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Despite significant advances in technology and technique, coronary restenosis remains the primary limitation of percutaneous transluminal coronary angioplasty (PTCA). Among patients undergoing PTCA, between 20% and 50% of patients who do not receive a stent and 10%-30% of those who do receive a stent develop restenosis within 6 months of the procedure. Drug-eluting stents, which release high local concentrations of antiproliferative or immunosuppressive agents directly into the vessel wall at the site of the lesion, have dramatically reduced the incidence of restenosis in patients undergoing PTCA. However, even with drug-eluting stents, a significant percentage of higher-risk patients develop in-stent restenosis. These data suggest that a role remains for effective, well-tolerated systemic pharmacologic therapies to further reduce the rate of restenosis. To date, the majority of systemic agents tested for restenosis prevention have failed to show significant benefit. Only 2 agents, probucol and cilostazol, have consistently demonstrated efficacy in preventing restenosis. In addition, the investigational agent AGI-1067 has demonstrated promising efficacy in early clinical trials. Together with drug-eluting stents, these therapies may for the first time reduce the rate of restenosis to near zero, even in high-risk patients, such as individuals with diabetes mellitus.

Background: The CREST trial demonstrated that after successful coronary stent implantation, the 6-month rate of target vessel revascularization (TVR) was similar (15.4% vs 16%, P = .90) for the 2 treatment groups, but restenosis rate was lower (22.0% vs 34.5%, P = .002) in cilostazol-treated patients. We sought to evaluate resource use, cost, and cost-effectiveness of cilostazol in CREST., Methods: A total of 705 patients were randomized to cilostazol 100 mg twice daily (n = 354) versus placebo (n = 351) for 6 months. Resources included rehospitalizations, medications, and outpatient services. Costs were determined from the Medicare fee schedule. Cilostazol was priced at 1.64 dollars a day. Base-case cost and cost-effectiveness analysis was performed for the entire population using TVR as a measure of effectiveness. Sensitivity analysis was conducted among 526 patients because restenosis data were available only for this patient population. A bootstrap resample approach (5000 samples) was used to obtain confidence intervals for cost differences., Results: For the entire population, costs of rehospitalizations, concomitant medications, outpatient tests, and physician or emergency department visits were lower during follow-up for cilostazol-treated patients. Overall, total 6-month follow-up costs remained 447 dollars lower for cilostazol (4178 dollars vs 4625 dollars), although this difference did not reach significance (95% CI -1458 dollars to 515 dollars). Cilostazol is likely a cost-saving strategy (similar rate of TVR and lower costs). Sensitivity analysis showed that cilostazol is likely a dominant strategy (lower restenosis rate and costs, 85% dominant, 88.9% <1000 dollars per restenosis averted)., Conclusions: Treatment with cilostazol is likely a cost-saving or dominant strategy in patients with successful coronary bare metal stent implantation. Cilostazol may offer a low-cost alternative to restenosis prevention in patients who do not receive drug-eluting stents.

The success of percutaneous coronary intervention (PCI) has historically been limited by a relatively high rate of restenosis, a response of the coronary artery to trauma induced during PCI. Bare-metal stents, by providing a supportive intravascular scaffolding, have significantly reduced the incidence of restenosis compared with traditional balloon PCI. However, significant loss of lumen within the bare-metal device (in-stent restenosis) occurs in 10-30% of patients within 6 months of the procedure. The recent introduction of drug-eluting stents, permitting local delivery of high concentrations of immunosuppressive or anti-proliferative agents, promises to prevent the processes underlying restenosis. Although these devices have been successful in providing an incremental reduction in rates of restenosis, they are expensive. To date, clinical trials of pharmacologic treatment have failed to demonstrate a clinically significant impact on restenosis. Recently, results of the Cilostazol for Restenosis (CREST) trial, a randomized, double-blind study, show that cilostazol reduces the risk of restenosis in patients who receive bare-metal stents, including high-risk patients. Effective adjunct pharmacologic therapy to prevent in-stent restenosis, therefore, remains desirable, particularly in patients receiving bare-metal stents, and potentially in patients receiving drug-eluting stents who are at high risk for restenosis (i.e., those with diabetes, long lesions, and small vessels).

Background: Restenosis after implantation of coronary artery stents remains a significant clinical problem. We undertook a randomized, double-blind, placebo-controlled trial to determine whether cilostazol, a drug that suppresses intimal proliferation, would reduce renarrowing in patients after stent implantation in native coronary arteries., Methods and Results: We assigned 705 patients who had successful coronary stent implantation to receive, in addition to aspirin, cilostazol 100 mg BID or placebo for 6 months; clopidogrel 75 mg daily was administered to all patients for 30 days. Restenosis was determined by quantitative coronary angiography at 6 months. The minimal luminal diameter at 6 months for cilostazol-treated patients was 1.77 mm for the analysis segment (stent plus 5-mm borders) compared with 1.62 mm in the placebo group (P=0.01). Restenosis, defined as > or =50% narrowing, occurred in 22.0% of patients in the cilostazol group and in 34.5% of the placebo group (P=0.002), a 36% relative risk reduction. Restenosis was significantly lower in cilostazol-treated diabetics (17.7% versus 37.7%, P=0.01) and in those with small vessels (23.6% versus 35.2%, P=0.02), long lesions (29.9% versus 46.6%, P=0.04), and left anterior descending coronary artery site (19.3% versus 39.8%, P=0.001). There was no difference in bleeding, rehospitalization, target-vessel revascularization, myocardial infarction, or death., Conclusions: Treatment with the drug cilostazol resulted in a significantly larger minimal luminal diameter and a significantly lower binary restenosis rate compared with placebo-treated patients. These favorable effects were apparent in patients at high risk for restenosis.

Objective: To determine economic and quality of life outcomes for the Cilostazol for RESTenosis (CREST) trial, which is investigating the efficacy of cilostazol vs. placebo in preventing post-stent restenosis., Design: CREST is a prospective, multicenter, randomized, placebo-controlled, double-blind trial., Setting: 20 clinical sites; the Emory Center for Outcomes Research (ECOR) will serve as the economic and data coordinating center., Patients: 705 patients (>18 years) who have undergone successful, uncomplicated placement of an intracoronary stent in a native coronary artery., Intervention: Cilostazol (100 mg twice daily) or placebo for 6 months., Costs: Primary endpoint, total direct medical costs at 6 months; secondary endpoints, initial hospital costs and follow-up costs. QOL: Health-related quality of life (QOL) will be assessed using the EQ-5D and the Seattle Angina Questionnaire at baseline and at 1, 3, and 6 months. Cost-effectiveness analysis: Preliminary data show that cilostazol is clinically superior to placebo and if the mean cost for the cilostazol arm is higher than that for placebo, cost-effectiveness analysis will be determined for the cost per episode of restenosis prevented, the cost per episode of major clinical and angiographic endpoints averted, and the cost per quality-adjusted life-years gained.

Restenosis remains a major limitation of percutaneous transluminal coronary intervention. Stenting made an important contribution in restenosis reduction, but in-stent restenosis is becoming a growing problem. Although radiation therapy was traditionally used to kill relatively fast-growing tumor cells, it has also been used to clinically treat benign but problematic hyperplastic conditions. In addition, in vitro studies have shown that radiation inhibits serum-stimulated growth of arterial smooth muscle cells and fibroblasts, and decreases collagen synthesis by fibroblasts. The effects of radiation on neointimal inhibition after vascular injury were investigated in animal models using various catheter- and stent-based endovascular approaches (brachytherapy) as well as externally delivered x-irradiation. These studies have consistently shown that ionizing radiation delivered by the endoluminal approach results in remarkable suppression of neointima formation. However, animal studies also demonstrate altered vessel wall healing with increased thrombogenicity. The catheter-based approach with gamma- or beta-emitters showed feasibility and appears promising in early human clinical trials, whereas the strategy of using radiation stents is more problematic in the clinical arena. A number of randomized multicenter trials have been initiated and the results are eagerly awaited. More work needs to be done to define the optimal dosage, and to study the short- and long-term vascular biologic effects of brachytherapy. Additionally, if this form of therapy proves efficacious in the large, randomized, clinical trials, its cost-effectiveness will then need to be established. This review touches on some of the basic concepts involved in using the strategy of endovascular irradiation therapy for restenosis prevention after percutaneous coronary intervention and reviews the evidence of clinical efficacy and safety.