Skip to main content

Advertisement

SpringerLink
Log in

Effects of ezetimibe and anticoagulant combined therapy on progressing stroke: a randomized, placebo-controlled study

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Despite the high prevalence of progressing stroke in patients with acute stroke, preventative treatments are still the unmet needs for those patients. The aim of this study was to evaluate, prospectively, the efficacy and safety of ezetimibe in the prevention of acute progressing stroke and thereby the improvement of patient outcome. A total of 423 patients (267 men and 156 women with a mean age of 65.2 years) were randomly assigned to receive ezetimibe (10 mg daily oral administration, n = 209) or placebo (n = 214) for 14 consecutive days. Analytical procedures performed at baseline (i.e., day 1) and 14 days after the treatments were completed. These included a real-time three-dimensional ultrasound (RT-3DU) examination for carotid plaque volume, clinical laboratory analyses of serum levels of IL-6 and MMP-9, as well as lipid parameters and liver dysfunction marker ALT and TBIL. Ezetimibe significantly reduced the average NIHSS score after 14 days of treatment and attenuated the stroke progression rate, which was associated with reduction in carotid plaque volume and attenuation of serum levels of IL-6, MMP-9, and LDL, without inducing liver dysfunction. Ezetimibe treatment may be a beneficial and effective strategy for preventing progressing stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF (2007) Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 38:1655–1711

    Article  PubMed  Google Scholar 

  2. Barer D (1997) Interpretation of IST and CAST stroke trials. International Stroke Trial. Chinese Acute Stroke Trial. Lancet 350:440 (author reply 443–444)

    Article  CAS  PubMed  Google Scholar 

  3. Battaggia A, Donzelli A, Font M, Molteni D, Galvano A (2015) Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized controlled trials. PLoS One 10:e0124587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bays HE, Moore PB, Drehobl MA, Rosenblatt S, Toth PD, Dujovne CA, Knopp RH, Lipka LJ, Lebeaut AP, Yang B, Mellars LE, Cuffie-Jackson C, Veltri EP (2001) Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 23:1209–1230

    Article  CAS  PubMed  Google Scholar 

  5. Berry CN, Girardot C, Lecoffre C, Lunven C (1994) Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost 72:381–386

    CAS  PubMed  Google Scholar 

  6. Berthold HK, Berneis K, Mantzoros CS, Krone W, Gouni-Berthold I (2013) Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C-reactive protein. Scand Cardiovasc J Suppl 47:20–27

    Article  CAS  PubMed  Google Scholar 

  7. Britton M, Roden A (1985) Progression of stroke after arrival at hospital. Stroke 16:629–632

    Article  CAS  PubMed  Google Scholar 

  8. Davalos A, Cendra E, Teruel J, Martinez M, Genis D (1990) Deteriorating ischemic stroke: risk factors and prognosis. Neurology 40:1865–1869

    Article  CAS  PubMed  Google Scholar 

  9. Davie EW, Fujikawa K, Kisiel W (1991) The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30:10363–10370

    Article  CAS  PubMed  Google Scholar 

  10. Davies MJ (1995) Acute coronary thrombosis–the role of plaque disruption and its initiation and prevention. Eur Heart J 16(Suppl L):3–7

    Article  PubMed  Google Scholar 

  11. Dawson JA, Choke E, Loftus IM, Cockerill GW, Thompson MM (2011) A randomised placebo-controlled double-blind trial to evaluate lipid-lowering pharmacotherapy on proteolysis and inflammation in abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 41:28–35

    Article  CAS  PubMed  Google Scholar 

  12. Denes A, Thornton P, Rothwell NJ, Allan SM (2010) Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun 24:708–723

    Article  CAS  PubMed  Google Scholar 

  13. Di Nisio M, Middeldorp S, Buller HR (2005) Direct thrombin inhibitors. N Engl J Med 353:1028–1040

    Article  PubMed  Google Scholar 

  14. Dollery CM, McEwan JR, Henney AM (1995) Matrix metalloproteinases and cardiovascular disease. Circ Res 77:863–868

    Article  CAS  PubMed  Google Scholar 

  15. Dujovne CA, Ettinger MP, McNeer JF, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP (2002) Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 90:1092–1097

    Article  CAS  PubMed  Google Scholar 

  16. Duke RJ, Bloch RF, Turpie AG, Trebilcock R, Bayer N (1986) Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med 105:825–828

    Article  CAS  PubMed  Google Scholar 

  17. Godley RW, Hernandez-Vila E (2016) Aspirin for Primary and Secondary Prevention of Cardiovascular Disease. Tex Heart Inst J 43:318–319

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hashikata T, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Namba S, Kitasato L, Hashimoto T, Ishii S, Kameda R, Shimohama T, Tojo T, Ako J (2016) Ezetimibe enhances and stabilizes anticoagulant effect of warfarin. Heart Vessels

  19. Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R (1989) Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation 80:749–756

    Article  CAS  PubMed  Google Scholar 

  20. Hirsh J (1985) Progress review: the relationship between dose of aspirin, side-effects and antithrombotic effectiveness. Stroke 16:1–4

    Article  CAS  PubMed  Google Scholar 

  21. Ishibashi T, Takeishi Y (2011) Ezetimibe and vascular inflammation. Curr Vasc Pharmacol 9:99–108

    Article  CAS  PubMed  Google Scholar 

  22. Jiang XB, Yuan WS, Wang JS, Liu Z, Liu DH, Shi ZS (2014) Matrix metalloproteinase-9 expression in carotid atherosclerotic plaque and contrast-enhanced MRI in a swine model. J Neurointerv Surg 6:24–28

    Article  PubMed  Google Scholar 

  23. Jones HR Jr, Millikan CH, Sandok BA (1980) Temporal profile (clinical course) of acute vertebrobasilar system cerebral infarction. Stroke 11:173–177

    Article  PubMed  Google Scholar 

  24. Leira R, Davalos A, Aneiros A, Serena J, Pumar JM, Castillo J (2002) Headache as a surrogate marker of the molecular mechanisms implicated in progressing stroke. Cephalalgia 22:303–308

    Article  CAS  PubMed  Google Scholar 

  25. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE 3rd, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H (1983) Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396–403

    Article  PubMed  Google Scholar 

  26. Lipka LJ, Knopp RH, Gitter H, Truitt T, Grp ES (2001) Ezetimibe significantly lowers low-density lipoprotein cholesterol in subjects with primary hypercholesterolaemia. Eur Heart J 22:252

    Google Scholar 

  27. Liu CH, Chen TH, Lin MS, Hung MJ, Chung CM, Cherng WJ, Lee TH, Lin YS (2016) Ezetimibe-simvastatin therapy reduce recurrent ischemic stroke risks in type 2 diabetic patients. J Clin Endocrinol Metab. doi:10.1210/jc.2016-1831

    PubMed Central  Google Scholar 

  28. Loftus IM, Naylor AR, Goodall S, Crowther M, Jones L, Bell PR, Thompson MM (2000) Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke 31:40–47

    Article  CAS  PubMed  Google Scholar 

  29. McColl BW, Allan SM, Rothwell NJ (2009) Systemic infection, inflammation and acute ischemic stroke. Neuroscience 158:1049–1061

    Article  CAS  PubMed  Google Scholar 

  30. Nakamura T, Tsuruta S, Uchiyama S (2012) Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: a pilot study. J Neurol Sci 313:22–26

    Article  CAS  PubMed  Google Scholar 

  31. Okazaki S, Sakaguchi M, Miwa K, Furukado S, Yamagami H, Yagita Y, Mochizuki H, Kitagawa K (2014) Association of interleukin-6 with the progression of carotid atherosclerosis: a 9-year follow-up study. Stroke 45:2924–2929

    Article  CAS  PubMed  Google Scholar 

  32. Putman SF, Adams HP Jr (1985) Usefulness of heparin in initial management of patients with recent transient ischemic attacks. Arch Neurol 42:960–962

    Article  CAS  PubMed  Google Scholar 

  33. Roden-Jullig A, Britton M, Malmkvist K, Leijd B (2003) Aspirin in the prevention of progressing stroke: a randomized controlled study. J Intern Med 254:584–590

    Article  CAS  PubMed  Google Scholar 

  34. Savarese G, De Ferrari GM, Rosano GM, Perrone-Filardi P (2015) Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol 201:247–252

    Article  PubMed  Google Scholar 

  35. Serena J, Rodriguez-Yanez M, Castellanos M (2006) Deterioration in acute ischemic stroke as the target for neuroprotection. Cerebrovasc Dis 21(Suppl 2):80–88

    Article  PubMed  Google Scholar 

  36. Shimizu H, Tominaga T, Ogawa A, Kayama T, Mizoi K, Saito K, Terayama Y, Ogasawara K, Mori E (2013) Cilostazol for the prevention of acute progressing stroke: a multicenter, randomized controlled trial. J Stroke Cerebrovasc Dis 22:449–456

    Article  PubMed  Google Scholar 

  37. Slivka A, Levy D (1990) Natural history of progressive ischemic stroke in a population treated with heparin. Stroke 21:1657–1662

    Article  CAS  PubMed  Google Scholar 

  38. Smith JB, Willis AL (1971) Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol 231:235–237

    Article  CAS  PubMed  Google Scholar 

  39. Stein E (2001) Results of phase I/II clinical trials with ezetimibe, a novel selective cholesterol absorption inhibitor. Eur Heart J Suppl 3:E11–E16

    Article  CAS  Google Scholar 

  40. Sumer M, Ozdemir I, Erturk O (2003) Progression in acute ischemic stroke: frequency, risk factors and prognosis. J Clin Neurosci 10:177–180

    Article  PubMed  Google Scholar 

  41. Tamaki N, Ueno H, Morinaga Y, Shiiya T, Nakazato M (2012) Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. J Atheroscler Thromb 19:532–538

    Article  CAS  PubMed  Google Scholar 

  42. Van Heek M, France CF, Compton DS, McLeod RL, Yumibe NP, Alton KB, Sybertz EJ, Davis HR Jr (1997) In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. J Pharmacol Exp Ther 283:157–163

    PubMed  Google Scholar 

  43. Wang X, Zhao X, Li L, Yao H, Jiang Y, Zhang J (2016) Effects of combination of ezetimibe and rosuvastatin on coronary artery plaque in patients with coronary heart disease. Heart Lung Circ 25:459–465

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Health Department of Hebei Province, and all the medical staff in Department of Neurology, The Second Hospital of Hebei Medical University for the help. This study was supported by The Key Project of Medical Science Research in Hebei Province 2016 (20160567).

Author information

Authors and Affiliations

  1. The Second Hospital of Hebei Medical University, Shijiazhuang, China

    Lan Yang, Jing Zhao, Juan Wang & Xiaopeng Wang

  2. The Third Hospital of Shijiazhuang, Shijiazhuang, China

    Pingping Zhao

  3. Quyang County People’s Hospital, Quyang, China

    Lei Shi

Authors
  1. Lan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pingping Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaopeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaopeng Wang.

Ethics declarations

Conflicts of interest

The authors have no conflict of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, L., Zhao, P., Zhao, J. et al. Effects of ezetimibe and anticoagulant combined therapy on progressing stroke: a randomized, placebo-controlled study. J Neurol 263, 2438–2445 (2016). https://doi.org/10.1007/s00415-016-8283-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-016-8283-0

Keywords

Search

Navigation