Diabetic Artery Obstruction: is it Possible to Reduce Ischemic Events With Cilostazol?

Diabetes Mellitus, Type 2 Clinical Trial

— DORIC  

Official title:

Study of the Efficacy and Safety of Cilostazol in the Prevention of Ischemic Vascular Events in Diabetic Patients With Symptomatic Peripheral Artery Disease.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02983214
• Other study ID #: Cilo-UoI-2016
• Status: Completed
• Phase: Phase 4
• Start date: November 2016
• Est. completion date: October 2019

Study information

• Verified date: December 2020
• Source: University of Ioannina
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Investigation of the clinical efficacy and safety of dual antiplatelet therapy with clopidogrel and cilostazol versus clopidogrel alone in preventing ischemic vascular events in patients with type 2 diabetes and symptomatic peripheral arterial disease.

Description:

Cilostazol is a quinoline derivative that selectively and reversibly inhibits cellular cyclic adenosine monophosphate (cAMP) phosphodiesterase III, thus suppressing cAMP degradation and maintaining its high intracellular levels. Through this mechanism, cilostazol inhibits platelet aggregation, exerting significant antiplatelet and antithrombotic activity. Cilostazol also improves endothelial function and exerts anti-inflammatory, anti-atherogenic and vasodilatory effects. Additionally, cilostazol inhibits equilibrative nucleoside transporter-1 (ENT-1) which is responsible for the cellular uptake of adenosine, reducing its plasma concentration. Through this mechanism, cilostazol maintains high extracellular adenosine concentration allowing adenosine to exert its biological effects. Thus, cilostazol not only shows potent antithrombotic activity, but also prevents restenosis after percutaneous coronary intervention (PCI). Finally, cilostazol has beneficial effects in the lipidemic profile reducing triglyceride levels and increasing HDL-cholesterol. Clinical studies have shown that in patients with intermittent claudication, cilostazol increases the walking distance. Based on these studies, cilostazol administration in combination with an antiplatelet drug (clopidogrel or aspirin) is recommended for patients with intertermittent claudication. Recent pharmacodynamic studies have demonstrated that adding cilostazol to aspirin or clopidogrel may represent an effective way to overcome high on-treatment platelet reactivity. Additionally, clinical studies have shown that the addition of cilostazol to dual antiplatelet therapy with aspirin and clopidogrel (triple antiplatelet therapy, TAPT) in patients with acute coronary syndrome undergoing PCI offers significant clinical benefit. This favorable effect of cilostazol was confirmed in a recent meta-analysis which included nine studies and a total of 2,179 patients undergoing PCI. Furthermore, other clinical studies have shown that administration of TAPT with cilostazol reduces restenosis after PCI. Finally, the administration of dual antiplatelet therapy with cilostazol and aspirin significantly reduces the progression of symptomatic intracranial arterial stenosis compared to monotherapy with aspirin. The aim of The Diabetic artery Obstruction: is it possible to Reduce Ischemic events with Cilostazol? (DORIC) trial is to investigate the clinical efficacy and safety of dual antiplatelet therapy (DAPT) with clopidogrel and cilostazol versus clopidogrel alone in preventing ischemic vascular eventsin patients with type 2 diabetes (DM2) and symptomatic peripheral arterial disease (PAD).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 826
• Est. completion date: October 2019
• Est. primary completion date: October 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• Patients aged =50 years with DM2 and symptomatic PAD diagnosed clinically (according to Fontaine criteria, stage IIa or IIb and III) and by measuring the ???.

Exclusion Criteria:

• Congestive heart failure, history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular extrasystoles or QTc prolongation.
• Patients with atrial fibrillation taking any anticoagulant therapy or patients with a history of cardioembolic ischemic stroke or hemorrhagic stroke.
• Patients with a history (= 12 months) of acute coronary syndrome receiving dual antiplatelet therapy, or patients receiving monotherapy with aspirin.
• Patients with hepatic impairment (child-Pugh staging, calibration = 5) or renal impairment (creatinine clearance = 30ml / min), recent peptic ulcer, a history of hypersensitivity to cilostazol, cancer patients undergoing treatment.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Ischemia
• Ischemic Stroke
• Peripheral Arterial Disease
• Peripheral Artery Disease

Intervention

Drug:
• Clopidogrel

• Cilostazol

Locations

Country	Name	City	State
Greece	Atherothrombosis Research Centre / Laboratory of Biochemistry, University of Ioannina	Ioannina	Epirus

Sponsors (2)

Lead Sponsor	Collaborator
University of Ioannina	LIBYTEC Pharmaceutical S.A.

Country where clinical trial is conducted

Greece, 

References & Publications (15)

Chapman TM, Goa KL. Cilostazol: a review of its use in intermittent claudication. Am J Cardiovasc Drugs. 2003;3(2):117-38. Review. — View Citation

Chen Y, Zhang Y, Tang Y, Huang X, Xie Y. Long-term clinical efficacy and safety of adding cilostazol to dual antiplatelet therapy for patients undergoing PCI: a meta-analysis of randomized trials with adjusted indirect comparisons. Curr Med Res Opin. 2014 Jan;30(1):37-49. doi: 10.1185/03007995.2013.850067. Epub 2013 Oct 18. Review. — View Citation

Dindyal S, Kyriakides C. A review of cilostazol, a phosphodiesterase inhibitor, and its role in preventing both coronary and peripheral arterial restenosis following endovascular therapy. Recent Pat Cardiovasc Drug Discov. 2009 Jan;4(1):6-14. Review. — View Citation

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; Cilostazol for Restenosis Trial (CREST) Investigators. Coronary stent restenosis in patients treated with cilostazol. Circulation. 2005 Nov 1;112(18):2826-32. Epub 2005 Oct 24. — View Citation

Jeong YH, Tantry US, Bliden KP, Gurbel PA. Cilostazol to overcome high on-treatment platelet reactivity in korean patients treated with clopidogrel and calcium-channel blocker. Circ J. 2011;75(11):2534-6. Epub 2011 Oct 5. — View Citation

Kalantzi KI, Tsoumani ME, Goudevenos IA, Tselepis AD. Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives. Expert Rev Clin Pharmacol. 2012 May;5(3):319-36. doi: 10.1586/ecp.12.19. Review. — View Citation

Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, Lee JH, Kim JS. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke. 2005 Apr;36(4):782-6. Epub 2005 Mar 3. — View Citation

Liu Y, Fong M, Cone J, Wang S, Yoshitake M, Kambayashi J. Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication. J Cardiovasc Pharmacol. 2000 Sep;36(3):351-60. — View Citation

Min PK, Jung JH, Ko YG, Choi D, Jang Y, Shim WH. Effect of cilostazol on in-stent neointimal hyperplasia after coronary artery stenting: a quantative coronary angiography and volumetric intravascular ultrasound study. Circ J. 2007 Nov;71(11):1685-90. — View Citation

Panagiotakos DB, Georgousopoulou EN, Pitsavos C, Chrysohoou C, Metaxa V, Georgiopoulos GA, Kalogeropoulou K, Tousoulis D, Stefanadis C; ATTICA Study group. Ten-year (2002-2012) cardiovascular disease incidence and all-cause mortality, in urban Greek population: the ATTICA Study. Int J Cardiol. 2015 Feb 1;180:178-84. doi: 10.1016/j.ijcard.2014.11.206. Epub 2014 Nov 26. — View Citation

Rizzo M, Corrado E, Patti AM, Rini GB, Mikhailidis DP. Cilostazol and atherogenic dyslipidemia: a clinically relevant effect? Expert Opin Pharmacother. 2011 Mar;12(4):647-55. doi: 10.1517/14656566.2011.557359. Epub 2011 Feb 2. Review. — View Citation

Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society for Vascular Medicine; Society for Vascular Surgery. 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011 Nov 1;58(19):2020-45. doi: 10.1016/j.jacc.2011.08.023. Epub 2011 Oct 6. — View Citation

Spiliopoulos S. Antiplatelet therapy in critical limb ischemia: update on clopidogrel and cilostazol. J Cardiovasc Surg (Torino). 2014 Oct;55(5):631-40. Epub 2014 May 28. Review. — View Citation

Toyoda K, Uchiyama S, Hoshino H, Kimura K, Origasa H, Naritomi H, Minematsu K, Yamaguchi T; CSPS.com Study Investigators. Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial. Int J Stroke. 2015 Feb;10(2):253-8. doi: 10.1111/ijs.12420. Epub 2014 Dec 8. — View Citation

Tselepis AD. Cilostazol-based triple antiplatelet therapy in the era of generic clopidogrel and new potent antiplatelet agents. Curr Med Res Opin. 2014 Jan;30(1):51-4. doi: 10.1185/03007995.2013.850070. Epub 2013 Oct 18. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants who suffer from the primary efficacy end point which is composite of acute ischemic stroke/transient ischemic attack (TIA), myocardial infarction (MI), or death from vascular causes during the entire follow-up period.	Death from vascular causes: cardiovascular or cerebrovascular	12 months
Primary	Number of participants who suffer from bleeding events as defined by the Bleeding Academic Research Consortium (BARC) criteria during the entire follow-up period.		12 months
Secondary	Number of participants whose major secondary efficacy end point desribed in the description section is observed.	Acute ischemic stroke / TIA, AMI, coronary stent thrombosis, PCI, coronary restenosis, death from cardiovascular causes, death from any cause, hospitalization for acute limb ischemia, lower extremity arterial revascularization, improvement of ABI and pain-free walking distance values.	12 months
Secondary	Number of participants who suffer from the secondary safety end points which are palpitations, tachycardia, headache, diarrhea, urticaria, neoplasms, blood disorders, drug interruption.	Blood disorders: transient thrombocytopenia, leukopenia	12 months