Cost-effectiveness analysis of CYP2C19 genotype-guided antiplatelet therapy for patients with acute minor ischemic stroke and high-risk transient ischemic attack in China.

AIMS: The study aimed to estimate the cost-effectiveness of CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel, compared to conventional antiplatelet therapy with clopidogrel and aspirin. METHODS: A 90-day decision tree and 30-year Markov model were employed to assess the costs and quality-adjusted life years (QALYs) of personalized antiplatelet therapy for patients with minor ischemic stroke and high-risk transient ischemic attack, compared to conventional antiplatelet therapy in the Chinese healthcare system. The primary outcome was the incremental cost-effectiveness ratio (ICER). The data sources included clinical trials, published literature, official documents and local prices. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to confirm the robustness of the findings. RESULTS: The base-case analysis indicated that the CYP2C19 genotype-guided antiplatelet strategy was cost-effective, and cilostazol group and ticagrelor group yielded an ICER of 3327.40 US dollars (USD)/QALY and 3426.92 USD/QALY, respectively, which were less than threshold. The one-way sensitivity analysis showed the results were robust, where the most sensitive parameter was the disability distribution in the modified Rankin scale 3-5. The probabilistic analysis showed that the CYP2C19 genotype-guided antiplatelet therapy with either cilostazol or ticagrelor was 100% cost-effective under the willingness-to-pay threshold. CONCLUSIONS: CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel appeared to be more cost-effective than conventional antiplatelet therapy for acute minor ischemic stroke and high-risk transient ischemic attack patients over 30 years in China.

Cost-Effectiveness of Cilostazol Added to Aspirin or Clopidogrel for Secondary Prevention After Noncardioembolic Stroke.

Background The objective of the study was to assess the cost-effectiveness of cilostazol (a selective phosphodiesterase 3 inhibitor) added to aspirin or clopidogrel for secondary stroke prevention in patients with noncardioembolic stroke. Methods and Results A Markov model decision tree was used to examine lifetime costs and quality-adjusted life years (QALYs) of patients with noncardioembolic stroke treated with either aspirin or clopidogrel or with additional cilostazol 100 mg twice daily. Cohorts were followed until all patients died from competing risks or ischemic or hemorrhagic stroke. Probabilistic sensitivity analysis using Monte Carlo simulation was used to model 10 000 cohorts of 10 000 patients. The addition of cilostazol to aspirin or clopidogrel is strongly cost saving. In all 10 000 simulations, the cilostazol strategy resulted in lower health care costs compared with aspirin or clopidogrel alone (mean $13 488 cost savings per patient; SD, $8087) and resulted in higher QALYs (mean, 0.585 more QALYs per patient lifetime; SD, 0.290). This result remained robust across a variety of sensitivity analyses, varying cost inputs, and treatment effects. At a willingness-to-pay threshold of $50 000/QALY, average net monetary benefit from the addition of cilostazol was $42 743 per patient over their lifetime. Conclusions Based on the best available data, the addition of cilostazol to aspirin or clopidogrel for secondary prevention following noncardioembolic stroke results in significantly reduced health care costs and a gain in lifetime QALYs.

Simple assessment of quality of life and lower limb functional capacity during cilostazol treatment - results of the SHort-tERm cIlostazol eFFicacy and quality of life (SHERIFF) study.

Background: Symptomatic peripheral arterial disease (intermittent claudication) is a major cause of disability and mobility loss in older men and women and thus has a significant negative impact on the patients' quality of life. Both surgical and endovascular revascularization procedures and noninvasive medical therapies, such as supervised training and drug treatment, can improve walking capacity. Cilostazol is the only drug having a class I (level of evidence A) recommendation for the treatment of intermittent claudication (IC). The aim of this study was to evaluate the effect of three-month cilostazol treatment on the health-related quality of life and on the lower limb functional capacity in patients with IC in the clinical practice. Patients and methods: The study was a multicenter, non-interventional trial, performed in Hungary in 2018. 812 PAD patients (Fontaine II stage, mean age: 67.17 years, male/female: 58.25/41.75 %) were enrolled, who received cilostazol (50 or 100 mg b.i.d.) for 3 months. 802 patients completed the study. Quality of life was evaluated with the EQ-5D-3L questionnaire functional capacity with the WELCH (Walking Estimated-Limitation Calculated by History) questionnaire. Pain-free and maximal walking distance, ankle-brachial index (ABI) were measured at baseline and after 3-month treatment. Results: Upon conclusion of the study, the EQ-5D-3L index improved (baseline: -0.46 ± 0.22, 3rd month: -0.26 ± 0.18; p < 0.0001) and there was a significant increase in the WELCH score as well (19 ± 14, 31 ± 18; respectively, p < 0.0001). Both pain-free and maximal walking distance improved significantly by 54.52 % (median: 53.85 %) and 42.5 % (median: 34.68 %); respectively (p < 0.001). Adverse events occurred in 10 patients, 1 patient stopped cilostazol treatment because of side effects. Conclusions: Three months cilostazol treatment significantly improved quality of life and lower limb functional capacity in patients with intermittent claudication. The WELCH questionnaire is a useful tool for the evaluation of intermittent claudication treatment in the clinical practice.

Medical Management of Functional Impairment in Peripheral Artery Disease: A Review.

Lower extremity peripheral artery disease (PAD) now affects 200 million people worldwide and is a major cause of disability. Cilostazol is the only Federal Drug Administration approved medication for PAD-related ischemic symptoms that is recommended by clinical practice guidelines. Supervised treadmill exercise significantly improves treadmill walking performance in PAD. Recent evidence shows that home-based exercise interventions that include occasional medical center visits and incorporate behavioral change techniques also significantly improve walking endurance in PAD. Upper and lower extremity ergometry (cycling) also improve walking ability in PAD. A recent decision by the Center for Medicaid and Medicare Services to cover supervised exercise for people with symptomatic PAD will increase access to exercise for the large number of people disabled by PAD.

Antiplatelet Therapy of Cilostazol or Sarpogrelate with Aspirin and Clopidogrel after Percutaneous Coronary Intervention: A Retrospective Cohort Study Using the Korean National Health Insurance Claim Database.

BACKGROUND/OBJECTIVES: Addition of cilostazol or sarpogrelate to the standard dual antiplatelet therapy of aspirin and clopidogrel has been implemented in patients that underwent percutaneous coronary intervention (PCI) with stents in Korea. This study aimed to evaluate the efficacy and safety of triple antiplatelet therapies. METHODS: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service from January 1, 2009 to December 31, 2014. The study cohort population consisted of patients with ischemic heart diseases and a history of PCI. They were treated with antiplatelet therapy of aspirin, clopidogrel (AC); aspirin, clopidogrel, cilostazol (ACCi); or aspirin, clopidogrel, sarpogrelate (ACSa) during the index period from January 1, 2010 to December 31, 2011. During the follow-up period up to December 31, 2014, the major adverse cardiac or cerebral events (MACCE) including death, myocardial infarction, target lesion revascularization, and ischemic stroke were assessed. Bleeding complications were also evaluated as adverse drug events. RESULTS: Out of 93,876 patients with PCI during the index period, 69,491 patients started dual (AC) or triple therapy (ACSa or ACCi). The clinical outcomes of comparing ACSa and ACCi therapy showed beneficial effects in the ACSa group in the prevention of subsequent cardiac or cerebral events. After Propensity score-matching between ACSa and ACCi groups, there were significant differences in MI and revascularization, with corresponding HR of 0.38 (95% CI, 0.20-0.73) and 0.66 (95% CI, 0.53-0.82) in ACSa vs. ACCi at 12 months, respectively. At the 24-month follow-up, the triple therapy groups (ACS or ACC) had a higher incidence of MACCE compared to the dual therapy (AC) group; ACSa vs. AC HR of 1.69 (95% CI, 1.62-1.77); ACC vs. AC HR of 1.22 (95% CI, 1.06-1.41). There was no significant difference in severe or life-threatening bleeding risk among three groups; ACSa vs. AC, HR of 0.68 (95% CI, 0.37-1.24), ACCi vs. AC, HR of 0.91 (95% CI, 0.77-1.09). CONCLUSION: Sarpogrelate-containing triple antiplatelet therapy demonstrated comparable rates of MACCE prevention to the conventional dual antiplatelet therapy after PCI without significantly increasing bleeding risk during the two-year follow-up period.

Cilostazol and freedom from amputation after lower extremity revascularization.

OBJECTIVE: Cilostazol, an antiplatelet agent with vasodilating properties, has not been well evaluated in conjunction lower extremity revascularization (LER). We evaluated the association between cilostazol and limb salvage after endovascular or open surgery for LER. METHODS: Patients aged ≥65 years undergoing LER were identified from 2007 to 2008 Medicare Provider Analysis and Review and Carrier files using International Classification of Diseases-9 Edition-Clinical Modification and Current Procedural Terminology-4 codes. Covariates included demographics, comorbidities, and disease severity. Use of cilostazol was identified using National Drug Codes and Part D files. Outcomes were compared using χ(2) and Kaplan-Meier analyses and Cox regression. RESULTS: We identified 22,954 patients undergoing LER: 8128 (35.4%) with claudication, 3056 (13.3%) with rest pain, and 11,770 (51.3%) with ulceration/gangrene. Among them, 1999 patients (8.7%) used cilostazol before LER. More patients received endovascular (14,353) than open (8601) procedures. Cilostazol users had fewer amputations than nonusers at 30 days (7.8% vs 13.4%), 90 days (10.7% vs 18.0%), and 1 year (14.8% vs 24.0%; P < .0001 for all). Cox proportional hazards regression with adjustment for age, gender, race, comorbidities, type of procedure, and atherosclerosis severity showed noncilostazol users were more likely to undergo amputation ≤1 year after surgery (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.02-1.29; P = .02). Subgroup analyses using Cox proportional hazards models adjusted for age, gender, and comorbidities demonstrated significantly improved 1-year amputation-free survival for patients with renal failure (HR, 1.61; 95% CI, 1.28-2.02; P < .001) and diabetes (HR, 1.61; 95% CI, 1.36-1.92; P < .001) who were taking cilostazol. CONCLUSIONS: In patients undergoing LER, cilostazol use was associated with improved 1-year freedom from amputation. Patients with renal failure and diabetes also demonstrated a significant benefit from taking cilostazol. Further studies are needed to evaluate the benefits of cilostazol after LER.

Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Quantitative assessment of changes in carotid plaques during cilostazol administration using three-dimensional ultrasonography and non-gated magnetic resonance plaque imaging.

INTRODUCTION: Cilostazol, an antiplatelet agent, is reported to induce the regression of atherosclerotic changes. However, its effects on carotid plaques are unknown. Hence, we quantitatively investigated the changes that occur within carotid plaques during cilostazol administration using three-dimensional (3D) ultrasonography (US) and non-gated magnetic resonance (MR) plaque imaging. METHODS: We prospectively examined 16 consecutive patients with carotid stenosis. 3D-US and T1-weighted MR plaque imaging were performed at baseline and 6 months after initiating cilostazol therapy (200 mg/day). We measured the volume and grayscale median (GSM) of the plaques from 3D-US data. We also calculated the contrast ratio (CR) of the carotid plaque against the adjacent muscle and areas of the intraplaque components: fibrous tissue, lipid, and hemorrhage components. RESULTS: The plaque volume on US decreased significantly (median at baseline and 6 months, 0.23 and 0.21 cm(3), respectively; p = 0.03). In the group exhibiting a plaque volume reduction of more than 10%, GSM on US increased significantly (24.8 and 71.5, respectively; p = 0.04) and CR on MRI decreased significantly (1.13 and 1.04, respectively; p = 0.02). In this group, in addition, the percent area of the fibrous component on MRI increased significantly (68.6% and 79.4%, respectively; p = 0.02), while those of the lipid and hemorrhagic components decreased (24.9% and 20.5%, respectively; p = 0.12) (1.0% and 0.0%, respectively; p = 0.04). There were no substantial changes in intraplaque characteristics in either US or MRI in the other group. CONCLUSIONS: 3D-US and MR plaque imaging can quantitatively detect changes in the size and composition of carotid plaques during cilostazol therapy.

A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE: To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE: Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS: Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS: Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS: Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

Impact of cilostazol on left ventricular geometry and function: assessment by tissue Doppler imaging and two-dimensional speckle-tracking echocardiography.

OBJECTIVES: Cilostazol, a type III phosphodiesterase inhibitor, is an antiplatelet agent with vasodilating properties. Positive inotropic and chronotropic effects are frequently observed with cilostazol, but there are few reports on the influence of cilostazol on left ventricular function. The aim of this study was to assess this effect using tissue Doppler imaging (TDI) and two-dimensional speckle-tracking echocardiography (2D-STE). METHODS: Thirty-five patients with normal left ventricular ejection fraction were enrolled in the study. Left ventricular cardiac function was assessed by TDI and 2D-STE before and after oral administration of cilostazol. Peak strain was defined using the peak radial strain (PRS), peak circumferential strain (PCS) and peak longitudinal strain (PLS). Time to peak strain was defined based on the times to PRS, PCS, and PLS, as T-PRS, T-PCS, and T-PLS, respectively. RESULTS: After cilostazol administration, there were significant decreases in the left ventricular end-diastolic and end-systolic diameters (47.3 ± 5.2 vs. 43.3 ± 4.9 mm, P < 0.0001; 29.3 ± 6.4 vs. 26.0 ± 5.5 mm, P < 0.0001, respectively), and significant increases in the left ventricular ejection fraction (70.6 ± 9.5 vs. 72.7 ± 7.8%, P = 0.0381) and peak systolic annular velocity (7.9 ± 1.7 vs. 9.5 ± 3.1 cm/sec, P < 0.0001). PRS, PCS, and PLS all increased significantly and T-PRS, T-PCS, and T-PLS all decreased significantly after cilostazol administration. CONCLUSION: Positive inotropic and chronotropic effects of cilostazol were found based on assessment by TDI and 2D-STE. We suggest that periodic echocardiographic assessment should be performed before and after oral administration of cilostazol.

Pharmacologic therapy for intermittent claudication.

Peripheral artery disease, defined as atherosclerosis in the lower extremities, affects nearly 8.5 million people in the United States. Due to the frequent asymptomatic manifestation of peripheral artery disease, diagnosis may be delayed and its true incidence underestimated. However, some patients may experience aching pain, numbness, weakness, or fatigue, a condition termed intermittent claudication. Peripheral atherosclerosis is associated with cardiovascular risk and physical impairment; therefore, treatment goals are aimed at decreasing cardiovascular risk, as well as improving quality of life. Little debate exists regarding the management of cardiovascular risk reduction, which consists of both antiplatelet therapy and risk factor modification. Despite recently published guidelines, the treatment of intermittent claudication is less well established and the management remains controversial and uncertain. Exercise remains the first-line therapy for intermittent claudication; however, pharmacologic treatment is often necessary. Although only two prescription drugs have been approved by the U.S. Food and Drug Administration for the treatment of intermittent claudication, several supplements and investigational agents have been evaluated. Therapeutic optimization should balance the anticipated improvements in quality of life with the potential safety risks.

[Recurrent idiopathic cerebral infarction in a 5-year-old boy, with emphasis on the importance of platelet aggregation analysis for appropriate selection of anti-platelet drugs].

We present a 5-year-old boy with recurrent idiopathic cerebral infarction in which analysis of platelet hyperaggregability was useful in choosing appropriate anti-platelet drugs. The patient presented with gait disturbance at the age of 5 years and 1 month. Brain MRI demonstrated multiple infarctions in the right thalamus and left cerebellum. There were no apparent underlying diseases including hematological, cardiac and vascular abnormalities. He was diagnosed as idiopathic cerebral infarction. First, we administered ticlopidine and he remained stable with persistent mild intention tremor in the left upper extremity for 4 months. Then he developed the second stroke at the age of 5 years and 5 months, and multiple infarctions in the right celebellum and cerebellar vermis were demonstrated. On platelet aggregation analysis, adenosine diphosphate (ADP)-induced aggregation was inhibited, probably due to ticlopidine administration. Collagen- and epinephrine-induced platelet aggregation showed hyperaggregation, so we started to administer cilostazol, which inhibits only epinephrine-induced hyperaggregation. We also added aspirin, which inhibits collagen-induced hyperaggregation. The combination of anti-platelet drugs inhibited epinephrine-, collagen- and ADP-induced hyperaggregation in this patient. He has been stable on the triple combination of anti-platelet drugs without further episodes of cerebral infarction or transient ischemic attack for 4 years to date. Appropriate selection of anti-platelet therapy was achieved by the simple and repeatable platelet aggregation analyses, which must be considered even in pediatric patients with cerebral infarction.

Reduced 6-month resource use and costs associated with cilostazol in patients after successful coronary stent implantation: results from the Cilostazol for RESTenosis (CREST) trial.

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.

Pharmacoeconomic analysis of cilostazol for the secondary prevention of cerebral infarction.

BACKGROUND: The antiplatelet agent, cilostazol, is known to reduce the risk of subsequent cerebral infarction. However, the cost effectiveness of such treatment in comparison to aspirin has not been studied. METHODS AND RESULTS: A Markov model was developed to calculate the health outcomes and associated costs for 65-year-old patients with cerebral infarction who were treated with 200 mg/day cilostazol or 81 mg/day aspirin. Cilostazol was more effective, but also more expensive than aspirin. Cilostazol would extend quality-adjusted life years (QALY) by 0.64, while increasing life-time costs by approximately Yen 1.1 million. The incremental cost-effectiveness ratio of cilostazol in comparison with aspirin was estimated to be Yen 1.8 million per QALY. CONCLUSIONS: The use of cilostazol to prevent recurrence of cerebral infarction appears to be cost effective.

Regional differences in incidence and management of stroke - is there any difference between Western and Japanese guidelines on antiplatelet therapy?

PURPOSE: There have not been many discussions on the differences between the guidelines for the management of stroke used in eastern and western countries. The purpose of this paper was to examine whether or not there are substantial differences between western countries and Japan in the prevalence of stroke and the frequencies of stroke subtypes, as well as in the recommended therapy for secondary prevention of ischemic stroke. RESULTS AND CONCLUSIONS: Although there are racial differences and differences in approved drugs between the East and West, the prevalence of stroke and the frequencies of stroke subtypes tend to converge throughout the world. However, the ratio of stroke to ischemic heart disease is still different between the East and West. Comparison of various countries' guidelines shows that recommendations on antiplatelet therapy for secondary prevention of ischemic stroke are fundamentally similar in the East and West, but the recommended doses of antiplatelets, especially aspirin and ticlopidine, are smaller in Japan. Furthermore, Japanese guidelines only recommend the use of antiplatelets (particularly cilostazol) for patients with lacunar infarction with evidence.

Simultaneous quantification of cilostazol and its primary metabolite 3,4-dehydrocilostazol in human plasma by rapid liquid chromatography/tandem mass spectrometry.

A simple, rapid, sensitive and selective liquid chromatography/electrospray tandem mass spectrometry method was developed and validated for the simultaneous quantification of cilostazol and its primary metabolite 3,4-dehydrocilostazol in human plasma using mosapride as an internal standard. The method involves a simple one-step liquid-liquid extraction with a diethyl ether and dichloromethane mixture (7:3). The analytes were chromatographed using an isocratic mobile phase on a reversed-phase C18 column and analyzed by mass spectrometry in the multiple reaction monitoring mode using the respective [M+H]+ ions, m/z 370/288 for cilostazol, m/z 368/286 for 3,4-dehydrocilostazol and m/z 422/198 for the internal standard. The assay exhibited a linear dynamic range of 5-2,000 ng/mL for cilostazol and 5-400 ng/mL for 3,4-dehydrocilostazol in human plasma. The lower limit of quantitation was 5 ng/mL for both cilostazol and its metabolite. Acceptable precision and accuracy were obtained for concentrations over the standard curve ranges. A run time of 2.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetics, bioavailability or bioequivalence studies.

Health care resources and costs for treating peripheral artery disease in a managed care population: results from analysis of administrative claims data.

OBJECTIVE: Peripheral arterial disease (PAD) is associated with high rates of morbidity and mortality and serves as an important marker for advanced systemic atherosclerosis accompanied by symptomatic or asymptomatic ischemia of the coronary, cerebral, and visceral vasculature. There are little published data on the use of health care resources and costs attributable to PAD. The objectives of this study were to evaluate, from a societal perspective, PAD-related health care resource utilization and to determine the total annualized costs and cost components for patients with PAD, with particular attention to the key outcomes of myocardial infarction (MI), transient ischemic attacks (TIA), stroke, and amputations. METHODS: This study examined medical, hospital and outpatient, and pharmacy claims from a large managed care database with dates of service from January 1, 1999, through August 31, 2003. Patients with PAD were identified from claims using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes (primary or secondary codes), ICD-9-CM procedure codes, current procedural terminology (CPT) codes, or by a pharmacy claim for cilostazol or pentoxifylline. The index date for each patient was the first occurrence of either a medical claim for PAD or a pharmacy claim for 1 of the 2 drugs. Patients were required to be a minimum of 18 years old with continuous plan eligibility. The prevalence of PAD in adults in a managed care setting was also determined, as were annual rates for the key outcomes of MI, TIA, stroke, and amputations. Health care resource utilization and costs were calculated for PAD patients after the index date for a period of at least 12 months per patient for medications, outpatient/physician office visits, laboratory/diagnostic procedures, emergency department visits, and hospitalization. Cost was defined as the allowed charge on each administrative claim, including the amount paid by the insurer plus the amount paid by the health plan members (copay, deductible, and coinsurance). RESULTS: Prior to application of exclusion criteria for patients aged 18 years or older and the minimum period of continuous eligibility, the overall prevalence of PAD was 1.18% of the total managed care organization population.s 6.67 million members. The PAD study cohort consisted of 30,561 patients with a mean age of 70.7 years at index. The most common comorbidities identified in the preindex period for these PAD patients included hypertension (67% of patients); metabolic disorders/hypercholesterolemia (57%); heart disease including cardiomyopathy, dysrhythmias, and heart failure (55%); and ischemic heart disease (47%). Over a mean postindex period of 25.2 months (median 23.4 months), the total mean annualized PAD-related cost was $5,955 per patient per year (PPPY). Hospitalizations accounted for the largest component cost category, averaging $4,442 PPPY or 75% of the total annualized PAD-related cost per PAD patient. PAD-related noncoronary procedures averaged $729 PPPY (12.2% of total annual PAD-related costs), and PAD-related medications (including antihypertensives and lipid-lowering therapy) totaled $610 (10.2% of total annual costs), including $313 PPPY for antihypertensives and $207 for lipid-lowering therapy. For the subgroup of 24,075 newly identified PAD patients, 8,479 (35.2%) were hospitalized during an average 25.2 months of follow-up, with the mean time to first hospitalization of 8.9 months. CONCLUSIONS: Approximately 75% of the total PAD-related patient cost in an average of 25 months of follow-up is contributed by hospital costs, and 35% of patients newly diagnosed with PAD experienced a hospitalization in a mean of 8.9 months after the index diagnosis. Based upon mean annual health and member costs of only $313 PPPY for antihypertensives and $207 for lipid-lowering therapy, drug therapy in PAD patients may be underutilized.

Cost effectiveness of cilostazol compared with naftidrofuryl and pentoxifylline in the treatment of intermittent claudication in the UK.

OBJECTIVE: To estimate the cost effectiveness of cilostazol (Pletal) compared to naftidrofuryl and pentoxifylline (Trental) in the treatment of intermittent claudication in the UK. DESIGN AND SETTING: This was a modelling study on the management of patients with intermittent claudication who are 40 years of age or above and have at least six months history of symptomatic intermittent claudication, secondary to lower extremity arterial occlusive disease. The study was performed from the perspective of the UK's National Health Service (NHS). METHODS: Clinical outcomes attributable to managing intermittent claudication were obtained from the published literature and resource utilisation estimates were derived from a panel of vascular surgeons. Using decision analytical techniques, a decision model was constructed depicting the management of intermittent claudication with cilostazol, naftidrofuryl and pentoxifylline over 24 weeks in the UK. The model was used to estimate the cost effectiveness (at 2002/2003 prices) of cilostazol relative to the other treatments. MAIN OUTCOME MEASURES AND RESULTS: Starting treatment with cilostazol instead of naftidrofuryl is expected to increase the percentage improvement in maximal walking distance by 32% (from 57% to 75%) for a 12% increase in NHS costs (from 801 pounds sterling to 895 pounds sterling). Treatment with cilostazol instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 67% (from 45% to 75%) and reduce NHS costs by 2% (from 917 pounds sterling to 895 pounds sterling). Treatment with naftidrofuryl instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 27% (from 45% to 57%) and decrease NHS costs by 14% (from 917 pounds sterling to 801 pounds sterling). CONCLUSION: Within the limitations of our model, starting treatment with cilostazol is expected to be a clinically more effective strategy for improving maximal walking distance at 24 weeks than starting treatment with naftidrofuryl or pentoxifylline and potentially the most cost effective strategy. Moreover, the acquisition cost of a drug should not be used as an indication of the cost effectiveness of a given method of care.