Taxol-Based Eluting Stents — From Theory to Human Validation: Clinical and Intravascular Ultrasound Observations<br />

Reduction of restenosis remains an important goal of percutaneous coronary interventions. Although coronary stents reduce the rate of primary restenosis compared with balloon angioplasty,1–3 20–30% of treated vessels still develop recurrent in-stent restenosis.4,5 Initial studies with intracoronary radiation therapy showed promise as a treatment for both primary restenosis and recurrent in-stent restenosis,6,7 but recent studies have reported shortcomings, namely, edge restenosis and late thrombosis.8–10 While the treatment of in-stent restenosis is important, a therapeutic strategy to prevent primary restenosis would eliminate the need for additional procedures with their inherent risks and costs. Currently, treatment with antiproliferative drugs via coated stents appears to be the most promising approach to both mechanically remodel target lesions and biologically reduce neointimal hyperplasia.11,12 Drug-eluting stents can maximize local drug effects and minimize the potential for systemic toxic effects. With proven efficacy in other therapeutic arenas, many drugs aimed at inhibiting cell proliferation (paclitaxel, sirolimus, tacrolimus and everolimus), cell migration (batimastat, a matrix metalloproteinase inhibitor) and abnormal healing (estradiol) are currently under clinical investigation. This review describes the effects of a lipophilic microtubular inhibitor, paclitaxel, a strong antiproliferative agent under clinical investigation, and to define the vascular response to taxol-based eluting stents by intravascular ultrasound (IVUS). Background. The taxanes are an important new class of anticancer agents that exert their cytotoxic effects through a unique mechanism. A crude extract is obtained from the Pacific yew tree Taxus brevifolia, found in the Northwestern United States and Canada. In the 1960s, preclinical studies observed its cytotoxic activity against many tumors, and in 1971, paclitaxel was identified as the active agent of this extract.13 Although it had a novel chemical structure (Figure 1) and broad preclinical activity, development was slowed because it did not appear to be more effective against experimental tumors than other agents under development. Interest was revived in 1979 when paclitaxel’s unique mechanism of action as an antitumor drug was identified, and was further stimulated when impressive activity was demonstrated in the National Cancer Institute tumor screening program. In the 1980–90s, paclitaxel was evaluated for the treatment of ovarian and breast cancer as well as for the treatment of cancers of the lung, head and neck, bladder and esophageal origins.14–16 Currently, it is used as a broad-spectrum chemotherapeutic agent in oncology. Mechanism of action. Paclitaxel binds to microtubules and stabilizes their structure by shifting the dynamic equilibrium between soluble and insoluble tubulin, thereby enhancing microtubule assembly, resulting in inhibition of cellular replication. While the cells remain viable, paclitaxel inhibits cell processes that are dependent on microtubule turnover, such as mitosis, migration, endocytosis and secretion (Figure 2).16,17 Unlike other antiproliferative agents, paclitaxel has several properties that make it an excellent candidate for local drug therapy aimed at decreasing restenosis. First, its highly lipophilic character promotes rapid cellular uptake by enabling easy passage through the hydrophilic barrier of cell membranes.18 Second, its unique mode of action supports a long-lasting antiproliferative action even after a brief, single-dose application at very low concentrations.19 When used in high-dose chemotherapy, paclitaxel may produce a number of toxic effects. Among the principal toxic effects seen are hypersensitivity reactions (dyspnea with bronchospasm, urticaria, hypotension), neutropenia and peripheral neuropathy. Paclitaxel also causes cardiac rhythm disturbances described mostly as transient asymptomatic bradycardia.16 Of importance, the plasma levels of local paclitaxel stent-based delivery are 100- to 1000-fold lower than those seen in cancer chemotherapy.20 Vascular actions. Several in vitro studies have demonstrated paclitaxel-induced inhibition of proliferation and migration of vascular smooth muscle cells (SMC). Systemic administration of paclitaxel in rats was initially reported by Sollott et al.,20 who demonstrated a significant (70%) reduction in neointimal proliferation. In addition, SMC proliferation and migration was achieved with blood concentrations 100 times lower than antineoplastic levels. In human cultured cell models, Axel et al.21 delivered paclitaxel locally via a balloon catheter in concentrations ranging between 0.01 and 10 µmol/l; they demonstrated that even after single-dose application, paclitaxel prevented growth factor-stimulated vascular SMC migration and proliferation. Furthermore, a dose-dependent inhibition of endothelial cell growth at higher concentrations (0.01 to 10 µmol/l) of paclitaxel was observed. Systemic treatment is associated with considerable side effects; conversely, local drug delivery can provide high local concentrations of drug at the treatment site without detectable systemic levels. As an alternative to systemic therapy, Hou et al.22 examined the effects of catheter-based intrapericardial instillation of paclitaxel on neointimal proliferation in a porcine model. In response to balloon overstretch of the porcine coronary arteries, a single dose of paclitaxel into the pericardial space resulted in inhibition of SMC proliferation and promotion of positive vascular remodeling. To further evaluate long-term safety of this approach, additional research and follow-up will be required. Herdeg et al.23 evaluated the effects of locally delivered paclitaxel with a double-balloon catheter in a rabbit model. Local delivery of paclitaxel (10 ml/10 µmol/l) resulted in reduced neointimal proliferation and enlargement in vessel size. They concluded that these effects of paclitaxel contributed to the preservation of vessel shape, likely being caused by a structural alteration of the cytoskeleton. However, reduction in neointimal formation could not be demonstrated when using the same perfusion catheter in the pig coronary stent model.24 In the setting of coronary stenting, sustained arterial wall delivery achieved by stent coatings may be preferable to other local delivery technologies. Several animal studies have evaluated whether paclitaxel-containing stent coatings or biodegradable particles with sustained release could inhibit neointimal growth. Drachman et al.25 showed that poly (lactide-co-S-caprolactone) copolymer (pLA/pCL)-coated stents containing 200 µg of paclitaxel permitted sustained paclitaxel delivery in a slow manner that virtually abolished rabbit neointimal hyperplasia months after stent implantation. In their experimental model, a 2-month period was required to release most of the paclitaxel from this stent (Figure 3); the effect of paclitaxel persisted 180 days after stent implantation. Regarding the inflammatory response to stenting, there was a 10-fold reduction in the number of intimal macrophages between 56 and 180 days (from 57 ± 9 cells to 6 ± 4 cells in uncoated stents). Conversely, in paclitaxel-coated stents, intimal macrophage numbers were elevated after 28 and 56 days (120 ± 30 cells to 168 ± 39 cells) and did not fall substantially at 180 days (157 ± 25 cells). This persistent inflammation may be an early local harbinger for late neointimal proliferation. Heldman et al.26 showed that locally applied paclitaxel (bare stent with a dip-coating technique) produced a significant dose-dependent inhibition (0, 0.2, 15 and 187 µg/stent) of porcine neointimal hyperplasia at 4 weeks. Yet with this technique, most drug loss occurred before stent expansion and deployment. Although the dip-coated stent may offer advantages for efficacy and safety, further improvements on this technique should be investigated. Farb et al.27 showed that stents coated with chondroitin sulfate and gelatin (CSG) containing paclitaxel suppressed rabbit neointimal formation at 28 days in a dose-dependent manner without systemic toxicity. However, there was greater intimal fibrin deposition, intimal hemorrhage, intimal cell proliferation and intimal inflammation associated with paclitaxel-coated stents. By 90 days, local toxicity associated with paclitaxel resolved, but in-stent neointimal growth suppression was not maintained. One reason for the failure of CSG-coated stents to suppress neointima at 90 days may reflect differences in the pharmacokinetics between this stent and the stent reported by Drachman et al. Hwang et al.28 investigated the local pharmacokinetics of paclitaxel, including physiological transport forces and drug physiochemical properties. Overall, mean tissue concentrations can be misleading indicators of delivery efficiency. Therefore, drug concentrations were measured in the arterial wall after stent-based delivery using a fluorescent microscope (compared with concentration profile obtained by bulk elution measurement) and computational modeling. Although hydrophobic and hydrophilic compounds manifest similar drug variation patterns, hydrophobic compounds (such as paclitaxel) distribute better than hydrophilic ones. In addition, hydrophobic drugs achieve significantly higher tissue levels with relatively larger concentration variability in the arterial wall than hydrophilic drugs. Given their lower concentration variability, the hydrophilic nature may be advantageous when that drug possesses a small therapeutic window, whereas the hydrophilic nature may be advantageous to maintain high therapeutic doses close to the intima. Hwang et al.28 also showed how strut placement affects drug delivery. Mean drug concentrations were independent of strut arrangement, but increased with strut number. Hydrophobic drugs distributed significantly more into the arterial wall than hydrophilic drugs. Uniformity of drug distribution was also increased with strut number. The variation in concentration of hydrophobic drugs was also less than that of hydrophilic drugs. Drug distribution within the vessel wall also seemed to be significantly affected by the stent expansion pattern (uniform or non-uniform). Lessons from animal studies. From these animal studies, there appear to be a number of problems related to drug-eluting stents that must be considered. First, poor drug retention in the surrounding vascular tissues and too rapid release of the drug from the stent resulted in lack of long-term benefit. Thus, sustained drug availability may be important for persistent intimal inhibition. Second, persistent fibrin deposition and increased inflammation in the surrounding vascular tissues was observed. Fibrin stimulates SMC migration and proliferation, perhaps heralding late neointimal catch-up. Current clinical trials. Recently, several human trials have been reported (or initiated) to evaluate the pharmacokinetics, effective dosage and safety of a number of antiproliferative drugs in clinical practice. To identify the best delivery platform, either polymer-based or nonpolymer-based stents have been examined. Studies of polymer carriers or paclitaxel directly applied to the struts for paclitaxel-eluting stents have reported extremely low rates of restenosis in humans (Table 1).29–34 However, further long-term investigation of polymer-based drug delivery may be needed. IVUS was utilized as an initial and follow-up observational tool in these studies. The need for this level of information is essential to evaluate the reactions to and mechanisms of the vascular response to locally delivered antiproliferative drugs. Serial IVUS observations from the first human trial with the QP2 (a taxol derivative)-eluting polymer stent system (a subset of 122 patients in the SCORE trial) revealed a low amount of neointimal proliferation (14 ± 11%) in the stented segments at 6-month follow-up versus bare metal stents (42 ± 23%; p Conclusion. At present, drug-eluting stents represent one of the fastest growing fields in current interventional cardiology. Current clinical data regarding acute- and intermediate-term effects of drug-eluting stents in coronary arteries are promising, with an extremely low rate of clinical events and restenosis. IVUS observations from several trials revealed excellent suppression of neointimal hyperplasia by stent-eluting paclitaxel and sirolimus. Qualitative assessment by IVUS did not reveal any evidence of high-risk complications over the short- and mid-term. However, the clinical significance of observations such as incomplete stent apposition remains to be determined and further long-term follow-up will be necessary. Finally, a theoretical understanding of the pharmacokinetics of the drug as well as close inspection of its effects on the vessel wall with IVUS will help to assess this new strategy for more successful treatment of the patient with coronary artery disease.

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