<br />
Drug-Eluting Stents: Current Outcomes <br />
and Potential Impact on Coronary Disease Management<br />
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Introduction. Coronary intervention has made remarkable advances over the past 25 years. Technical advancements have markedly improved immediate procedure safety and success. With the advent of drug-eluting stents, opportunities for even greater long-term success appears to be a reality. The major remaining obstacles to wider application of percutaneous revascularization are special complex anatomic and patient subsets including total occlusions, bifurcation lesions and diabetes mellitus, as well as the need for further reduction in restenosis. To date, stents have contributed to a decrease in restenosis, and thus have contributed to more competitive outcomes compared to coronary bypass surgery as demonstrated in the ARTS and SoS Trials.2 These trials demonstrate no survival differences with a lower rate of late revasculariation for coronary intervention compared to bypass surgery than was demonstrated in prior balloon angioplasty trials. Thus, differences between coronary intervention and bypass surgery have narrowed in the stent area. For improvements in coronary intervention to occur, a further reduction in restenosis is necessary, particularly in subgroups such as diabetics. As late outcomes improve for intervention, the need for additional revascularization procedures may continue to grow significantly. For example, in higher risk patients, perhaps some of whom are not good surgical candidates, there is under of use all treatments including revascularization. This was recently reported from the National Registry for Myocardial Infarction (NRMI) II data.3 In that report, patients with acute myocardial infarction complicated by congestive heart failure received less appropriate medical therapy, one-half the primary and elective percutaneous coronary intervention (PCI) with 3 times greater mortality than patients without congestive heart failure. Thus, improvement in percutaneous interventional outcomes will not only make interventional therapy more competitive to bypass surgery but perhaps more applicable to higher risk subgroups. Thus, the impact of lower restenosis and improved clinical outcomes has the potential to markedly impact patient management and coronary disease outcome. However, achieving that goal will require not only a reduction in restenosis, but continued application of adjunctive medical management such as glycoprotein (GP) IIb/IIIa antagonists in high-risk populations. Drug-eluting stents have shown striking promise in reducing restenosis. The following summary discusses mechanisms as well as current and future issues of drug-eluting stents in the further prevention of restenosis. Restenosis. Restenosis post-balloon angioplasty is the result of multiple factors (Table 1), but post-stent is primarily secondary to proliferation. Proliferation is actually increased following stenting, compared to balloon angioplasty alone. Recoil and remodeling following balloon angioplasty have been essentially eliminated by the mechanical stability provided by stents. Over the years, multiple drug treatments have been administered systemically without a definitive effect on restenosis. Factors contributing to drug failure include limited local drug levels (to avoid systemic toxicity), as well as the fact that any pharmacological effect on proliferation during the balloon era may have been unrecognizable because of the more potent mechanical effects of recoil and remodeling. Thus, the evolution of drug-eluting stents with the ability to locally deliver high doses of a drug is an exceptional opportunity. Drug-eluting stents. Drug-eluting stents deliver potentially high doses of drugs locally for variable time periods in the area of stent implantation directed at the potential restenosis site. While this is currently achievable, optimal pharmacological therapy is still evolving. Proliferation, the prime cause of restenosis in the stent error, is the result of a local injury response modulated by platelet and fibrinolytic effects, inflammation as well vascular (endothelial) healing. Choosing the optimal drug(s) and doses for stent delivery will require testing to optimally prevent proliferation while enhancing healing. The time course of drug delivery is also important. Finally, potential complications must be evaluated. These include subacute thrombosis, delayed proliferation with resultant later restenosis than currently seen, aneurysm formation and/or consequences of malapposition of the stent to the vessel wall. Table 1. Vascular mechanisms of restenosis. • Remodeling • Recoil • Proliferation Note: Remodeling and Recoil are predominantly related to balloon angioplasty, while proliferation occurs in both balloon and stent mediated restenosis, but is significantly augmented and the major factor in restenosis after stenting. Table 2. Partial list of potential local delivery drugs. • Sirolimus • Paclitaxel • Taxane • Batimastat • Dexamethasome • Tacrolimus • Actimomycin D • C-myc Antisense • Beta-Estradiol Table 3. Stages of cell replication. G0: Cell inactive G1: Cell makes new proteins and begins to enlarge S: DNA replication G2: Cell begins to divide M: (Mitosis) cell divides Multiple agents have, and are still undergoing investigation for local stent drug delivery. Table 2 summarizes these agents. These agents encompass several major pharmacologic categories, but the drugs currently closest to FDA approval involve antineoplastic or antiproliferative agents. Prior systemic uses of many of these agents include tumor suppression, treatment of transplant rejection, or inflammation. More novel agents include genetic modulation of proliferation using antisense as a decoy in protein synthesis. Current significantly evaluated clinical agents affect different stages of cell replication (Table 3). For example, sirolimus is an immunosuppressive macrolide antibiotic which blocks the G1S cellular phase of cell replication. In contrast, paclitaxel (Taxol) is an anti-microtubular agent with antineoplastic properties. Mechanistically, it produces an inhibition of cellular replication at the G0/G1 and G1/M phases. This impairment results in an in vitro decrease in smooth muscle migration and proliferation. Each of these agents has a specific and unique impact on 1 or more stages of cell replication and migration. Thus, significant potential exists for varying responses and outcome. These are potentially modulated further by the timing and local dose of a drug, both acutely and over the ensuing initial month after delivery. Further affecting the properties of drug-eluting stents is the method of attachment of the drug to the stent. In Paclitaxel, this can be accomplished directly to the bare metal stent. In contrast, sirolimus is attached to the stent via a local polymer coating. Sirolimus is mixed with a non-erodable polymer and then layered on the surface of a stainless steel, balloon-expandable BX Velocity™ stent (Cordis Corporation, Miami Lakes, Florida). The sirolimus dose on the metal surface is 140 microgram/sq. cm. A second polymer layer is applied as a perfusion barrier, prolonging release. Based on this and other studies, approximately 80% of the drug is eluted from the stent over 30 days. The potential of such coatings is significant as they deliver the drug to the outer aspects of the stent. Also, polymers may be designed to time drug release for early, high dose or more prolonged or potentially even pulsed release. However, the characteristics of the coating may also impact restenosis. Thus, after the drug is released, but before complete healing has occurred, there is the potential that these coatings may affect restenosis or local thrombus. For example, phosphorylcholine is a biologically inert coating that is non-thrombotic and may provide a useful platform for a variety of pharmacological agents. Thus, the science of drug elution is rapidly expanding. Related technology offers a remarkable potential for modulating local drug delivery aimed at optimally retarding proliferation while inducing healing. Clinical results. The largest body of data available on the clinical effect of drug-eluting stents involves the sirolimus (Rapamycin) drug-coated stent. In the RAVEL study,4 a total of 120 patients were randomly assigned to receive a sirolimus-eluting stent (described above) or a standard, uncoated stainless steel stent. Baseline characteristics were similar between both groups. Lesions tended to be B1 or B2 according to the ACC-AHA Lesion guidelines. At 6 months, there was a striking reduction in the late loss for the treated stents compared to the plain metal ones. In terms of binary restenosis, the rate was 0% for the Sirolimus group versus 41.7% (p = 0.0002) for the control group. Within the diabetic subgroup, there was significant retardation of late loss, although this population was small. Significant complications were not seen in the treated group compared to the control group. There was no in-stent thrombosis. Also, data from 1-year follow-up demonstrated a persistent lack of restenosis. The extent of coronary disease and the complexity of lesions was relatively limited in the RAVEL Trial. In contrast, the SIRIUS Trial presented at the 2002 TCT meeting was a much larger randomized trial from the United States, incorporating what has been described as a “sicker”, more “real world” population. The SIRIUS Trial was an 1,100-patient trial randomizing patients to either a sirolimus-coated stent or a standard stainless-steel stent. The primary endpoints were target vessel failure, cardiac death, MI or total vessel revascularization at 9 months. In addition, there was an 850-patient, eight-month angiographic substudy. In this trial, the binary in-stent restenosis rates were 3.2% versus a 35.4% restenosis rate in the control group (p Future directions. Multiple drugs and stent coatings will no doubt become available, including consideration for biodegradable stents. The effect of such “designer” stents, in conjunction with other agents, is yet to be determined. In addition, there is still the question of whether or not similar drug therapy might be administered orally with a lower risk of overall restenosis, particularly related to edge restenosis. To that end, a recent animal study using everolimus by Farb et al. demonstrated that a low oral dose in animals was associated with excellent 30-day healing of stent associated injury. The preliminary ORBIT trial was presented by Waksman et al. at the European Society meeting in 2002. In the trial, the preliminary results from a low-dose rapamycin cohort resulted in reasonable patient tolerance and only modest restenosis. The numbers are small, but one possibility may be that adjunctive low-dose oral therapy may enhance the results of local drug delivery. Practical application of drug-eluting stents. As these stents become available, multiple issues have to be addressed. The first is cost, which has at least been initially addressed by the Medicare approval of an increased DRG value taking effect April 1, 2003, for drug-eluting stents. Issues regarding the cost of multiple stents are yet to be resolved. However, if the outcome for these stents persists as preliminary data suggests, based on the evolution of prior technology over time, drug-eluting stents will unquestionably become the standard of use. Given that occurs, and given that the restenosis rate has been significantly reduced, the approach to coronary intervention will markedly shift, with greater use of coronary intervention in high-risk patients as a competitor to bypass surgery. It is important to emphasis that lower restenosis will increase interventional use in higher risk populations. Thus, a changing patient population with increased acuity will require greater use of adjunctive treatment management to optimize results. All of the adjunctive medical therapies that have markedly enhanced the outcome of patients with acute coronary syndromes and acute MI angioplasties over the last several years will continue to be required. The value of these agents is additive to any reduced rate of restenosis, as they optimize the acute and subacute results. In summary, the drug-eluting stents are extremely promising, both in terms of improving outcome for patients, as well as for advancing the field of interventional cardiology. While providing outcome improvement, optimal results are achievable for the reduction of restenosis, but continued development will be needed along with continued utilization of adjunctive pharmacology.

1. Pugh PJ, O’Toole L, Channer KS, et al. Coronary artery bypass surgery versus stenting for multivessel disease. N Engl J Med 2002;345:1641–1643. 2. SoS Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implementation in patients with multivessel coronary artery disease. The Stent or Surgery Trial: A randomized controlled trial. Lancet 2002;360:965–970. 3. Wu AH, Parsons L, Every NR, et. al. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction. J Am Coll Cardiol 2002;40:1389–1394. 4. Morice MC, Serruys PW, Sousa JE, et al., for the RAVEL Study group. A randomized comparison of Sirolimul-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 5. Farb A, John M, Acambado E, et al. Oral everolimus inhibits in-stent neo-intimal growth. Circulation (online) 2002.