, Volume 14, Issue 3, pp 784–791 | Cite as

Cilostazol Use Is Associated with Reduced Risk of Dementia: A Nationwide Cohort Study

  • Shu-Yu Tai
  • Chen-Yu Chien
  • Yu-Han Chang
  • Yuan-Han Yang
Original Article


Whether antiplatelet agents have a preventive effect on cognitive function remains unknown. We examined the potential association between the use of cilostazol, an antiplatelet agent and cyclic adenosine monophosphate phosphodiesterase 3 inhibitor, and the risk of dementia in an Asian population. Patients initiating cilostazol therapy between 1 January 2004 and 31 December 2009 without a prior history of dementia were identified from Taiwan's National Health Insurance database. Participants were stratified by age, sex, comorbidities, and comedication. The outcome of interest was all-cause dementia (ICD-9-CM codes 290.0, 290.4, 294.1, 331.0). Cox regression models were used to estimate the hazard ratio (HR) of dementia. The cumulative cilostazol dosage was stratified by quartile of defined daily doses using no cilostazol use as a reference. A total of 9148 participants 40 years of age or older and free of dementia at baseline were analyzed. Patients using cilostazol (n = 2287) had a significantly decreased risk of incident dementia compared with patients not using the drug [n = 6861; adjusted HR (aHR) 0.75; 95% confidence interval (CI) 0.61–0.92]. Notably, cilostazol use was found to have a dose-dependent association with reduced rate of dementia emergence (p for trend = 0.001). Subgroup analysis identified a decline of dementia in cilostazol users with diagnosed ischemic heart disease (aHR 0.44, 95% CI 0.24–0.83) and cerebral vascular disease (aHR 0.34, 95% CI 0.21–0.54). These observations suggest that cilostazol use may reduce the risk to develop dementia, and a high cumulative dose further decreases the risk of dementia. These findings should be examined further in randomized clinical trials.

Key Words

Dementia cilostazol cohort studies 



This study was supported by grants from Kaohsiung Medical University Hospital (KMUH103-3R68 and KMUH105-5R64), the Ministry of Science and Technology (MOST103-2314-B-037-004-MY3), and Research Center for Environmental Medicine, Kaohsiung Medical University (KMU-TP104A34), none of which have had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are grateful for the assistance of the Statistical Analysis Laboratory, Department of Medical Research, Kaohsiung Municipal Ta-Tung Hospital.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflict of interest to declare.

Supplementary material

13311_2017_512_MOESM1_ESM.doc (52 kb)
Table S1 (DOC 51 kb)
13311_2017_512_MOESM2_ESM.pdf (524 kb)
ESM 1 (PDF 524 kb)


  1. 1.
    Department of Statistics, Ministry of the Interior, Taiwan, [online]. Available at: Accessed January 25, 2017.
  2. 2.
    The China Post news staff. Taiwan must address the challenges of an aging society [online]. Available at: Accessed October 13, 2013.
  3. 3.
    Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 2007;3(3):186–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Drugs for Alzheimer's disease: best avoided. No therapeutic advantage. Prescrire international. 2012;21(128):150.Google Scholar
  5. 5.
    Birks J, Flicker L. Donepezil for mild cognitive impairment. The Cochrane database of systematic reviews. 2006(3):CD006104.Google Scholar
  6. 6.
    Taguchi A. Vascular factors in diabetes and Alzheimer's disease. J Alzheimers Dis. 2009;16(4):859–64.CrossRefPubMedGoogle Scholar
  7. 7.
    Gresele P, Momi S, Falcinelli E. Anti-platelet therapy: phosphodiesterase inhibitors. British Journal of Clinical Pharmacology. 2011;72(4):634–46.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. The Lancet Neurology. 2010;9(10):959–68.CrossRefPubMedGoogle Scholar
  9. 9.
    Kasahara Y, Nakagomi T, Matsuyama T, Stern D, Taguchi A. Cilostazol Reduces the Risk of Hemorrhagic Infarction After Administration of Tissue-Type Plasminogen Activator in a Murine Stroke Model. Stroke. 2012;43(2):499–506.CrossRefPubMedGoogle Scholar
  10. 10.
    Tanaka K, Gotoh F, Fukuuchi Y, Amano T, Uematsu D, Kawamura J, et al. Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia. Stroke. 1989;20(5):668–73.CrossRefPubMedGoogle Scholar
  11. 11.
    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. Biochem Biophys Res Commun. 2011;408(4):602–8.CrossRefPubMedGoogle Scholar
  12. 12.
    WHO Collaborating Centre for Drug Statistics Methodology. Defined daily dose: definition and general considerations [online]. Available at: Accessed December 20, 2016.
  13. 13.
    Stricker BH, Stijnen T. Analysis of individual drug use as a time-varying determinant of exposure in prospective population-based cohort studies. Eur J Epidemiol. 2010;25(4):245–51.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hong KW, Lee JH, Kima KY, Park SY, Lee WS. Cilostazol: therapeutic potential against focal cerebral ischemic damage. Curr Pharm Des. 2006;12(5):565–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Zheng XT, Chen KY, Liu T, Xu LX, Che JJ, Rha SW, et al. Low-dose adjunctive cilostazol in patients with complex lesions undergoing percutaneous coronary intervention. Clin Exp Pharmacol Physiol. 2016;43(1):29–33.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang W, Zhang L, Liu W, Zhu Q, Lan Q, Zhao J. Antiplatelet Agents for the Secondary Prevention of Ischemic Stroke or Transient Ischemic Attack: A Network Meta-Analysis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2016;25(5):1081–9.CrossRefGoogle Scholar
  17. 17.
    Ueda H, Kido A, Matsuhisa S, Asawa K, Yoshida N, Tsujimoto M, et al. Addition of cilostazol to aspirin therapy for secondary prevention of cardiovascular and cerebrovascular disease in patients undergoing percutaneous coronary intervention: A randomized, open-label trial. Am Heart J. 2016;173:134–42.CrossRefPubMedGoogle Scholar
  18. 18.
    Lee JH, Park SY, Shin YW, Hong KW, Kim CD, Sung SM, et al. Neuroprotection by cilostazol, a phosphodiesterase type 3 inhibitor, against apoptotic white matter changes in rat after chronic cerebral hypoperfusion. Brain research. 2006;1082(1):182–91.CrossRefPubMedGoogle Scholar
  19. 19.
    Heckman PR, Wouters C, Prickaerts J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimer's disease: a translational overview. Curr Pharm Des. 2015;21(3):317-31.CrossRefPubMedGoogle Scholar
  20. 20.
    Arai H, Takahashi T. A combination therapy of donepezil and cilostazol for patients with moderate Alzheimer disease: pilot follow-up study. Am J Geriatr Psychiatry. 2009;17(4):353–4.CrossRefPubMedGoogle Scholar
  21. 21.
    Mochizuki Y, Oishi M, Mizutani T. Effects of cilostazol on cerebral blood flow, P300, and serum lipid levels in the chronic stage of cerebral infarction. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2001;10(2):63–9.CrossRefGoogle Scholar
  22. 22.
    Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005;25(29):6887–97.CrossRefGoogle Scholar
  23. 23.
    Watanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T. Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke. 2006;37(6):1539–45.CrossRefPubMedGoogle Scholar
  24. 24.
    Lee JH, Park SY, Shin YW, Kim CD, Lee WS, Hong KW. Concurrent administration of cilostazol with donepezil effectively improves cognitive dysfunction with increased neuroprotection after chronic cerebral hypoperfusion in rats. Brain research. 2007;1185:246–55.CrossRefPubMedGoogle Scholar
  25. 25.
    Bellew KM, Pigeon JG, Stang PE, Fleischman W, Gardner RM, Baker WW. Hypertension and the rate of cognitive decline in patients with dementia of the Alzheimer type. Alzheimer disease and associated disorders. 2004;18(4):208–13.PubMedGoogle Scholar
  26. 26.
    Taguchi A, Takata Y, Ihara M, Kasahara Y, Tsuji M, Nishino M, et al. Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis. Psychogeriatrics. 2013;13(3):164–9.CrossRefPubMedGoogle Scholar
  27. 27. [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: (NLM Identifier: NCT01409564). Accessed July 12, 2016.
  28. 28.
    Ihara M, Nishino M, Taguchi A, Yamamoto Y, Hattori Y, Saito S, et al. Cilostazol add-on therapy in patients with mild dementia receiving donepezil: a retrospective study. PLoS One. 2014;9(2):e89516.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    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. Geriatr Gerontol Int. 2013;13(1):90–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Chi Y-W, Lavie CJ, Milani RV, White CJ. Safety and efficacy of cilostazol in the management of intermittent claudication. Vascular Health and Risk Management. 2008;4(6):1197–203.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  • Shu-Yu Tai
    • 1
    • 2
    • 3
    • 4
  • Chen-Yu Chien
    • 5
    • 6
    • 7
  • Yu-Han Chang
    • 8
  • Yuan-Han Yang
    • 9
    • 10
  1. 1.Department of Family Medicine, School of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan
  2. 2.Department of Family Medicine, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiung CityTaiwan
  3. 3.Department of Family Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiung CityTaiwan
  4. 4.Research Center for Environmental MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan
  5. 5.Department of Otorhinolaryngology, School of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan
  6. 6.Department of Otorhinolaryngology, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiung CityTaiwan
  7. 7.Department of Otorhinolaryngology, Kaohsiung Municipal Hsiao-Kang HospitalKaohsiung Medical UniversityKaohsiung CityTaiwan
  8. 8.Management Offices, Kaohsiung Municipal Ta-Tung HospitalKaohsiung Medical UniversityKaohsiung CityTaiwan
  9. 9.Department of Neurology, Kaohsiung Municipal Ta-Tung HospitalKaohsiung Medical UniversityKaohsiung CityTaiwan
  10. 10.Department of Master’s Program in Neurology, Faculty of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan

Personalised recommendations