg is preferable to higher maintenance doses. If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (<12 months) of P2Y12 inhibitor therapy is reasonable.
Prasugrel should not be administered to patients with a prior history of stroke or transient ischemic attack. In patients aged >75 years, prasugrel generally is not recommended because of the increased risk of fatal and intracranial bleeding and the uncertain benefit. Additional risk factors for bleeding include body weight <60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding, such as warfarin, heparin, fibrinolytic therapy, and chronic nonsteroidal anti-inflammatory drugs. On a 10-mg once-daily maintenance dose, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding. Consideration should be given to lowering the maintenance dose to 5 mg in patients weighing <60 kg.54-56
Antiplatelet Therapy Failure
Clopidogrel Resistance: The effectiveness of clopidogrel is dependent upon its activation to an active metabolite by the cytochrome. In patients who are CYP2C19 poor metabolizers, clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function. Patients with ACS who are poor metabolizers or those undergoing PCI who are treated with clopidogrel may be at higher risk for a CV event than patients with normal CYP2C19 function. The FDA issued a warning concerning genetic differences in the metabolism of clopidogrel and its effectiveness. The warning addressed ways to test for these genetic differences and offered advice concerning alternative dosing strategies or the use of other medications in poor metabolizers (CYP450 system, mainly CYP2C19) of clopidogrel.57
Another concern is clopidogrel’s potential interaction with proton pump inhibitors (PPIs). PPIs may reduce clopidogrel’s efficacy, but the clinical significance is not known.55 In 2009, the FDA issued a warning recommending that the use of clopidogrel in combination with PPIs and other drugs, including cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine, be avoided.58
The 2011 ACCF/AHA/SCAI guideline for PCI states that it is reasonable to use PPIs in patients receiving DAPT who are at increased risk for gastrointestinal (GI) bleeding, although the routine use of PPIs should not be recommended for patients at low risk for GI bleeding.51 It adds that the routine clinical use of genetic testing to screen clopidogrel-treated patients who are undergoing PCI is not recommended. Genetic testing may be considered to determine whether a patient at high risk for poor clinical outcomes is predisposed to inadequate platelet inhibition with clopidogrel. When a patient is identified by genetic testing, treatment with an alternative P2Y12 inhibitor, such as prasugrel or ticagrelor, may be considered. Furthermore, platelet-function testing may be considered in patients at high risk for poor clinical outcomes.
Adherence to Antiplatelet Therapy: The AHA, American College of Cardiology, SCAI, American College of Surgeons, and American Dental Association addressed adherence to DAPT in an advisory released in 2007. A number of factors for premature discontinuation of antiplatelet agents were highlighted, including older age, lower educational level, being unmarried, lack of discharge instructions for medication use, lack of referral to cardiac rehabilitation, preexisting CV disease, anemia, and lack of health care due to cost.59 The high cost of antiplatelets was identified as prohibitive to adherence in some patients.60 Additionally, the FDA’s advisory recommends postponing elective surgery for 1 year and, if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients.60
Role of the Pharmacist
FDA advisories stress the importance of carrying out 12 months of DAPT after DES placement and advise educating the patient and health care providers about the hazards of premature discontinuation. The role of the pharmacist is to encourage patients to continue therapy through education and to promote the use of adherence programs provided through the pharmacy.
Acknowledgment: William Yu, PharmD, created Table 1.
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