Methods for the Economic and Quality of Life Supplement to the Cilostazol for RESTenosis (CREST) Trial

ABSTRACT: 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. Outcome Measures: 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. J INVAS CARDIOL 2004;16:257–259 Key words: cost-effectiveness, outcomes, quality of life Coronary angioplasty has emerged as a reasonable alternative to coronary artery bypass surgery in the treatment of patients with coronary artery disease (CAD), with equivalent rates of mortality and acute coronary events.^1–3 However, restenosis after PTCA occurs in 30–60% of patients and thus represents an important limitation to the long-term success of this procedure.⁴ Although stent implantation has reduced the incidence of restenosis, post-stent restenosis remains a problem. In addition to its potential clinical consequences, post-stent restenosis imposes an additional burden in terms of healthcare resource utilization and costs because of the need for additional procedures and follow-up.⁵ Assessments of healthcare costs and measures of quality of life (QOL) are increasingly seen as integral to a comprehensive evaluation of the clinical usefulness of a therapy.^6,7 Cilostazol is a potent antiplatelet and anti-thrombotic agent with vasodilatory and antiproliferative effects. It has a more rapid onset of action and a better side-effect profile than ticlopidine.⁸ The Cilostazol for RESTenosis (CREST) trial investigated the usefulness of cilostazol, an inhibitor of phosphodiesterase type III, for prevention of post-stent restenosis. Preliminary data presented at the American Heart Association meeting in 2003 showed that cilostazol decreased the rate of restenosis by almost 40%.⁹ The purpose of the Economic and Quality of Life Supplement to the CREST trial will determine the total medical costs of treatment and assess QOL using two standardized indices. If results show that cilostazol is superior to placebo for prevention of restenosis, a cost-effectiveness analysis will be performed. Methods Overall Trial Description. CREST is a multicenter, randomized, placebo-controlled, double-blind trial investigating the efficacy of cilostazol in preventing restenosis after coronary stent implantation in 705 patients. Baseline characteristics are shown in Table 1. All study patients received aspirin and clopidogrel before and after the stenting procedure. Subjects > 18 years old with successful placement of an intracoronary stent were randomized to receive cilostazol (100 mg twice daily) or placebo for 6 months. Follow-up assessments have been conducted at 1, 3, and 6 months. The primary endpoint was the minimal lumen diameter of each patient’s first stented lesion at 6 months, and the secondary endpoint was binary restenosis defined as greater than 50% diameter narrowing at 6 months angiography as determined by quantitative coronary angiography at the angiographic core laboratory. Costs. The primary economic endpoint will be total direct medical care costs at 6 months. Secondary endpoints will be the initial hospital cost and the cost of all follow-up health care resources consumed. Direct costs include hospital costs, as well as the professional costs associated with all hospitalizations, follow-up direct outpatient costs (including physician and diagnostic procedure expenses), and medications (cilostazol as well as other cardiac drugs) (Table 2). Initial hospital costs will be determined using the UB-92, a uniform billing statement used by all third-party insurers in the United States. The UB-92 summarizes hospital charges by department and provides a more useful estimate of hospital costs than line-item charges. Hospital charges will be reduced to costs using the cost-to-charge ratios from the Hospital Cost Report (HCR), based on annual reports from hospitals to the Centers for Medicare & Medicaid Services on the relation of costs to charges. Professional costs will be determined using the percent share by diagnosis-related group (DRG) as described by Becker.¹⁰ As an alternative costing strategy, the initial hospitalization and all follow-up hospitalizations will be assigned a DRG using a standard algorithm. The cost of each hospitalizations will then be estimated form a multivariate regression model estimated from a sample of all Medicare beneficiaries undergoing a PCI procedure in any U.S. Hospital in 2002.¹¹ Direct outpatient charges will be identified from resource use recorded on case report forms (CRFs), and the costs determined on the basis of Medicare payments for services. The average wholesale price will be used to represent the cost of medications. Health-related Quality of Life. Health-related QOL will be assessed at baseline and at 1, 3, and 6 months using two measures: a disease-specific index, the Seattle Angina Questionnaire (SAQ), and a generic health utility index, the EQ-5D. The SAQ is a 19-item self-administered questionnaire that assesses the functional status of patients with CAD in five dimensions: physical limitation, anginal stability, anginal frequency, treatment satisfaction, and disease perception.¹² The SAQ is highly responsive to change in angina.¹³ The EQ-5D provides a health state utility score that integrates all aspects of a patient's health into a single number between 0, representing death, and 1, representing perfect health.14 By multiplying utility (the quality of life) by survival (the duration of life), quality-adjusted life years (QALYs) can be derived. A comparison of QALYs between treatment arms therefore reflects both morbidity and mortality influences. Measurement of utility at various time points avoids the need to assume a constant utility throughout the entire follow-up period.¹⁵ In the CREST trial, QALYs will be calculated as the area under the utility function over the time interval from baseline to a specified time as follows: 0 to 2 weeks (baseline utility), 2 to 8 weeks (1-month utility), 2 to 4.5 months (3-month utility), and 4.5 to 6 months (6-month utility). Cost-Effectiveness Analysis. If CREST demonstrates that cilostazol is clinically superior to placebo in preventing restenosis, in QALYs, or for other major angiographic or clinical endpoints, and if the mean 6-month costs for the cilostazol arm are higher than for the placebo arm, cost-effectiveness analyses will be performed to determine the incremental cost per unit of effectiveness. Survival will be estimated long-term from published data from Framingham.¹⁶ These data may then be used to estimate the life years lost due to cardiovascular events by gender and age group.¹⁷ Cost-effectiveness ratios will be determined for the following primary endpoints, where the numerator is the difference in mean cost and the denominator is the difference in mean effectiveness: • Cost per episode of restenosis prevented • Cost per episode of major angiographic and clinical endpoints averted • Cost per QALYs gained in trial • Cost per QALYs gained long-term Costs will not be discounted because the duration of the trial is less than one year. Survival estimates will be discounted at 3% per year.¹⁷Statistical Analysis. Mean cardiac-related costs, including hospitalization expenditures (both hospital and professional), medications, and expenses associated with outpatient visits and diagnostic procedures, will be calculated for the two treatment arms. Costs will be analyzed according to intention-to-treat. If the data are normally distributed, then a standard, two-sided 95% confidence interval for the difference (cilostazol minus placebo) in the mean costs will be constructed. If the data are not normally distributed, then nonparametric bootstrap analysis will be used to develop a 95% confidence interval.¹⁸ Costs for the cilostazol arm will be considered significantly higher than those for the placebo arm if the left-hand endpoint of the 95% confidence interval for the difference in mean costs is greater than zero. Confidence intervals for the cost-effectiveness ratios will be obtained using nonparametric bootstrap methods.¹⁹ In addition, associated plots of the joint distribution of cost and effectiveness differences will be generated, as well as cost-effectiveness acceptability curves showing the probability (y-axis) that the cost-effectiveness ratio lies below a range of values (x-axis).²⁰ Differences between treatment groups in the change from baseline at 1, 3, and 6 months will be assessed in each of the five SAQ subscale scores using analysis of covariance, adjusting for baseline value and baseline clinical characteristics (e.g., age, sex, diabetes). In addition, a repeated-measures analysis of variance utilizing SAQ data from all follow-ups will be carried out for each of the SAQ subscales. This analysis will provide insight into differences between treatment groups in the entire trajectory of SAQ scores over 6 months. Missing Data. While great effort will be extended towards minimizing missing data, some values will inevitably be absent in this type of trial. Multiple imputation methods will be used to impute missing utility data from the EQ-5D.21 For the SAQ, the primary analysis will be conducted on all available data. Sensitivity analyses will examine the influence of carrying forward the last observations of patients who are lost to follow-up. Analyses will also impute scores of zero for patients who die during follow-up. Discussion Cilostazol, a specific inhibitor of phosphodiesterase type III in platelets and vascular smooth muscle cells, is approved for the relief of symptoms of intermittent claudication in patients with peripheral arterial disease.²² Prior to the CREST trial, small, nonblinded studies have provided some evidence suggesting that cilostazol may prevent thrombosis and restenosis after angioplasty procedures. The CREST trial showed that cilostazol decreased post-stent restenosis using a randomized, double-blind design.⁹ Because of growing concerns over healthcare costs and the allocation of resources, there is a heightened interest in studying the economic and QOL benefits of therapies undergoing clinical trials. Cost-effectiveness analyses, can be essential to the decision-making efforts of healthcare providers and administrators. The Economic and Quality of Life Supplement to CREST will provide important comparative information on the total medical costs over a 6-month follow-up period for patients who receive cilostazol for the prevention of post-stent restenosis, relative to those who receive placebo. The evaluation of QOL, assessed by the EQ-5D and the SAQ, will provide information on the comparative physical and functional status of patients in the two treatment arms in the first 6 months after stent implantation. Finally, the cost-effectiveness analysis has the potential to provide important insights into the economic impact of cilostazol therapy for the prevention of restenosis after stent implantation.