Heart and Vessels

, Volume 26, Issue 5, pp 502–510 | Cite as

Cilostazol reduces the progression of carotid intima-media thickness without increasing the risk of bleeding in patients with acute coronary syndrome during a 2-year follow-up

  • Chul Min Ahn
  • Soon Jun HongEmail author
  • Jae Hyung Park
  • Jae Sang Kim
  • Do-Sun Lim
Original Article


Cilostazol, a phosphodiesterase III inhibitor, is known to have anti-proliferative activity. We investigated the effects of cilostazol 200 mg, in addition to aspirin 100 mg and clopidogrel 75 mg, on carotid intima-media thickness (IMT) progression during a 2-year follow-up period in patients with acute coronary syndrome (ACS) requiring stent implantation. Patients with ACS (n = 130) were randomly assigned to the cilostazol group (n = 64) or the control group (n = 66). Longitudinal images of left and right carotid IMT were measured at baseline, at 6, 12, and 24 months using a 10-MHz linear vascular probe. The primary endpoint was to compare the changes in maximum carotid IMT at 2 years. Other parameters such as inflammatory markers [interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP), and adiponectin] and bleeding risk were also compared. The carotid IMT showed no significant progression from baseline in the cilostazol group compared to significant progression in the control group at 12 months (0.78 ± 0.38 and 0.85 ± 0.41 mm, p = 0.034, respectively) and 24 months (0.82 ± 0.41 and 0.96 ± 0.39 mm, p = 0.022, respectively). Major bleeding (p = 1.00), minor bleeding (p = 0.68), and total bleeding rates (p = 0.74) were similar between the two groups during the 2-year follow-up. Decreases from baseline in IL-6 (−2.79 ± 2.83 and −2.14 ± 3.36 pg/ml, p = 0.010, respectively) and TNF-α (−2.81 ± 1.97 and −2.21 ± 2.68 pg/ml, p = 0.029, respectively) were significantly greater in the cilostazol group than the control group during the follow-up. Cilostazol treatment, with greater anti-inflammatory effect, inhibited the progression of carotid IMT without increasing the risk of bleeding in patients with ACS during the 2-year follow-up.


Carotid intima-media thickness Cilostazol Acute coronary syndrome 



The authors express their sincere appreciation to the study participants, and thank Boo Yong Lee, RN, Ki Tae Park, RN, Jun Won Kang, MPA, So Young Choi, RN, and Youn Won Lee, RN for their excellent assistance. This study was supported by Korea University Research Grants (R0804951, R0909361).

Conflict of interest

There is no conflict of interest in connection with any commercial associations, and all authors have nothing to disclose.

Supplementary material

380_2010_93_MOESM1_ESM.doc (38 kb)
Supplementary material 1 (DOC 38 kb)


  1. 1.
    Kablak-Ziembicka A, Przewlocki T, Tracz W, Pieniazek P, Musialek P, Sokolowski A, Drwila R, Rzeznik D (2008) Carotid intima-media thickness in pre- and postmenopausal women with suspected coronary artery disease. Heart Vessels 23:295–300PubMedCrossRefGoogle Scholar
  2. 2.
    Humphries SE, Morgan L (2004) Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol 3:227–235PubMedCrossRefGoogle Scholar
  3. 3.
    Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M (2007) Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115:459–467PubMedCrossRefGoogle Scholar
  4. 4.
    Fichet J, de Labriolle A, Giraudeau B, Arbeille P, Charbonnier B (2008) Reducing risk of stroke in patients with acute coronary syndrome: is screening for asymptomatic carotid disease useful? Heart Vessels 23:397–402PubMedCrossRefGoogle Scholar
  5. 5.
    Iannuzzi A, Licenziati MR, Vacca M, De Marco D, Cinquegrana G, Laccetti M, Bresciani A, Covetti G, Iannuzzo G, Rubba P, Parillo M (2009) Comparison of two diets of varying glycemic index on carotid subclinical atherosclerosis in obese children. Heart Vessels 24:419–424PubMedCrossRefGoogle Scholar
  6. 6.
    Wilcox R, Kupfer S, Erdmann E (2008) Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). Am Heart J 155:712–717PubMedCrossRefGoogle Scholar
  7. 7.
    LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352:1425–1435PubMedCrossRefGoogle Scholar
  8. 8.
    Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342:145–153PubMedCrossRefGoogle Scholar
  9. 9.
    Chen HQ, Tan HY, Yang YW, Qiu L, Liu XQ (2010) Effects of ramipril on serum monocyte chemoattractant protein 1, interleukin-18, and interleukin-10 in elderly patients with acute coronary syndrome. Heart Vessels 25:77–81PubMedCrossRefGoogle Scholar
  10. 10.
    Jia X, Wei M, Fu X, Gu X, Fan W, Zhang J, Xue L (2009) Intensive cholesterol-lowering therapy improves large artery elasticity in acute myocardial infarction patients. Heart Vessels 24:340–346PubMedCrossRefGoogle Scholar
  11. 11.
    Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O’Leary DH, Grobbee DE, Bots ML (2007) Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 297:1344–1353PubMedCrossRefGoogle Scholar
  12. 12.
    Crouse JR 3rd (2006) Thematic review series: patient-oriented research. Imaging atherosclerosis: state of the art. J Lipid Res 47:1677–1699PubMedCrossRefGoogle Scholar
  13. 13.
    Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, Hong MK, Kim HS, Ko JK, Park JH, Lee JH, Choi SW, Seong IW, Cho YH, Lee NH, Kim JH, Chun KJ, Park SJ (2008) Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (a randomized comparison of triple antiplatelet therapy with dual antiplatelet therapy after drug-eluting stent implantation in diabetic patients). J Am Coll Cardiol 51:1181–1187PubMedCrossRefGoogle Scholar
  14. 14.
    Han Y, Li Y, Wang S, Jing Q, Wang Z, Wang D, Shu Q, Tang X (2009) Cilostazol in addition to aspirin and clopidogrel improves long-term outcomes after percutaneous coronary intervention in patients with acute coronary syndromes: a randomized, controlled study. Am Heart J 157:733–739PubMedCrossRefGoogle Scholar
  15. 15.
    Huang Y, Cheng Y, Wu J, Li Y, Xu E, Hong Z, Li Z, Zhang W, Ding M, Gao X, Fan D, Zeng J, Wong K, Lu C, Xiao J, Yao C (2008) Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 7:494–499PubMedCrossRefGoogle Scholar
  16. 16.
    Hamada Y, Kawachi K, Nakata T, Tsunooka N, Takano S, Kohtani T (2000) Effects of a phosphodiesterase III inhibitor on circulating blood volume after cardiopulmonary bypass. Heart Vessels 15:70–73PubMedCrossRefGoogle Scholar
  17. 17.
    Ota H, Eto M, Kano MR, Ogawa S, Iijima K, Akishita M, Ouchi Y (2008) Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler Thromb Vasc Biol 28:1634–1639PubMedCrossRefGoogle Scholar
  18. 18.
    Hong SJ, Shim WJ, Choi JI, Joo HJ, Shin SY, Park SM, Lim SY, Lim DS (2007) Comparison of effects of telmisartan and valsartan on late lumen loss and inflammatory markers after sirolimus-eluting stent implantation in hypertensive patients. Am J Cardiol 100:1625–1629PubMedCrossRefGoogle Scholar
  19. 19.
    Shinoda-Tagawa T, Yamasaki Y, Yoshida S, Kajimoto Y, Tsujino T, Hakui N, Matsumoto M, Hori M (2002) A phosphodiesterase inhibitor, cilostazol, prevents the onset of silent brain infarction in Japanese subjects with type II diabetes. Diabetologia 45:188–194PubMedCrossRefGoogle Scholar
  20. 20.
    Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, Grines CL, Block E, Ghazzal ZM, Morris DC, Liberman H, Parker K, Jurkovitz C, Murrah N, Foster J, Hyde P, Mancini GB, Weintraub WS (2005) Coronary stent restenosis in patients treated with cilostazol. Circulation 112:2826–2832PubMedCrossRefGoogle Scholar
  21. 21.
    Morishita R (2005) A scientific rationale for the CREST trial results: evidence for the mechanism of action of cilostazol in restenosis. Atheroscler Suppl 6:41–46PubMedCrossRefGoogle Scholar
  22. 22.
    Inoue T, Uchida T, Sakuma M, Imoto Y, Ozeki Y, Ozaki Y, Hikichi Y, Node K (2004) Cilostazol inhibits leukocyte integrin Mac-1, leading to a potential reduction in restenosis after coronary stent implantation. J Am Coll Cardiol 44:1408–1414PubMedCrossRefGoogle Scholar
  23. 23.
    O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14–22PubMedCrossRefGoogle Scholar
  24. 24.
    Langenfeld MR, Forst T, Hohberg C, Kann P, Lubben G, Konrad T, Fullert SD, Sachara C, Pfutzner A (2005) Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 111:2525–2531PubMedCrossRefGoogle Scholar
  25. 25.
    Touboul PJ, Elbaz A, Koller C, Lucas C, Adrai V, Chedru F, Amarenco P (2000) Common carotid artery intima-media thickness and brain infarction: the Etude du Profil Genetique de l’Infarctus Cerebral (GENIC) case–control study. The GENIC Investigators. Circulation 102:313–318PubMedGoogle Scholar
  26. 26.
    Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G (2001) Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS). Circulation 103:1721–1726PubMedGoogle Scholar
  27. 27.
    Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo K (2001) Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 103:919–925PubMedGoogle Scholar
  28. 28.
    Bots ML, Evans GW, Riley WA, Grobbee DE (2003) Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view. Stroke 34:2985–2994PubMedCrossRefGoogle Scholar
  29. 29.
    Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 102:1296–1301PubMedGoogle Scholar
  30. 30.
    Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y (2001) Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103:1057–1063PubMedGoogle Scholar
  31. 31.
    Tan J, Hua Q, Li J, Fan Z (2009) Prognostic value of interleukin-6 during a 3-year follow-up in patients with acute ST-segment elevation myocardial infarction. Heart Vessels 24:329–334PubMedCrossRefGoogle Scholar
  32. 32.
    Devaraj S, O’Keefe G, Jialal I (2005) Defining the proinflammatory phenotype using high sensitive C-reactive protein levels as the biomarker. J Clin Endocrinol Metab 90:4549–4554PubMedCrossRefGoogle Scholar
  33. 33.
    Fantuzzi G (2005) Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 115:911–919PubMedCrossRefGoogle Scholar
  34. 34.
    Yun KH, Jeong MH, Oh SK, Rhee SJ, Park EM, Lee EM, Yoo NJ, Kim NH, Ahn YK, Jeong JW (2009) Response of high-sensitivity C-reactive protein to percutaneous coronary intervention in patients with acute coronary syndrome. Heart Vessels 24:175–180PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Chul Min Ahn
    • 1
  • Soon Jun Hong
    • 1
    Email author
  • Jae Hyung Park
    • 1
  • Jae Sang Kim
    • 1
  • Do-Sun Lim
    • 1
  1. 1.Department of Cardiology, Cardiovascular CenterKorea University Anam HospitalSeoulKorea

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