Background: Cilostazol (CL) is an antithrombotic agent that was approved for prescribing under Japan’s national health insurance system in 2000. Clinical and experimental studies of CL to treat Alzheimer’s disease (AD) have been reported since 2009.Aims: To use the propensity score method to ascertain whether CL reduced medical expenses among patients with AD in a prefecture of Japan.Methods: Records of 21,181 patients with AD (6,484 males and 14,697 females) from April 2010 to March 2011 were selected from a claims database of the National Health Insurance and the Long-term Care Insurance systems in a prefecture in Japan. Covariates were patient characteristics, comorbidities, and drugs prescribed for AD, i.e. psychoactive agents, narcotics, anticonvulsants, or cholinesterase inhibitors. The outcome variable was medical expenses for the whole year.Results: The propensity score indicated that patients receiving CL had medical expenses ¥10.9 higher than those of patients not receiving CL.Conclusion: According to the propensity score method, CL did not efficiently reduce medical expenses for patients with AD based on claims data

HATA Katsuhiko

ITO Susumu

KAMINAKA Toshiaki

KUBOYAMA Izumi

J-GLOBAL ID : 200901011395643320J-GLOBAL ID : 200901012516528555J-GLOBAL ID : 201701008130248251Background: Cilostazol (CL) is an antithrombotic agent that was approved for prescribing under Japan’s national health insurance system in 2000. Clinical and experimental studies of CL to treat Alzheimer’s disease (AD) have been reported since 2009.
Aims: To use the propensity score method to ascertain whether CL reduced medical expenses among patients with AD in a prefecture of Japan.
Methods: Records of 21,181 patients with AD (6,484 males and 14,697 females) from April 2010 to March 2011 were selected from a claims database of the National Health Insurance and the Long-term Care Insurance systems in a prefecture in Japan. Covariates were patient characteristics, comorbidities, and drugs prescribed for AD, i.e. psychoactive agents, narcotics, anticonvulsants, or cholinesterase inhibitors. The outcome variable was medical expenses for the whole year.
Results: The propensity score indicated that patients receiving CL had medical expenses ¥10.9 higher than those of patients not receiving CL.
Conclusion: According to the propensity score method, CL did not efficiently reduce medical expenses for patients with AD based on claims data.application/pdfdepartmental bulletin pape

KUBOYAMA, Izumi

21921

ITO, Susumu

21922

KAMINAKA, Toshiaki

21923

HATA, Katsuhiko

21924

Kokushikan University Academic Information Repository / 国士舘大学　学術情報リポジトリ

－15－Medical expenses for cilostazol to treat Alzheimer’s disease in JapanIzumi  KUBOYAMA*，Susumu  ITO**，Toshiaki  KAMINAKA***  and  Katsuhiko  HATA*ABSTRACTBackground: Cilostazol （CL） is an antithrombotic agent that was approved for prescribing under Japan’s national health insurance system in 2000. Clinical and experimental studies of CL to treat Alzheimer’s disease （AD） have been reported since 2009.Aims: To use the propensity score method to ascertain whether CL reduced medical expenses among patients with AD in a prefecture of Japan.Methods: Records of 21,181 patients with AD （6,484 males and 14,697 females） from April 2010 to March 2011 were selected from a claims database of the National Health Insurance and the Long-term Care Insurance systems in a prefecture in Japan. Covariates were patient characteristics, comorbidities, and drugs prescribed for AD, i.e. psychoactive agents, narcotics, anticonvulsants, or cholinesterase inhibitors. The outcome variable was medical expenses for the whole year. Results: The propensity score indicated that patients receiving CL had medical expenses ￥10.9 higher than those of patients not receiving CL.Conclusion: According to the propensity score method, CL did not efficiently reduce medical expenses for patients with AD based on claims data.Key words; Alzheimer’s disease, cilostazol, medical cost, propensity scoreBackgroundAlzheimer’s disease （AD） is a chronic progressive neurodegenerative disease （1-3） that poses a severe socioeconomic burden （4-6）．Cilostazol （CL） is an antithrombotic agent （7, 8） that has become available under Japan’s National Health Insurance system since 2000. CL is reported to prevent pathological changes of AD in experimental animal models （9, 10）．Clinical use of CL to treat AD was first reported in 2009 （11）， and subsequent studies have been reported （12-13, 16）．CL was occasionally prescribed to patients with AD for its antithrombotic effect since CL was not approved for prescription to patients with AD at the time. Therefore, one could assume that CL was prescribed to * Graduate School of Emergency Medical Systems, Kokushikan University** High-Tech Research Centre, Kokushikan University*** Research and Education Center for Natural Sciences, Keio UniversityTHE ANNUAL REPORTS OFHEALTH, PHYSICAL EDUCATIONAND SPORT SCIENCEVOL.37, 15-21, 2018原　　著Kuboyama  IZUMI，Ito  SUSUMU，Kaminaka  TOSHIAKI  and  Hata  KATSUHIKO－16－patients with AD in a seemingly random manner, representing a “natural experiment” （14）．If CD was clinically effective in treating AD, then it should reduce medical expenses for patients.A propensity score is the probability that a unit will be assigned to a particular treatment given a set of observed covariates, and it is used to reduce selection bias by equating groups based on covariates. A search revealed no studies of medical expenses for CL to treat AD. Therefore, the propensity score method was used to analyze medical expenses for CL to treat AD.AimsThe aim of this study was to use the propensity score method to ascertain whether CL reduced medical expenses among patients with Alzheimer’s disease in a prefecture of JapanMethodsRecords of 21,181 patients with AD （6,484 males and 14,697 females） from April 2010 to March 2011 in a prefecture in Japan were selected from a claims database of the National Health Insurance and the Long-term Care Insurance systems （Figure 1）．The characteristics of the prefecture were as described in a previous study （15）．Covariates were patient characteristics （age, sex, address）， comorbidities, and drugs prescribed for AD, i.e. psychoactive agents, narcotics, anticonvulsants, or cholinesterase inhibitors （Table 1）．The outcome variable was medical expenses （log-transformed） for the whole year （Table 2）．The propensity score method was used to compare patients who were prescribed CL and patients who were not prescribed CL. Comparison was performed using the open-source statistical software R （version 3.3.2）．Figure 1．Flow chart of the studyMedical expenses for cilostazol to treat Alzheimer’s disease in Japan －17－Ethical ConsiderationsThis study was approved by the ethical committee of Kokushikan University （no. 17-003）．FundingThis study was partially funded by the Institute of Health, Physical Education and Sport Science, Kokushikan University.Conflict of InterestsThere were no conflicts of interests in this study.ResultsThe profile of both groups of patients is shown in Table 1. Patient characteristics, comorbidities, and prescribed drugs differed markedly. Patients receiving CL had higher medical expenses than patients not receiving CL （Table 1）．The receiver operating characteristic （ROC） curve is shown in Figure 2, and the C-statistic was 0.7484 （95%CI 0.74‒0.7569）．The distribution of the 2 groups is shown in Figure 3. The distribution indicated that data were amenable for analysis using the propensity score method.The propensity score indicated that medical expenses for patients receiving CL were ￥10.9 higher than those of patients not receiving CL, and this difference was significant （Table 2）．DiscussionThe propensity score indicated that medical expenses for patients receiving CL were only 1 yen higher than those for patients not receiving CL, although this difference was significant. The difference was so small that one could not confidently claim that CL reduced medical expenses for patients with AD.Experimentally, CL has been tested in mice that received central injections with amyloid beta. Repeated administration of CL reduced the accumulation of amyloid beta and tau phosphorylation （9） and improved cognitive performance in several behavioral paradigms （10）．Kuboyama  IZUMI，Ito  SUSUMU，Kaminaka  TOSHIAKI  and  Hata  KATSUHIKO－18－In 2009, Arai et al. first reported administering 100 mg of CL per day as an add-on to donepezil to 10 patients with mild to moderate AD （11）．A subsequent study examined the effect of CL on cognition and regional cerebral blood flow in elderly patients with AD and cerebrovascular disease over a period of 6 months （16）， but patients receiving CL exhibited no change in cognitive function as reflected in their test scores, whereas the control group exhibited a cognitive decline on the Alzheimer’s Disease Assessment Scale-Cognitive subscale. When healthy subjects were acutely Table 1．profile of cilostazol （+） group and cilostazol （-） groupTable 2．results of propensity score method estimate std. error t-value p-valuemedical cost   ¥ 10.9 10.2 3.84 0.0001Medical expenses for cilostazol to treat Alzheimer’s disease in Japan －19－Figure 2．ROC and c-statisticsROC curve showed adequate separation of two groups as C-statistics was 0.7484 95% CI 0.7400-0.7569）．The C-statistics was acceptable for the propensity score method.Figure 3．distribution of propensity scoreThe two groups had clearly different shapes.Kuboyama  IZUMI，Ito  SUSUMU，Kaminaka  TOSHIAKI  and  Hata  KATSUHIKO－20－treated, an increase in cerebral blood flow was not noted. A later study compared the effects of CL and donepezil and donepezil alone on subcortical white matter hyperintensities in patients with mild to moderate AD. Patients receiving CL and donepezil or donepezil alone did not differ in cognitive measures, which included the Mini-Mental State Examination （MMSE） and the Cognitive subscale of the Alzheimer’s Disease Assessment Scale. A recent case-control study examined 60 patients with stable AD receiving acetylcholinesterase inhibitors; patients were equally divided into a placebo group and a group receiving CL as an add-on therapy for at least 12 months. CL was found to improve the MMSE score and the Clinical Dementia Rating sum of boxes scores of patients with AD already receiving acetylcholinesterase inhibitors （17）．In addition, two retrospective studies reported that average doses of CL for 6 months alleviated mild cognitive impairment according to the MMSE score （18, 19）．These clinical studies seem to indicate that CL might improve cognition, and particularly in patients with mild cognitive impairment and mild AD （13）．A randomized control trial of CL in treating mild cognitive impairment is reported to be underway （20）．An economic evaluation of using CL to treat AD is needed to reduce the economic burden of care for AD （1, 2）．LimitationsThe current study had several limitations. The first is that this study was an observational study and not a randomized control trial. The second limitation is that data on claims in one prefecture were selected from a database of the National Health Insurance and the Long-term Care Insurance systems. The prefecture had an average profile among the 47 prefectures in Japan （15）．Presumably, the current results could be generalized to Japan as a whole. The third limitation is that psychoactive agents and narcotics served as covariates to control for confounders. However, the propensity score method is not able to control for unmeasured confounders. Thus, uncontrolled confounders may exist. ConclusionAccording to the propensity score method, CL did not efficiently reduce medical expenses for patients with AD based on claims data.References１） Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia：a Delphi consensus study. Lancet. 2005；366（9503）：2112-7.２） Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016；388（10043）：505-17.３） Kozin SA, Barykin EP, Mitkevich VA, Makarov AA. Anti-amyloid Therapy of Alzheimer’s Disease：Current State and Prospects. Biochemistry Biokhimiia. 2018；83（9）：1057-67.４） Hay JW, Ernst RL. The economic costs of Alzheimer’s disease. American journal of public health. 1987；77Medical expenses for cilostazol to treat Alzheimer’s disease in Japan －21－（9）：1169-75.５） Maresova P, Mohelska H, Dolejs J, Kuca K. Socio-economic Aspects of Alzheimer’s Disease. Current Alzheimer research. 2015；12（9）：903-11.６） Schaller S, Mauskopf J, Kriza C, Wahlster P, Kolominsky-Rabas PL. The main cost drivers in dementia：a systematic review. International journal of geriatric psychiatry. 2015；30（2）：111-29.７） Shintani S, Toba Y, Suzuki S, Ninomiya S, Umezato M, Hiyama T. General pharmacological properties of cilostazol, a new antithrombotic drug. Part I：Effects on the central nervous system. Arzneimittel-Forschung. 1985；35（7A）：1157-62.８） Dawson DL, Cutler BS, Meissner MH, Strandness DE, Jr. Cilostazol has beneficial effects in treatment of intermittent claudication：results from a multicenter, randomized, prospective, double-blind trial. Circulation. 1998；98（7）：678-86.９） Park SH, Kim JH, Bae SS, Hong KW, Lee DS, Leem JY, et al. Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid beta-induced cognitive deficits associated with decreased amyloid beta accumulation. Biochemical and biophysical research communications. 2011；408（4）：602-8.10） Hiramatsu M, Takiguchi O, Nishiyama A, Mori H. Cilostazol prevents amyloid beta peptide（25-35）-induced memory impairment and oxidative stress in mice. British journal of pharmacology. 2010；161（8）：1899-912.11） Arai H TT. A combination therapy of donepezil and cilostazol for patients with moderate Alzheimer disease：pilot follow-up study. The American journal of geriatric psychiatry：official journal of the American Association for Geriatric Psychiatry. 2009；17：353-4.12） Sakurai H, Hanyu H, Sato T, Kume K, Hirao K, Kanetaka H, et al. Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer’s disease and cerebrovascular disease：a pilot study. Geriatrics & gerontology international. 2013；13（1）：90-7.13） Prickaerts J, Heckman PRA, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert opinion on investigational drugs. 2017；26（9）：1033-48.14） Rothman KJ. Epidemiology An Introduction, second edition. pp67-109, Oxford University Press, New York, 2012.15） Kuboyama I, Toyokawa S, Tomio J, Inada H, Tanihara S, Kobayashi Y. The Number of Patients and Therapeutic Profile of Spinal Stenosis Using Health Insurance Claims in Japan. Spine. 2016；41（14）：1146-52.16） Birk S, Kruuse C, Petersen KA, Jonassen O, Tfelt-Hansen P, Olesen J. The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow. Journal of cerebral blood flow and metabolism：official journal of the International Society of Cerebral Blood Flow and Metabolism. 2004；24（12）：1352-8.17） Tai SY, Chen CH, Chien CY, Yang YH. Cilostazol as an add-on therapy for patients with Alzheimer’s disease in Taiwan：a case control study. BMC neurology. 2017；17（1）：40.18） Taguchi A, Tajata Y, Ihara M, Kasahara Y, Tsuji M, Nishino M, Stern D, Ijada M. Cilostazol improves cognitive function in patients with mild cognitive impairment：a retrospective analysis. Psychogeriatrics：Official Journal Japanese Psychogeriatric Society. 2013；13：164-9.19） Ihara M, Nishino M, Taguchi A, Yamamoto Y, Hattori Y, Saito S, Takahashi Y, Tsuji M, Kasahara Y, Takata Y, Ijada M. Cilostazol add-on therapy in patients with mild dementia receiving donepezil：a retrospective study PLoS One. 2014；9：e89516.20） Saito S, Kojima S, Oishi N, Kakuta R, Maki T, Yasuno F, Nagatsuka K, Yamamoto H, Fukuyama H, Fukushima M, Ihara M. A multicenter, randomized, placebo-controlled trial for cilostazol in patients with mild cognitive impairment：The COMCID study protocol. Alzheimers Dement（N Y）．2016；2：250-257.

Medical expenses for cilostazol to treat Alzheimer's disease in Japan

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Medical expenses for cilostazol to treat Alzheimer\u27s disease in Japan

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Medical expenses for cilostazol to treat Alzheimer\u27s disease in Japan

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