Skip to main content
SpringerLink
Log in

Rationale and Design of the EPISTEME Trial: Efficacy of Post-Stroke Intensive Rosuvastatin Treatment for Aortogenic Embolic Stroke

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

Large atheromatous aortic plaques (AAPs) are associated with stroke recurrence. Rosuvastatin is a potent lipid-lowering agent and suppresses carotid and coronary artery atherosclerosis. It is unclear whether rosuvastatin has anti-atherogenic effects against AAPs in stroke patients. We designed a clinical trial in stroke patients to analyze changes in AAPs after rosuvastatin treatment using repeated transesophageal echocardiography (TEE).

Methods

This trial is a prospective randomized open label study. Inclusion criteria were patients were ischemic stroke with hypercholesterolemia and AAPs ≥4 mm in thickness. The patients are randomly assigned to either a group treated with 5 mg/day rosuvastatin or a control group. Primary endpoint is the changes in volume and composition of AAPs after 6 months using transesophageal echocardiography (TEE). Biochemical findings are analyzed. By using repeated TEE and binary image analysis, we will be able to compare the dynamic changes in plaque composition of AAPs before and after therapy in the two groups.

Conclusions

The EPISTEME trial will provide information on the changes in plaque volume and composition achieved by improvement of lipid profiles with rosuvastatin therapy in stroke patients with aortic atherosclerosis. The results of the study may provide evidence for a therapeutic strategy for aortogenic brain embolism. This study is registered with UMIN-CTR (UMIN000010548).

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

Similar content being viewed by others

References

  1. Kubo M, Hata J, Doi Y, Tanizaki Y, Iida M, Kiyohara Y. Secular trends in the incidence of and risk factors for ischemic stroke and its subtypes in Japanese population. Circulation. 2008;118:2672–8.

    Article  PubMed  Google Scholar 

  2. Kubo M, Kiyohara Y, Ninomiya T, et al. Decreasing incidence of lacunar vs other types of cerebral infarction in a Japanese population. Neurology. 2006;66:1539–44.

    Article  CAS  PubMed  Google Scholar 

  3. The French study of aortic plaques in stroke group. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med. 1996;334:1216–21.

    Article  Google Scholar 

  4. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med. 1994;331:1474–9.

    Article  CAS  PubMed  Google Scholar 

  5. Okuzumi A, Ueno Y, Shimada Y, et al. Impact of low-density lipoprotein to high-density lipoprotein ratio on aortic arch atherosclerosis in unexplained stroke. J Neurol Sci. 2013;326:83–8.

    Article  CAS  PubMed  Google Scholar 

  6. Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320:904–10.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang X, Patel A, Horibe H, et al. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol. 2003;32:563–72.

    Article  CAS  PubMed  Google Scholar 

  8. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97:1453–60.

    Article  CAS  PubMed  Google Scholar 

  9. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57.

    Article  Google Scholar 

  10. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–59.

    Article  CAS  PubMed  Google Scholar 

  11. Falk E. Why do plaques rupture? Circulation. 1992;86:III30–42.

    CAS  PubMed  Google Scholar 

  12. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med. 1992;326:310–8.

    Article  CAS  PubMed  Google Scholar 

  13. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation. 1996;94:2013–20.

    Article  CAS  PubMed  Google Scholar 

  14. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–65.

    Article  CAS  PubMed  Google Scholar 

  15. Underhill HR, Yuan C, Zhao XQ, et al. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial. Am Heart J. 2008;155:584.e581–8.

    Article  Google Scholar 

  16. Takayama T, Hiro T, Yamagishi M, et al. Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). Circ J. 2009;73:2110–7.

    Article  CAS  PubMed  Google Scholar 

  17. Otagiri K, Tsutsui H, Kumazaki S, et al. Early intervention with rosuvastatin decreases the lipid components of the plaque in acute coronary syndrome: analysis using integrated backscatter IVUS (ELAN study). Circ J. 2011;75:633–41.

    Article  CAS  PubMed  Google Scholar 

  18. Crouse 3rd JR, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. JAMA. 2007;297:1344–53.

    Article  CAS  PubMed  Google Scholar 

  19. Ueno Y, Chopp M, Zhang L, et al. Axonal outgrowth and dendritic plasticity in the cortical peri-infarct area after experimental stroke. Stroke. 2012;43:2221–8.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Nakaji K, Ihara M, Takahashi C, et al. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke. 2006;37:2816–23.

    Article  CAS  PubMed  Google Scholar 

  21. Teramoto T, Sasaki J, Ueshima H, et al. Diagnostic criteria for dyslipidemia. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler Thromb. 2007;14:155–8.

    Article  CAS  PubMed  Google Scholar 

  22. Ueno Y, Kimura K, Iguchi Y, et al. Mobile aortic plaques are a cause of multiple brain infarcts seen on diffusion-weighted imaging. Stroke. 2007;38:2470–6.

    Article  PubMed  Google Scholar 

  23. Yonemura A, Momiyama Y, Fayad ZA, et al. Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques detected by noninvasive magnetic resonance imaging. J Am Coll Cardiol. 2005;45:733–42.

    Article  CAS  PubMed  Google Scholar 

  24. Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation. 2004;110:2336–41.

    Article  CAS  PubMed  Google Scholar 

  25. Kutz SM, Lee VS, Tunick PA, Krinsky GA, Kronzon I. Atheromas of the thoracic aorta: A comparison of transesophageal echocardiography and breath-hold gadolinium-enhanced 3-dimensional magnetic resonance angiography. J Am Soc Echocardiogr. 1999;12:853–8.

    Article  CAS  PubMed  Google Scholar 

  26. Kronzon I, Tunick PA. Aortic atherosclerotic disease and stroke. Circulation. 2006;114:63–75.

    Article  PubMed  Google Scholar 

  27. Negishi K, Tsuchiya H, Nakajima M, et al. The seabed-like appearance of atherosclerotic plaques: three-dimensional transesophageal echocardiographic images of the aortic arch causing cholesterol crystal emboli. J Am Soc Echocardiogr. 2010;23:1222.e1221–4.

    Article  Google Scholar 

  28. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103:926–33.

    Article  CAS  PubMed  Google Scholar 

  29. Cheng SL, Shao JS, Halstead LR, Distelhorst K, Sierra O, Towler DA. Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/beta-catenin signaling and aortic fibrosis in diabetic arteriosclerosis. Circ Res. 2010;107:271–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Sukhova GK, Williams JK, Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol. 2002;22:1452–8.

    Article  CAS  PubMed  Google Scholar 

  31. Hara H, Tsunoda T, Nemoto N, et al. Distribution of ultrasonic radiofrequency signal amplitude detects lipids in atherosclerotic plaque of coronary arteries: an ex-vivo study. Cardiovasc Ultrasound. 2008;6:18.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Miyauchi K, Takaya N, Hirose T, et al. Rationale and design of the carotid plaque in human for all evaluations with aggressive rosuvastatin therapy (CHALLENGER trial): evaluation by magnetic resonance imaging. Circ J. 2009;73:111–5.

    Article  PubMed  Google Scholar 

  33. Soyama Y, Miura K, Morikawa Y, et al. High-density lipoprotein cholesterol and risk of stroke in Japanese men and women: the Oyabe Study. Stroke. 2003;34:863–8.

    Article  CAS  PubMed  Google Scholar 

  34. Nakaya N, Kita T, Mabuchi H, et al. Large-scale cohort study on the relationship between serum lipid concentrations and risk of cerebrovascular disease under low-dose simvastatin in Japanese patients with hypercholesterolemia: sub-analysis of the Japan Lipid Intervention Trial (J-LIT). Circ J. 2005;69:1016–21.

    Article  CAS  PubMed  Google Scholar 

  35. Amarenco P, Goldstein LB, Callahan A, et al. Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerosis. 2009;204:515–20.

    Article  CAS  PubMed  Google Scholar 

  36. Mahajan N, Ference BA, Arora N, et al. Role of non-high-density lipoprotein cholesterol in predicting cerebrovascular events in patients following myocardial infarction. Am J Cardiol. 2012;109:1694–9.

    Article  CAS  PubMed  Google Scholar 

  37. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326–33.

    Article  CAS  PubMed  Google Scholar 

  38. Takarada S, Imanishi T, Ishibashi K, et al. The effect of lipid and inflammatory profiles on the morphological changes of lipid-rich plaques in patients with non-ST-segment elevated acute coronary syndrome: follow-up study by optical coherence tomography and intravascular ultrasound. JACC Cardiovasc Interv. 2010;3:766–72.

    Article  PubMed  Google Scholar 

  39. Kimura T, Itoh T, Fusazaki T, et al. Low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol ratio predicts lipid-rich coronary plaque in patients with coronary artery disease-integrated-backscatter intravascular ultrasound study. Circ J. 2010;74:1392–8.

    Article  PubMed  Google Scholar 

  40. Machino-Ohtsuka T, Seo Y, Ishizu T, et al. Combined assessment of carotid vulnerable plaque, renal insufficiency, eosinophilia, and hs-CRP for predicting risky aortic plaque of cholesterol crystal embolism. Circ J. 2010;74:51–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

None.

Conflict of Interest

AstraZeneca K.K. participated in the preparation of the study design. However, the investigators made the final decision on the study design, wrote this manuscript and decided to submit the article. Dr. Daida and Dr. Urabe have received research grants from AstraZeneca K.K., and Shionogi Co., Ltd. Dr. Daida was an advisory member of AstraZeneca K.K. and Shionogi Co., Ltd. Dr. Miyauchi is an advisory member of AstraZeneca K.K. Dr. Daida, Dr. Urabe and Dr. Miyauchi have received honoraria for lectures from AstraZeneca K.K., and Shionogi Co., Ltd. The other authors have no conflict of interest.

Ethical Standard

All human studies have been approved by the independent ethics committee of Juntendo University Urayasu Hospital (2011–048) and Juntendo University Hospital (12–63), and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Author information

Authors and Affiliations

  1. Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan

    Yuji Ueno, Yasutaka Tanaka, Masao Watanabe, Nobukazu Miyamoto & Takao Urabe

  2. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

    Kazuo Yamashiro, Yoshiaki Shimada, Takuma Kuroki, Ryota Tanaka & Nobutaka Hattori

  3. Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan

    Masao Daimon, Katsumi Miyauchi & Hiroyuki Daida

Authors
  1. Yuji Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuo Yamashiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasutaka Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masao Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshiaki Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takuma Kuroki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobukazu Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masao Daimon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ryota Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Katsumi Miyauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroyuki Daida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nobutaka Hattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Takao Urabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuji Ueno.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ueno, Y., Yamashiro, K., Tanaka, Y. et al. Rationale and Design of the EPISTEME Trial: Efficacy of Post-Stroke Intensive Rosuvastatin Treatment for Aortogenic Embolic Stroke. Cardiovasc Drugs Ther 28, 79–85 (2014). https://doi.org/10.1007/s10557-013-6493-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-013-6493-6

Keywords

Search

Navigation