Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel-Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events

Kallirroi Kalantzi, Nikolaos Tentolouris, Andreas J Melidonis, Styliani Papadaki, Michail Peroulis, Konstantinos A Amantos, George Andreopoulos, George I Bellos, Dimitrios Boutel, Magdalini Bristianou, Dimitrios Chrisis, Nikolaos A Dimitsikoglou, John Doupis, Chrysoula Georgopoulou, Stergios A Gkintikas, Styliani Iraklianou, Κonstantinos Kanellas, Kalliopi Kotsa, Theocharis Koufakis, Maria Kouroglou, Anastasios G Koutsovasilis, Leonidas Lanaras, Eirini Liouri, Charalampos Lixouriotis, Akrivi Lykoudi, Efthymia Mandalaki, Evanthia Papageorgiou, Nikolaos Papanas, Spyridon Rigas, Maria I Stamatelatou, Ioannis Triantafyllidis, Aikaterini Trikkalinou, Aikaterini N Tsouka, Ourania Zacharopoulou, Christos Zoupas, Ioannis Tsolakis, Alexandros D Tselepis, Kallirroi Kalantzi, Nikolaos Tentolouris, Andreas J Melidonis, Styliani Papadaki, Michail Peroulis, Konstantinos A Amantos, George Andreopoulos, George I Bellos, Dimitrios Boutel, Magdalini Bristianou, Dimitrios Chrisis, Nikolaos A Dimitsikoglou, John Doupis, Chrysoula Georgopoulou, Stergios A Gkintikas, Styliani Iraklianou, Κonstantinos Kanellas, Kalliopi Kotsa, Theocharis Koufakis, Maria Kouroglou, Anastasios G Koutsovasilis, Leonidas Lanaras, Eirini Liouri, Charalampos Lixouriotis, Akrivi Lykoudi, Efthymia Mandalaki, Evanthia Papageorgiou, Nikolaos Papanas, Spyridon Rigas, Maria I Stamatelatou, Ioannis Triantafyllidis, Aikaterini Trikkalinou, Aikaterini N Tsouka, Ourania Zacharopoulou, Christos Zoupas, Ioannis Tsolakis, Alexandros D Tselepis

Abstract

Background Type 2 diabetes mellitus is a risk factor for lower extremity arterial disease. Cilostazol expresses antiplatelet, anti-inflammatory, and vasodilator actions and improves the claudication intermittent symptoms. We investigated the efficacy and safety of adjunctive cilostazol to clopidogrel-treated patients with type 2 diabetes mellitus exhibiting symptomatic lower extremity arterial disease, in the prevention of ischemic vascular events and improvement of the claudication intermittent symptoms. Methods and Results In a prospective 2-arm, multicenter, open-label, phase 4 trial, patients with type 2 diabetes mellitus with intermittent claudication receiving clopidogrel (75 mg/d) for at least 6 months, were randomly assigned in a 1:1 ratio, either to continue to clopidogrel monotherapy, without receiving placebo cilostazol (391 patients), or to additionally receive cilostazol, 100 mg twice/day (403 patients). The median duration of follow-up was 27 months. The primary efficacy end point, the composite of acute ischemic stroke/transient ischemic attack, acute myocardial infarction, and death from vascular causes, was significantly reduced in patients receiving adjunctive cilostazol compared with the clopidogrel monotherapy group (sex-adjusted hazard ratio [HR], 0.468; 95% CI, 0.252-0.870; P=0.016). Adjunctive cilostazol also significantly reduced the stroke/transient ischemic attack events (sex-adjusted HR, 0.38; 95% CI, 0.15-0.98; P=0.046) and improved the ankle-brachial index and pain-free walking distance values (P=0.001 for both comparisons). No significant difference in the bleeding events, as defined by Bleeding Academic Research Consortium criteria, was found between the 2 groups (sex-adjusted HR, 1.080; 95% CI, 0.579-2.015; P=0.809). Conclusions Adjunctive cilostazol to clopidogrel-treated patients with type 2 diabetes mellitus with symptomatic lower extremity arterial disease may lower the risk of ischemic events and improve intermittent claudication symptoms, without increasing the bleeding risk, compared with clopidogrel monotherapy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02983214.

Keywords: cilostazol; clopidogrel; coronary artery disease; diabetes mellitus; intermittent claudication; ischemic stroke.

Conflict of interest statement

None.

Figures

Figure 1. Consolidated Standards of Reporting Trials…
Figure 1. Consolidated Standards of Reporting Trials flow diagram showing the study design of the DORIC (Diabetic Artery Obstruction: Is It Possible to Reduce Ischemic Events With Cilostazol?) trial.
AF indicates atrial fibrillation; HF, heart failure; and ITT, intent to treat.
Figure 2. Kaplan‐Meier plot of the primary…
Figure 2. Kaplan‐Meier plot of the primary efficacy end point.
The primary efficacy end point was defined as acute ischemic stroke/transient ischemic attack, acute myocardial infarction, and death from cardiovascular causes. HR indicates hazard ratio.
Figure 3. Kaplan‐Meier plot of the primary…
Figure 3. Kaplan‐Meier plot of the primary safety end point.
The primary safety end point was defined by Bleeding Academic Research Consortium criteria. HR indicates hazard ratio.

References

    1. Krishna SM, Moxon JV, Golledge J. A review of the pathophysiology and potential biomarkers for peripheral artery disease. Int J Mol Sci. 2015;16:11294–11322.
    1. Firnhaber JM, Powell CS. Lower extremity peripheral artery disease: diagnosis and treatment. Am Fam Physician. 2019;99:362–369.
    1. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, Collet JP, Czerny M, De Carlo M, Debus S, et al; ESC Scientific Document Group . 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: endorsed by the European Stroke Organization (ESO): the Task Force for the diagnosis and treatment of peripheral arterial diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018;39:763–816.
    1. Hossain P, Kokkinidis DG, Armstrong EJ. How to assess a claudication and when to intervene. Curr Cardiol Rep. 2019;21:138.
    1. Meru AV, Mittra S, Thyagarajan B, Chugh A. Intermittent claudication: an overview. Atherosclerosis. 2006;187:221–237.
    1. Pistrosch F, Natali A, Hanefeld M. Is hyperglycemia a cardiovascular risk factor? Diabetes Care. 2011;34:S128–S131.
    1. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56:686–695.
    1. American Diabetes Association . Cardiovascular disease and risk management: standards of medical care in diabetes‐2020. Diabetes Care. 2020;43:S111–S134.
    1. Emerging Risk Factors Collaboration , Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta‐analysis of 102 prospective studies. Lancet. 2010;375:2215–2222.
    1. Verma A, Prasad A, Elkadi GH, Chi Y‐W. Peripheral arterial disease: evaluation, risk factor modification, and medical management. JCOM. 2011;18:74–84.
    1. Barochiner J, Aparicio LS, Waisman GD. Challenges associated with peripheral arterial disease in women. Vasc Health Risk Manag. 2014;10:115–128.
    1. Althouse AD, Abbott JD, Forker AD, Bertolet M, Barinas‐Mitchell E, Thurston RC, Mulukutla S, Aboyans V, Brooks MM; BARI 2D Study Group . Risk factors for incident peripheral arterial disease in type 2 diabetes: results from the bypass angioplasty revascularization investigation in type 2 diabetes (BARI 2D) trial. Diabetes Care. 2014;37:1346–1352.
    1. Tsoumani ME, Tselepis AD. Antiplatelet agents and anticoagulants: from pharmacology to clinical practice. Curr Pharm Des. 2017;23:1279–1293.
    1. Gresele P, Momi S, Falcinelli E. Anti‐platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol. 2011;72:634–646.
    1. Zheng H, Yang H, Gong D, Mai L, Qiu X, Chen L, Su X, Wei R, Zeng Z. Progress in the mechanism and clinical application of cilostazol. Curr Top Med Chem. 2019;19:2919–2936.
    1. Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2014;31:CD003748.
    1. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, Shinohara Y, Itoh E, Matsuda T, Sawada T, et al. Cilostazol stroke prevention study: a placebo‐controlled double‐blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis. 2000;9:147–157.
    1. Angiolillo DJ, Capranzano P, Ferreiro JL, Ueno M, Capodanno D, Dharmashankar K, Darlington A, Sumner S, Desai B, Charlton RK, et al. Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy. Thromb Haemost. 2011;106:253–262.
    1. Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, Mills JL, Ricco JB, Suresh KR, Murad MH, et al; GVG Writing Group for the Joint Guidelines of the Society for Vascular Surgery (SVS); European Society for Vascular Surgery (ESVS), and World Federation of Vascular Societies (WFVS) . Corrigendum to “global vascular guidelines on the management of chronic limb‐threatening ischemia.” Eur J Vasc Endovasc Surg. 2019;58/1S:1–109.
    1. Xu D, Zou L, Xing Y, Hou L, Wei Y, Zhang J, Qiao Y, Hu D, Xu Y, Li J, et al. Diagnostic value of ankle‐brachial index in peripheral arterial disease: a meta‐analysis. Can J Cardiol. 2013;29:492–498.
    1. Al‐Qaisi M, Nott DM, King DH, Kaddoura S. Ankle brachial pressure index (ABPI): an update for practitioners. Vasc Health Risk Manag. 2009;5:833–841.
    1. Mika P, Spodaryk K, Cencora A, Unnithan VB, Mika A. Experimental model of pain‐free treadmill training in patients with claudication. Am J Phys Med Rehabil. 2005;84:756–762.
    1. Hankey GJ, Blacker DJ. Is it a stroke? BMJ. 2015;350:h56.
    1. Brazzelli M, Chappell FM, Miranda H, Shuler K, Dennis M, Sandercock PAG, Muir K, Wardlaw JM. Diffusion‐weighted imaging and diagnosis of transient ischemic attack. Ann Neurol. 2014;75:67–76.
    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR; White HD and the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction . Third universal definition of myocardial infarction. Circulation. 2012;126:2020–2035.
    1. Gerhard‐Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017;135:e686–e725.
    1. Katsanos K, Spiliopoulos S, Saha P, Diamantopoulos A, Karunanithy N, Krokidis M, Modarai B, Karnabatidis D. Comparative efficacy and safety of different antiplatelet agents for prevention of major cardiovascular events and leg amputations in patients with peripheral arterial disease: a systematic review and network meta‐analysis. PLoS One. 2015;10:e0135692.
    1. Kalantzi KI, Tsoumani ME, Goudevenos IA, Tselepis AD. Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives. Expert Rev Clin Pharmacol. 2012;5:319–336.
    1. Kalantzi KI, Dimitriou AA, Goudevenos JA, Tselepis AD. The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment. Platelets. 2012;23:121–131.
    1. von Beckerath N, Kastrati A, Wieczorek A, Pogatsa‐Murray G, Sibbing D, Graf I, Schomig A. A double‐blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J. 2007;28:1814–1819.
    1. Aleil B, Jacquemin L, De Poli F, Zaehringer M, Collet JP, Montalescot G, Cazenave JP, Dickele MC, Monassier JP, Gachet C. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP‐02 (Vasodilator‐Stimulated Phosphoprotein‐02) randomized study. JACC Cardiovasc Interv. 2008;1:631–638.
    1. Kaikita K, Yoshimura H, Ishii M, Kudoh T, Yamada Y, Yamamoto E, Izumiya Y, Kojima S, Shimomura H, Tsunoda R, et al; for the CALDERA‐GENE Investigators . Tailored adjunctive cilostazol therapy based on CYP2C19 genotyping in patients with acute myocardial infarction—the CALDERA‐GENE Study. Circ J. 2018;82:1517–1525.
    1. Tang Y‐D, Wang W, Yang M, Zhang K, Chen J, Qiao S, Yan H, Wu Y, Huang X, Xu B, et al; on behalf of the CREATIVE Investigators . Randomized comparisons of double‐dose clopidogrel or adjunctive cilostazol versus standard dual antiplatelet in patients with high posttreatment platelet reactivity results of the CREATIVE trial. Circulation. 2018;137:2231–2245.
    1. Nakagawa I, Park HS, Wada T, Yokoyama S, Yamada S, Motoyama Y, Kichikawa K, Nakase H. Efficacy of cilostazol‐based dual antiplatelet treatment in patients undergoing carotid artery stenting. Neurol Res. 2017;39:695–701.
    1. Hernandez‐Suarez DF, Núñez‐Medina H, Scott SA, Lopez‐Candales A, Wiley JM, Garcia MJ, Melin K, Nieves‐Borrero K, Rodriguez‐Ruiz C, Marshall L, et al. Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy. Drug Metab Pers Ther. 2018;33:49–55.
    1. 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;30:37–49.
    1. Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, Sakai N, Okada Y, Tanaka K, Origasa H, et al; on behalf of the Trial Investigators . Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high‐risk ischaemic stroke in Japan: a multicentre, open‐label, randomised controlled trial. Lancet Neurol. 2019;18:539–548.
    1. de Donato G, Setacci F, Mele M, Giannace G, Galzerano G, Setacci C. Restenosis after coronary and peripheral intervention: efficacy and clinical impact of cilostazol. Ann Vasc Surg. 2017;41:300–307.
    1. Iftikhar O, Oliveros K, Tafur AJ, Casanegra AI. Prevention of femoropopliteal in‐stent restenosis with cilostazol: a meta‐analysis. Angiology. 2016;67:549–555.
    1. Niu P‐P, Guo Z‐N, Jin H, Xing Y‐Q, Yang YI. Antiplatelet regimens in the long‐term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta‐analysis. BMJ Open. 2016;6:e009013.
    1. Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence‐based clinical practice guidelines. Chest. 2012;141(suppl 2):e89S–e119S.
    1. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, et al; CSPS 2 Group . Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin‐controlled, double‐blind, randomised non‐inferiority trial. Lancet Neurol. 2010;9:959–968.

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