Restenosis and Drug-Eluting Stents

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7 Restenosis and Drug-Eluting Stentsimage

Ahmad Edris, Nauman Siddiqi, Morton J. Kern

Restenosis

Restenosis is defined as vessel narrowing of a previous angioplasty site. After balloon expansion, this narrowing occurs as a result of two mechanisms, negative remodeling (vessel constriction after stretching) and reaccumulation of material within the lumen (or stent). Reaccumulation of cellular material (also known as endothelial proliferation) is initiated by vessel injury with a release of thrombogenic, vasoactive, and mitogenic factors. Endothelial and deeper injury leads to platelet aggregation, thrombus formation, inflammation, and activation of smooth muscle cells and macrophages. The production and release of growth factors and cytokines promotes further synthesis of such factors and release from the cells involved. These factors result in the migration of new smooth muscle cells from their location within the arterial media to the endovascular lumen. These cells become a synthetic type of cell that produces extracellular matrix, leading to cellular proliferation and mechanical obstruction of the vessel lumen.

The second component of restenosis, recoil and negative remodeling of the arterial wall is inhibited by stents. Compared to balloon angioplasty, stents have reduced restenosis from 40% to 50% after percutaneous transluminal coronary angioplasty (PTCA) to 20% after bare-metal stenting. Drug-eluting stents (DESs) have brought restenosis rates to <10% in most patient subgroups. Restenosis still occurs inside stents (called in-stent restenosis [ISR]) mostly, if not exclusively, as a result of endothelial cell proliferation. Rarely does vascular recoil make a contribution, but it must be considered in treating the ISR lesion. Restenosis is not device-specific but rather a function of the anatomic substrate and the type of injury produced (Fig. 7-1).

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Figure 7-1 Interventional devices and presumed mechanisms of action of arterial plaque in vessel wall lead to restenosis. The indication of immediate outcome and restenosis rates depend on both the device and the arterial substrate encountered.

(From Waller BF, Pinkerton CA, Orr CM. Restenosis 1 to 24 months after clinically successful coronary balloon angioplasty: A necropsy study of 20 patients. J Am Coll Cardiol 1991;17:58–70.)

Definitions of Restenosis

There are two types of restenosis recognized in patients, angiographic and clinical, which are not mutually exclusive.

Angiographic Restenosis

Angiographically measured luminal renarrowing after PCI has been the “gold standard” for restenosis. Angiographic restenosis is a continuous phenomenon, with no obvious threshold separating “restenosers” from “nonrestenosers.” Studies have shown that the percentage of stenosis or minimal lumen diameter has a near Gaussian (normal) distribution on follow-up angiograms after balloon angioplasty. Thus, restenosis is best measured as a continuous variable. Nevertheless, because of practicality, the most commonly used definition of restenosis employs a dichotomous value (e.g., 50% diameter narrowing).

Several different angiographic definitions of restenosis have been published with overlapping differences in some patients. Most studies define angiographic restenosis as either a greater than 50% loss of initial gain after intervention or an absolute lesion stenosis of greater that or equal to 50% at follow-up angiogram. The late loss of the acute luminal enlargement, or net gain in millimeters at the lesion site 6 months after treatment by quantitative angiography, should be around 0.7 mm for balloon angioplasty.

The late loss index is the loss at the lesion site divided by the amount of acute gain (Fig. 7-2). The loss index is accepted as the most sensitive measure of the effectiveness of the technique and should range from 0.4 to 0.6 mm for balloon angioplasty. The lower the loss index is, the more effective the antirestenosis treatment will be.

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Figure 7-2 Calculations of acute gain, late loss, and loss index.

Restenosis is both a lumen-related and a vessel wall–related phenomenon. It appears that 40% to 60% of the acute luminal gain is lost during follow-up in all patients treated, independent of the devices. A similar degree of intimal thickening (restenosis by wall measurements) may or may not cause a significant luminal narrowing (restenosis by lumen measurement). As expected, the vessel size itself exerts a significant positive influence on minimal lumen diameter at follow-up and an equally negative effect on late loss. A larger artery will have a larger lumen at follow-up and vice versa for a smaller artery. Using percentage stenosis rather than absolute lumen diameter will neutralize this effect by correcting automatically for artery size.

Intravascular ultrasound (IVUS) imaging is superior to angiography for anatomic and morphologic restenosis definitions. Recent IVUS studies have shown that an important component of restenosis is vessel recoil, a feature prevented by stenting. Normal vessel modeling maintains the coronary lumen. Late negative remodeling of the injured vessel is also prevented by stenting (Figs. 7-3 and 7-4).

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Figure 7-3 The Glagov phenomenon. According to serial intravascular ultrasound, normal segments showed proximal enlargement of the vessel as plaque volume increases. Vascular dilatation is compensated for by substantial plaque formation inside the vessel wall leaving the vessel’s angiographic appearance unchanged and normal looking.

(From Glagov S, Wisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371–1375.

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Figure 7-4 Adequacy of arterial remodeling with respect to changes in vessel size.

(From Schwartz RS. Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol 1998;81:16E.)

Clinical Restenosis

Clinical restenosis is defined as recurrent angina or anginal-equivalent symptoms after PCI. Other causes of symptoms might be mistaken for clinical restenosis, such as disease progression in the nondilated arterial segment, which occurs in 10% to 15% of cases late after PCI or new disease elsewhere. Incomplete revascularization also causes symptoms in about 10% of patients. Recurrence of typical angina after an asymptomatic period following angioplasty is a very specific clinical indicator for restenosis. On the other hand, atypical chest pain is a poor predictor. Restenosis is documented in 15% of asymptomatic cases.

Early (<1 month) exercise tests after balloon angioplasty (PTCA) were often persistently positive and failed to predict future restenosis and recurrent events. An exercise test at 6 months in patients who have not yet presented with clinical recurrence shows a modest positive predictive value. Exercise testing early after PCI is not recommended. For symptoms appearing late after PCI in which restenosis is suspected, angiography is recommended. If the angiographic restenosis severity is intermediate (40%–70%), then in-lab functional testing with fractional flow reserve can be helpful in making a decision regarding whether repeat stenting is required.

Risk Factors for Restenosis

It is not possible to predict reliably whether restenosis will occur in a given patient. A multivariate analysis found the following conditions are predictors of restenosis: severe angina, left anterior descending artery lesions, diabetes, a higher degree of residual restenosis, hypertension, absence of an intimal tear, eccentric lesion morphology, and older age.

It is difficult to obtain follow-up angiograms in all patients undergoing coronary angioplasty. Less than complete angiographic follow-up with preferential recatheterization of symptomatic patients creates bias in that symptomatic patients artificially increase the restenosis rate in that population. At the same time, asymptomatic restenosis cases will go unrecognized clinically. This approach may underestimate the actual angiographic restenosis rate. Target vessel revascularization (TVR) rate is another surrogate for angiographic restenosis rates.

Time Course

Stents prevent very early (<24 hr) restenosis due to elimination of acute elastic recoil. The incidence of restenosis increases, peaking around 6 months. Late restenosis occurs uncommonly after 12 months. Restenosis after angioplasty using non-balloon, non-stent devices alone was highly variable with a reported incidence of restenosis between 15% and 55% (see Suggested Readings).

Different mechanisms produce restenosis in a time-dependent manner. Early restenosis is due to thrombus, whereas late restenosis is related more to remodeling (Fig. 7-5).

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Figure 7-5 The four phases of vascular repair after stent-induced arterial injury in terms of time after stenting. A, Platelet-rich thrombus accumulates at areas of deep strut injury and peaks at 3 to 4 days after stent deployment, accounting for most early lumen loss. B, Coincident with thrombus deposition, inflammatory cells are recruited to the injury site, both at and between stent struts. At 3 to 7 days after stenting, the surface-adherent monocytes (SAMs) migrate into the neointima as tissue-infiltrating monocytes (TIMs) and remain in place. C, Proliferation of smooth muscle cells and monocyte macrophages within the neointima peaks at 7 days after implantation and continues above baseline levels for weeks thereafter. D, Collagen deposition in the adventitia and throughout the tunica media and neointima leads to arterial shrinkage or remodeling, causing compression of the artery on stent struts from without.

(Modified from Garasic J, Edelman E, Rogers C. Stent design and the biologic response. In Beyar R, Keren G, Leon M, Serruys PW, eds. Frontiers in interventional cardiology. London: Martin Dunitz, 1997: 95–100.)

Patient Subsets at Higher Risk of Restenosis

Diabetes Mellitus

Poor outcomes can be seen in diabetic patients undergoing percutaneous coronary intervention (PCI). In one study, angiographic follow-up at 6 months in 418 diabetic and 2672 non-diabetic patients undergoing PCI showed that restenosis occurred in 550 of 2672 (20.6%) non-diabetic and 130 of 418 (31.1%) diabetic patients (P = 0.01). Vessel caliber, stented length of vessel, and lower BMI were reported predictors of in-stent restenosis in patients with diabetes. Another study evaluated 1288 patients (263 diabetic patients [21%]) and showed that repeat revascularization of the stented lesion was performed more frequently during the first year in patients with diabetes (16% vs. 10.9%, P = 0.01). Also, cardiac death and myocardial infarction (MI) were more frequent among patients with diabetes (5-year rates, 25.4% vs. 17.9%, P = 0.008) and remained significant after adjustments were made for differences in baseline characteristics.

Chronic Renal Failure

It has been reported that patients with chronic renal failure who undergo PCI have a high restenosis rate (>30%). A study compared 40 lesions in 34 patients with end-stage renal disease (ESRD) with 80 lesions from patients without renal impairment who underwent coronary stenting. Despite comparable initial angiographic results over the 9-month follow-up period, repeat TVR was twice as frequent in the ESRD group compared with the control group (35% vs. 16%, P < 0.05). Another study evaluated the effect of moderate renal insufficiency in patients undergoing primary angioplasty for acute MI and found that significant restenosis was seen more frequently in patients with renal insufficiency compared to those with normal renal function (20.6% vs. 11.8%, P = 0.024).

Transplantation

Cardiac allograft vasculopathy (CAV) is a rapidly progressive form of atherosclerosis and is one of the main limitations to long-term survival after orthotopic heart transplantation. PCI has been used as a palliative treatment option for CAV but is associated with worse clinical outcomes and greater rate of restenosis compared with PCI of native coronary arteries. Several studies have shown that when compared with BMS, PCI with DESs was safe and reduced the rate of angiographic restenosis in patients with CAV. However, treatment of patients with CAV with DESs does not seem to alter the natural deleterious history of this disease process.

Acute Myocardial Infarction

Several randomized trials have demonstrated that PCI is superior to thrombolysis in reducing mortality, the recurrence of MI, and TVR. However, restenosis occurs in 40% to 50% of patients after initial successful angioplasty and in 20% to 30% of patients after stenting. The choice of DESs or bare-metal stents (BMSs) for STEMI PCI is based on vessel size and ability to maintain dual antiplatelet therapy over the following year.

Chronic Total Occlusion

Total occlusion has a higher restenosis rate than subtotal stenosis. The recurrence of total occlusion lesions seldom results in MI because of reformation of prior collateral protection.

A recent study, the ACROSS/TOSCA-4 trial, examined angiographic and clinical outcomes with DESs in coronary total occlusion (CTO) revascularization. Patients with CTO (n = 200) (78.8% >6 weeks CTO age) were enrolled for treatment with DESs. The primary end point was 6-month angiographic binary restenosis within the treated segment. A total of 199 patients (99.5%) were treated with DESs, and procedural success was 98.0%. The 6-month binary restenosis rates were 9.5% in-stent, 12.4% in-segment, and 22.6% in-“working length” representing the entire treatment segment. Rates of 1-year target lesion revascularization (TLR), MI, and target vessel failure were 9.8%, 1.0%, and 10.9%, respectively.

Saphenous Vein Graft Lesions

Saphenous vein graft (SVG) lesions are associated with a higher restenosis rate, particularly in the proximal anastomotic (58%) and body (52%) portions of the graft. Distal anastomotic narrowing responds to angioplasty well, especially in patients with recurrent coronary artery bypass graft surgery. The time course of restenosis in vein grafts is different than in native coronary vessels, with continued significant attrition beyond 6 months.

The long-term patency rate of the SVG has improved with advances in medical therapies but still remains suboptimal. A review of several studies evaluating SVG durability consistently shows poor graft patency and a high rate of total occlusion. One study evaluated 27,211 patients and showed a 5-year SVG patency rate (defined as less than 70% stenosis) of less than 40%.

Internal Mammary Artery Graft Lesions

The internal mammary graft anastomotic site responds very favorably to angioplasty, with a 10% to 15% or less restenosis rate. One study comparing the SVG and internal mammary artery graft showed 10-year patency rate of 57% and 90%, respectively, with patency defined as not totally occluded.

Non-Balloon Device Restenosis

Rotational Atherectomy

Rotational atherectomy has distinct mechanical advantages for calcified lesions in the native coronary circulation. The 6-month restenosis rate after percutaneous transluminal coronary rotational angioplasty (PTCRA) approximates the rates observed after standard balloon–only angioplasty. In some circumstances, the PTCRA restenosis rate exceeded the expected PTCA rate. The predisposition to restenosis after PTCRA has limited the use of stand-alone PTCRA to rare cases where stents cannot be used afterward.

In-Stent Restenosis

In-stent restenosis (ISR) is primarily due to neointimal hyperplasia produced by vessel injury of the balloon and/or stent struts. The injured segments promote activation of platelets, mural thrombus, and inflammatory cells. Vascular injury, mural thrombus, and a metallic foreign body activate circulating neutrophils and tissue macrophages. These elements release cytokines and growth factors, activating smooth muscle as well as stimulating upregulation and expression of genes promoting cell division, such as c-myc, leading to further cell proliferation. Metalloproteinases are produced, leading to increased matrix material and remodeling of the extracellular support matrix, initiating smooth muscle cell migration. Uncontrolled proliferation of vascular smooth muscles into the vessel intima and the deposition of extracellular matrix lead to significant in-stent luminal narrowing 3 to 6 months after PCI.

There are two major categories of in-stent restenosis—focal and diffuse (Fig. 7-6)—and within each category several subtypes of responses relative to the proliferation within and/or adjacent to the stent are noted. Figure 7-7 suggests a scheme for the treatment of ISR. Note that brachytherapy is now rarely used.

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Figure 7-6 Classification system proposed for in-stent restenosis (ISR).

(From Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis classification and implications for long-term outcome. Circulation 1999;100:1872–1878.)

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Figure 7-7 Algorithm for treatment of in-stent restenosis.

(Modified from Topol EJ. Textbook of interventional cardiology, 4th ed. Philadelphia: Saunders, 2003: 468.)

Stent fracture is associated with in-stent restenosis in Drug-Eluting Stents.

Lee MS et al. reviewed angiograms on 530 of 2728 patients who underwent drug-eluting stenting from 2003 to 2005. The incidence of DES fracture–related adverse events was rare and identified in 10 patients. None of these fractures was detectable at the time of stent placement. The median time from implant to fracture detection was 226 days (range, 7–620 days). Adverse stent fracture events occurred in seven patients (six patients had binary restenosis and one patient had stent thrombosis), all necessitating repeat intervention. Factors predisposing to stent fracture included excessive tortuosity in the proximal segment, and overlapping stents. In this small patient registry, all stents were sirolimus DESs.

Management of Restenosis

IVUS, Balloon Angioplasty, and Restenting

The ISR lesion may be due to underexpansion of the stent for the size of the vessel on the initial implantation or exuberant neointimal hyperplasia or a combination of these mechanisms. The treatment of ISR should begin with IVUS assessment of vessel/stent relationship. Then an appropriately sized balloon can be used to expand the stent and compress the hyperplastic tissue. A repeat IVUS is often helpful to gauge success of this maneuver. Recently, use of optical coherence tomography in patients undergoing balloon angioplasty of ISR shows tissue disruption, leading the operator to select another stent to seal this material. Although appealing to the operator, there are few data to support this routine approach at this time.

The success and complication rates are lower than for the initial procedure because the restenosis lesion is primarily fibroproliferative rather than an atherosclerotic plaque. Stenting of restenotic lesions, although easily performed, may not resolve the problem long term since outcomes after multiple overlapping stents may predisposed to higher subacute thrombosis rates.

Surveillance angiography is not recommended because of the potential for false positive restenosis, that is, narrowing without significant clinical importance. Intermediately severe ISR lesions (40%–70%) should be associated with evidence of ischemia. It is appropriate to use stress testing or fractional flow reserve measurement (FFR) before treatment.

Use of intravenous ultrasound is critical to decide whether to reexpand an underdeployed stent relative to the vessel size or attack the endothelial proliferation and consider an additional stent.

Use of a cutting balloon should be considered because blades provide excellent balloon stability inside stent during inflations.

Brachytherapy

Vascular brachytherapy, using beta and gamma emitters for treating PCI-related restenosis, and especially in-stent restenosis, had demonstrated safety and marginal efficacy. Brachytherapy is not currently used for routine treatment of in-stent restenosis because of logistical complexity and complications such as late thrombosis and edge effects after radiation therapy. A full discussion of this topic can be found elsewhere.

The adverse effects of brachytherapy included the following:

• Edge effects

• Late thrombotic occlusion

• Stent vessel separation

• Long-term effects

Of all the adverse effects, late thrombosis occurring more than 30 days after radiation therapy was one of the most feared major complications of vascular brachytherapy. Late thrombosis in early clinical trials was reported in up to 14% of patients. Late thrombosis also occurs with other vascular brachytherapy and relates to the healing arrest and lack of stent re-endothelialization. An effective strategy to prevent late rethrombosis is limiting restenting at the time of radiation treatment. It is essential to administer at least 12 months of antiplatelet therapy, preferably clopidogrel in addition to aspirin, for all radiation cases, both beta and gamma emitters. Definitions of artery and stent segments address by brachytherapy are shown on Figure 7-8.

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Figure 7-8 Definition of vessel segments. A, Preprocedural in-stent stenosis in stent segments. B, Angioplasty determines the injured segments. C, After angioplasty, the radiation source is placed in the vessel.

(From Cheneau E, Wolfram R, Leborgne L, et al. Understanding and preventing the edge effect. J Interv Cardiol 2000;16:1–7.)

Drug-Eluting Stents

Compared to BMSs, DESs reduce the rate of TLR and in-stent restenosis. The components of a DES system are (1) the specific metal stent design, (2) the use and type of polymer for drug absorption, and (3) the type of antiproliferative agent and its elution kinetics.

Current DESs available in the United States include drug compounds that contain antiproliferative agents such as paclitaxel, sirolimus, everolimus, or zotarolimus (Fig. 7-9).

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Figure 7-9 Cell designs of drug-eluting stents: Cypher (top left), Taxus (top right), Xience (bottom left), Endeavor stent (bottom right).

Stent Design

Drug delivery is dependent on strut spacing, the number of struts, and the homogeneity of strut placement over the target surface. Stents were initially designed to physically scaffold arterial dissection flaps, not for drug delivery. Significant changes were made to allow for drug coating and elution. The geometry of the stent must allow a sufficient area for delivery of the agent. The drug-carrying units of the stent cells must allow a sufficient area for diffusion to deliver optimal tissue drug levels. Biodegradable stents with temporary scaffolding and drug delivery during the healing process are currently being tested.

Coating

Passive stent coatings to modify the surface characteristics of stainless steel or cobalt chromium alloy have included ceramics, noble metals, polishing, thermal plating, and biochemical mimicry with phosphorylcholine or fibrin. Polymeric materials act as drug repositories and allow for controlled drug release over time. Pharmacologic agents can be maintained in the polymer reservoir when covered by a film on or within a polymeric matrix. Drug release occurs through three mechanisms—diffusion, chemical reaction, or solvent activation. Nondegradable polymers enable drug release by particle dissolution, whereas biodegradable polymers permit drug diffusion in concert with matrix degradation. For the current generation of DESs, drug release from the polymer occurs by passive diffusion.

Drugs for Coated Stents (Fig. 7-10)

Drugs used for stent coatings to reduce neointimal proliferation should have a large therapeutic window and a low inflammatory potential, inhibit multiple mechanisms of the complex restenotic biology, and reduce smooth muscle cell proliferation without unacceptable toxicity to the medial and adventitial cell layers. Unlike radiation, local drug elution should not inhibit stent re-endothelialization. Drugs for coated stents should have favorable local pharmacokinetics and distribution properties. Hydrophilic drugs, such as heparin, permeate into tissue but are rapidly cleared. Hydrophobic agents, such as paclitaxel or sirolimus, are insoluble in the aqueous phase and bind to hydrophobic sites on the arterial wall. Both hydrophilic and hydrophobic drugs have large spatial concentration gradients across the arterial wall, with hydrophobic drugs distributing better and more homogeneously than hydrophilic agents.

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Figure 7-10 Sites of action in the cell phase for selected pharmacologic stent coating to inhibit restenosis.

Sirolimus is rapamycin, a naturally occurring macrocyclic lactone discovered in the soil of Easter Island (Rapa Nui) in the 1960s. Rapamycin is a product of fermentation of Streptomyces hygroscopicus and was used as an antifungal antibiotic. Sirolimus blocks the cell cycle of proliferating cells binding to the high-affinity cytosolic receptor protein FK506, leading to the inhibition of mammalian target of rapamycin (mTOR), which prevents downregulation of tumor suppressive cell P27. The gene p27 inhibits cell-dependent kinase activity and blocks G1- to S-phase cell cycle progression. Sirolimus is lipophilic and easily crosses the cell membrane. The inhibition of mTOR suppresses T-cell proliferation and is a powerful antiproliferative and antimigratory agent acting on smooth muscle cells. Systemic sirolimus reduces neointimal proliferation after balloon injury in porcine coronary arteries. Local sirolimus administration inhibits neointimal proliferation.

Paclitaxel is a powerful antineoplastic drug found in the Pacific yew tree (Taxus brevifolia) and is used in the treatment of malignant ovarian and breast cancer. Paclitaxel stabilizes polymerized microtubules and enhances microtubular assembly, forming unorganized and decentralized microtubules in the cytoplasm. Cell replication is inhibited predominately in the G0/G1 and G2/M phase of the cell cycle. Paclitaxel is highly lipophilic, promoting rapid uptake through hydrophobic cell membranes and minimizing systemic loss. Paclitaxel is suitable for polymer-based delivery. It has long-lasting antiproliferative effects after a single administration and can be directly applied to metal as a durable simple coating.

Everolimus is a novel semisynthetic highly lipophilic macrolide with immunosuppressant and antiproliferative properties. The chemical name is 40-O-(2-hydroxyethyl)-rapamycin and it is created by modifying rapamycin. Similar to rapamycin, inhibiting mTOR is the likely mechanism for suppression of cell proliferation. At the cellular level, it blocks growth factor–driven transduction signals in the T-cell response to alloantigen and proliferation of both hematopoietic and non-hematopoietic cells. Following stimulation of the IL-2 receptor on the activated cell, it inhibits p70 S6 kinase, thereby arresting the cell cycle in the late G1 phase. Systemic everolimus suppresses in-stent neointimal growth in the rabbit iliac artery following stenting.

Zotarolimus is also a novel semisynthetic derivative of rapamycin, which was designed to have a shorter in vivo half-life. It is a highly lipophilic immunosuppressive and antiproliferative agent. As with rapamycin and everolimus, zotarolimus inhibits mTOR, blocks growth factor–driven cell proliferation, which ultimately results in cell cycle arrest in the G1 phase.

Drug-Eluting Stent Systems

The Cypher (Cordis Corp., Bridgewater, NJ) sirolimus-eluting coronary stent system is comprised of two components: a BX Velocity coronary stent system (Cordis Corp., Bridgewater, NJ) and the sirolimus drug product. It was approved for clinical use by the U.S. Food and Drug Administration (FDA) in April 2003. It comes premounted on either an over-the-wire (OTW) or rapid exchange (RX) delivery system. The Cypher stent is comprised of 316 L stainless steel with six to seven circumferential cells. The inactive ingredients are parylene C and two non-erodible polymers: polyethylene-co-vinyl acetate (PEVA) and poly n-butyl methacrylate (PBMA). The base coat is made of a combination of the two polymers and sirolimus (67%/33%). This is then applied to the stent, which has been pretreated with parylene C. A solution of PBMA polymer is applied as a topcoat to the stent. Lastly, the drug/polymer combination solution is applied to the entire surface. The drug delivery kinetics allows for 80% of the sirolimus to be released over 30 days. The stent is available in 2.25 mm to 3.5 mm diameter sizes and 8 mm to 33 mm in length. It currently has the FDA-approved indications for improving coronary luminal diameter in patients with symptomatic ischemic heart disease due to discrete de novo lesions of 30 mm in native coronary arteries with a reference vessel diameter of 2.25 mm to 3.50 mm.

This stent is contraindicated in patients with known hypersensitivity to sirolimus, polymethacrylate, or polyolefin copolymers. It is also contraindicated in patients who are unable to take recommended antiplatelet and anticoagulant therapy.

The benefit of the Cypher stent in reducing in-stent restenosis was documented in the large, pivotal, randomized controlled trial SIRIUS and the smaller randomized supportive trial RAVEL.

The SIRIUS trial compared the Cypher stent with the control BX Velocity bare-metal stent in de novo coronary artery lesions in 1058 patients. These were considered somewhat complex patients because many were diabetics and had, on average, long lesions (14.4 mm) and small vessels (2.8 mm). Overall, 92% of patients had AHA/ACC type B1, B2, or C lesions. It examined target vessel failure at 9 months as the primary end point, which was defined as cardiac death, MI, or TVR. The Cypher stent was found to significantly lower the primary end point to 8.6% from 21% in the BMS group. This was largely driven by reduction in TLR in the Cypher arm (4% vs. 17%). Overall improvements were seen in rates of in-stent restenosis (3% vs. 35%) and late lumen loss (0.17 mm vs. 1.0 mm), which were assessed by angiography and IVUS. The lower rates of TLR persisted at 2 years (5.8% vs. 21.3%). Follow-up data reveal no significant difference in late stent thrombosis compared with BMS at 4 to 5 years (0.8% vs. 0.6%).

The RAVEL trial compared the Cypher stent with the control BX Velocity bare-metal stent in de novo coronary artery lesions in 238 patients. There was a significant reduction in the primary end point, which was late lumen loss assessed by angiography (−0.01 mm vs. + 0.80 mm in BMS) at 6 months. There was also a significant reduction in neointimal hyperplasia (2.5 mm3 vs. 37 mm3 in BMS) and the frequency of restenosis of more than 50% of the lumen diameter (0 vs. 27%). TLR at 1 year was 5.8% in the sirolimus group and 28.8% in the control group. Neointimal hyperplasia was also markedly inhibited in the sirolimus group by IVUS substudy.

The Taxus (Boston Scientific Corp., Natick, MA) paclitaxel-eluting coronary stent system is comprised of a balloon-expandable Liberté stent coated with an 8.8% slow-release formulation of paclitaxel. It is available in either the Taxus Express or Taxus Liberté versions. The Taxus Express was first approved for clinical use by the FDA in March 2004, and the Liberté was approved in October 2008. Liberté is newer, has thinner struts, and has more flexible cell geometry. Express and Liberté have similar polymers, drug delivery, and release kinetics but different stent geometry and different strut size. Both are available premounted on either an RX or OTW delivery system.

The stent itself is made of 316 L stainless steel. The Taxus system uses the inactive compound Translute, a tri-block copolymer that is made of SIBS [poly(styrene-b-isobutylene-b-styrene)]. The polymer is mixed with paclitaxel and then applied to the entire surface of the metal stent without primer or top coat. The stent is currently available in 2.25 mm to 4.0 mm diameter sizes and 8.0 mm to 32 mm (Express) or 38 mm (Liberté) in length. It currently has FDA-approved indications for improving the luminal diameter for de novo native coronary artery lesions of 2.25 mm to 4.00 mm in diameter in lesions of 28 mm in length (Express) or 34 mm (Liberté). Taxus Express has the additional indication in bare-metal stent restenotic lesions of 2.5 to 3.75 mm in diameter and 28 mm in length. It is contraindicated in patients with known hypersensitivity to paclitaxel or Translute. It is also contraindicated in patients who are unable to take recommended antiplatelet and anticoagulant therapy.

The benefit of the Taxus stent systems in reducing in-stent restenosis was evaluated in the TAXUS trials.

The TAXUS II randomized controlled trial randomly assigned 536 patients to the Taxus stent or a BMS in patients with a single primary lesion in native coronary arteries. Primary end points were percentage of in-stent net volume obstruction at 6 months as measured by IVUS. Taxus use was associated with significantly lower rates of in-stent restenosis (3.5% vs. 19.1%) and lower rates of TLR (3.9% vs. 13.3%) at 6 months. The incidence of major adverse cardiac events at 12 months was significantly reduced at 10.9% versus 22%. There was no difference in the slow- versus moderate-release formulations in the Taxus stent. Cordis currently markets only a slow-release formulation.

The TAXUS IV trial was a large randomized trial that assigned 1314 patients with a single previously untreated coronary artery stenosis to the Taxus stent or a BMS. The primary end point was the rate of ischemia-driven TVR at 9 months. Taxus use was associated with significant reductions in angiographic restenosis (8% vs. 27%), TLR (3% vs. 11%), and late lumen loss (0.39 mm vs. 0.92 mm) at 9 months. These significant benefits persisted to 1 year, with additional reductions in major adverse cardiac events (10.8% vs. 20%). The incidence of stent thrombosis at 4 years was not significantly different as compared to BMS (1.6% vs. 1.1%).

Xience V (Abbott Vascular, Santa Clara, CA) everolimus-eluting stent system is comprised of the inactive non-erodible polymer PBMA, which adheres to the stent and drug coating. It was first approved for clinical use by the FDA in July 2008. It also contains PVDF-HFP (vinylidene fluoride and hexafluoropropylene monomers) as the drug matrix layer containing everolimus. The drug matrix copolymer is mixed with everolimus (83%/17%) and applied to the entire PBMA coated stent surface without a topcoat. The stent itself is L-605 cobalt chromium alloy. The system is available premounted on either RX or OTW delivery systems. The stent is available in 2.5 mm to 4.0 mm diameter sizes and 8 mm to 28 mm in length. It is indicated in patients with symptomatic heart disease for improving coronary luminal diameter in de novo coronary artery lesions of 28 mm in length and with reference diameters of 2.5 mm to 4.2 mm.

This stent is contraindicated in patients who cannot receive recommended antiplatelet and anticoagulant therapy; in lesions where proper placement and complete balloon angioplasty is not possible; and in patients with hypersensitivity to everolimus, cobalt, chromium, nickel, tungsten, acrylic, or fluoropolymers.

The Xience stent system was studied in SPIRIT clinical trials. SPIRIT III was a randomized clinical trial involving 1002 lower risk patients which demonstrated the non-inferiority of Xience compared to Taxus Express. The primary end point was in-segment late loss at 240 days and the co-primary end point was ischemic-driven TVF (composite of cardiac death, MI, clinically driven TVR) at 270 days. Xience was found to be significantly superior to Taxus with reference to in-segment late loss (0.14 mm vs. 0.28 mm). Xience was also found to be non-inferior in TVF at 9 months (7.6% vs. 9.7%). Two-year follow-up data reveal that stent thrombosis occurred in 1% of patients in the Xience arm at 2 years, with 0.3% occurring very late (>1–2 years). Of note, Boston Scientific also markets the Xience stent under its trade name Promus.

Endeavor (Medtronic Vascular, Santa Rosa, CA) zotarolimus-eluting stent system is comprised of a thin strut, low profile, cobalt chromium alloy Driver (Medtronic Vascular, Santa Rosa, CA) stent, phosphorylcholine polymer, and zotarolimus. It was first approved for clinical use by the FDA in July 2008. The polymer used is a hydrophilic biomimetic polymer that is similar to erythrocyte membranes. The stent contains a dose of 10 μg of zotarolimus per 1 mm of stent length. This allows for 98% of the drug to be eluted within 2 weeks and treatment level doses for approximately 28 days after implantation. The stent is available in 2.5 mm to 3.5 mm diameter sizes and 8 mm to 30 mm in length. It is indicated in patients with ischemic heart disease to improve coronary luminal diameter in de novo coronary artery lesions of 27 mm in length and with reference vessel diameter of 2.5 mm to 3.5 mm.

This stent is contraindicated in patients with known hypersensitivity to zotarolimus, cobalt-based alloy (cobalt, chromium, nickel, tungsten), or phosphorylcholine polymer. As with all coronary stents, it is contraindicated in patients who are unable to receive recommended antiplatelet or anticoagulant therapy, as well as in those that have a lesion that prevents complete balloon angioplasty or proper stent placement.

The Endeavor stent system was studied in the large ENDEAVOR II clinical trial, which compared the stent to the Driver BMS in 1197 patients with single coronary artery stenosis. The primary end point was TVF (composite of TVR, MI, cardiac death) at 9 months. Endeavor was found to significantly reduce TVF (7.9% vs. 15.1%). There was no difference in stent thrombosis between the two arms.

The ENDEAVOR III randomized trial compared the Endeavor stent versus Taxus in 436 patients. The follow-up data at 3 years revealed no significant difference in TVF or major adverse cardiac events between the two arms.

The Future—Bioabsorbable Stents

Bioabsorbable stents are currently being evaluated. Just as the need to deliver antiproliferative drugs is temporary, so is the need to scaffold the vessel with a metal stent. The goal with bioabsorbable DESs is to limit the shortcomings of metal DESs, which include the requirement of prolonged dual antiplatelet therapy, possible permanent side branch occlusion, difficulty of subsequent surgical revascularization, elimination of reactive vasomotion, and the risks of late stent thrombosis. An absorbable stent would need to be in place long enough to protect against vessel recoil and subacute closure, which typically leads to restenosis.

One particular stent system, the bioabsorbable everolimus-eluting stent system by Abbott Vascular (BVS) has been studied in the ABSORB open-label study to assess its safety and efficacy. The stent is made from a bioabsorbable polylactic acid that is coated with a more rapidly absorbed polylactic acid that contains everolimus and controls its release. Elution kinetics allowed for 80% of the everolimus to be eluted within 28 days. A total of 30 patients with de novo single coronary artery lesions were enrolled. The composite end point was cardiac death, MI, and ischemia-driven TLR, measured at 6 and 12 months. The study reported only one MI at 12 months, with no stent thromboses or TLR. At 6 months, there was angiographic late loss of 0.44 mm, mainly due to a mild reduction in stent area as measured by IVUS (−11.8%). This degree of late lumen loss is similar to data reported from Taxus DES trials. Recently, 2-year follow-up data were reported. A multi-imaging approach was taken, which revealed that by echogenicity, virtual histology, and optical coherence tomography, the stent was incorporated into the vessel wall and absorbed. No stent thrombosis occurred despite the discontinuation of thienopyridine drugs. In-stent late loss was 0.48 mm, which did not differ significantly from 6 months. Vasomotion was also noted to occur at stented segments in response to administration of vasoactive agents. There is no FDA-approved bioabsorbable DES available currently, but it may prove to be an option for the treatment of coronary artery disease in the near future.

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