The paclitaxel (TAXUS)-eluting stent: a review of its use in the management of de novo coronary artery lesions.

UNLABELLED

The TAXUSExpress stent contains paclitaxel 1 microg/mm(2). On deployment, paclitaxel is slowly released into the intimal tissue of the coronary artery to prevent cell proliferation and neointimal hyperplasia. When deployed in patients with previously untreated coronary artery lesions, the paclitaxel-eluting stent (PES) effectively reduces the need for revascularization without increasing the risk of in-stent thrombosis. While long-term outcomes data and comparative efficacy and cost-benefit trials versus other drug-eluting stents are required, the PES appears to be an attractive alternative for the management of de novo coronary artery lesions. PHARMACOLOGIC PROPERTIES: The PES comprises a stainless steel stent coated with a non-erodible biocompatible polyolefin matrix containing paclitaxel 1 microg/mm(2). Paclitaxel dose dependently inhibits vascular smooth muscle cell proliferation at therapeutic concentrations as a result of binding to and stabilizing cellular microtubules. This prevents the cascade of events associated with obstructive in-stent neointimal hyperplasia. Paclitaxel was released in a controlled manner from the stent coating in in vitro studies. The higher release rate in the first 2 days after implantation (to reduce response to implantation injury) slows over the next 8-10 days. The drug is rapidly taken up by intimal cells with minimal dispersion in the plasma; it was not detected systemically after stent deployment in clinical trials. Paclitaxel is extensively bound to proteins (88-98%), and is principally metabolized in the liver, undergoing biliary clearance after systemic administration. THERAPEUTIC EFFICACY: The efficacy of the PES was compared with that of a bare-metal stent (BMS) in a number of randomized, double-blind, multicenter trials in patients with de novo coronary artery lesions. The TAXUS I and II trials used the NIR stent, while the pivotal TAXUS IV trial used the Express stent. The primary endpoints of the well designed TAXUS II and IV trials indicated superiority for the PES over the BMS. Twice as many patients receiving the BMS required target vessel revascularization at 9 months postprocedure and, 6 months following the procedure, the in-stent neointimal volume in the PES system was only one-third of that in the BMS. The incidence of cumulative major adverse cardiac events (MACE; cardiac death, myocardial infarction [MI], or target vessel revascularization [TVR]) was also significantly lower in PES than BMS recipients at 9 and 12 months postprocedure. The incidence of cardiac death and MI was low and similar between treatment groups; however, TVR was significantly reduced by the PES versus the BMS. Other secondary endpoints, such as target lesion revascularization, luminal diameter stenosis, minimal luminal diameter, and serial intravascular ultrasound measurements from one or both trials supported these results. Preliminary analysis of the subgroup of patients with diabetes mellitus in the TAXUS IV trial suggested that the PES was also effective in diabetic patients who receive oral medications. The group receiving insulin was too small to draw meaningful conclusions.

TOLERABILITY

Because of the small paclitaxel dosages and the mainly local uptake, systemic adverse events associated with the PES are considered unlikely. The incidences of cardiac death and MI were very low and similar in both groups. Local events such as in-stent aneurysms, incomplete stent apposition, or in-stent thrombosis occurred at a similar rate in PES and BMS recipients. There has been no evidence of late thrombosis in PES recipients followed for 2 years. The rate of late luminal loss in the 5mm of vessel proximal and distal to the stent edges was significantly lower in PES than BMS systems. PHARMACOECONOMIC CONSIDERATIONS: Initial deployment costs associated with the PES are likely to be offset by savings in repeat procedures, according to a cost-effectiveness analysis in the UK.