restenosis after coronary and peripheral intervention efficacy and clinical impact of cilostazol

Accepted Manuscript Restenosis after Coronary and Peripheral Intervention: Efficacy and Clinical Impact of Cilostazol Gianmarco de Donato, Francesco Setacci, Maria Agnese Mele, Giovanni Giannace, Giuseppe Galzerano, Carlo Setacci PII: S0890-5096(17)30262-5 DOI: 10.1016/j.avsg.2016.08.050 Reference: AVSG 3144 To appear in: Annals of Vascular Surgery Received Date: 12 July 2016 Revised Date: 26 August 2016 Accepted Date: 26 August 2016 Please cite this article as: de Donato G, Setacci F, Mele MA, Giannace G, Galzerano G, Setacci C, Restenosis after Coronary and Peripheral Intervention: Efficacy and Clinical Impact of Cilostazol, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2016.08.050 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT TITLE PAGE RESTENOSIS AFTER CORONARY AND PERIPHERAL INTERVENTION: EFFICACY AND CLINICAL IMPACT OF CILOSTAZOL RI PT Authors: Gianmarco de Donato, Francesco Setacci, Maria Agnese Mele, Giovanni Giannace, Giuseppe Galzerano, Carlo Setacci Affiliation: Department of Medicine, Surgery and Neuroscience – University of Siena, Italy SC M AN U 10 11 12 TE D 13 14 15 EP 16 Corresponding author 18 19 20 21 22 23 24 Gianmarco de Donato Department of Medicine, Surgery and Neuroscience University of Siena, Italy Policlinico Le Scotte Viale Bracci 1, 53100 Siena Tel & fax: 0039.0577.585123 dedonato@unisi.it AC C 17 25 26 ACCEPTED MANUSCRIPT ABSTRACT Restenosis is one of the main complications in patients undergoing coronary or peripheral revascularization procedures and is the leading cause for their long-term failures Cilostazol is the only pharmacotherapy that showed an adequate efficacy for preventing restenosis in randomized, controlled studies after coronary or peripheral revascularization procedures The present review sums up the main clinical evidence supporting the use of cilostazol after revascularization interventions, focusing on all its benefits, warnings and administration schedules SC RI PT Keywords Cilostazol; restenosis; revascularization; coronary arteries; carotid artery; lower limbs; peripheral 11 arteries AC C EP TE D M AN U 10 ACCEPTED MANUSCRIPT MANUSCRIPT Introduction Restenosis is one of the main complications in patients undergoing coronary or peripheral revascularization procedures It can be considered as a re-occlusion process of the vascular treated lumen due to an excessive proliferation of the target vessel wall Restenosis is the leading cause for the long-term failure of revascularization procedures [1] Clinical impact of restenosis is well reported in literature, showing a strong correlation with poor clinical outcomes after both cardiac and peripheral interventions [1, 2] Pathogenic mechanisms underlying restenosis development are still not entirely known, but they show 10 similar features both at coronary and peripheral level In patients undergoing a revascularization 11 intervention, mechanical lesions of the target artery wall will induce an endothelial irritation, leading to 12 a complex series of inflammatory responses characterized by thrombotic events, platelet activation, 13 fibrin deposition, leukocyte migration, together with extracellular matrix build-up and smooth muscle 14 cell hyperproliferation [3] 15 Variable rates of restenosis after a revascularization procedure are observed, based on patients and 16 procedure characteristics An incidence of about 15-25% after a coronary stent implantation [3] and 17 from 5% to 70% after a peripheral revascularization [4] can be esteemed 18 Up to now, there are no authorized drugs for preventing a restenosis after cardiac and peripheral 19 revascularization procedures; in fact, the only useful strategy is now represented by medical devices: 20 drug-eluting stents releasing anti-proliferative drugs [5] Oral anti-platelet aggregation drugs (e.g., 21 aspirin, clopidogrel, prasugrel, ticlopidine, ticagrelor) should be administered after a cardiac 22 revascularization procedure for preventing the occurrence of a stent or by-pass reocclusion essentially 23 due to thrombotic events, but they have no relevant effects on reocclusion phenomena caused by target 24 vessel restenosis (hyperproliferative events) Also statins have been proposed as anti-restenosis agents, 25 however, adequate clinical findings are absent and their impact on stent restenosis is still under debate 26 Cilostazol is the only pharmacotherapy that showed an adequate efficacy for preventing restenosis in 27 randomized and controlled studies after coronary and peripheral revascularization procedures 28 The aim of the present review is to sum up the main clinical evidence supporting the use of cilostazol 29 after revascularization interventions, focusing on all its benefits, warnings and administration schedules, 30 in order to provide clinicians with practical information for a proper use of the drug AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT Cilostazol Cilostazol was launched in Italy in 2008 and it’s indicated for the improvement of the maximal and pain-free walking distances in patients with intermittent claudication (peripheral arterial disease - Fontaine stage II) Cilostazol is a selective phosphodiesterase III inhibitor with known antiplatelet, vasodilative and anti- proliferative effects on vessel smooth muscle cells and positive effects on HDL cholesterol and triglyceride levels Also, several studies evaluated its pharmacological effects for the prevention of restenosis, suggesting favourable effects on re-endothelialisation mediated by Hepatocyte Growth 10 Factor [6] and endothelial precursor cells [7], as well on the inhibition of smooth muscle cell 11 proliferation [8] and the inhibition of leukocyte adhesion to endothelium therefore exerting an anti- 12 inflammatory effect [9] (figure 1) These effects may, at least in part, explain the clinical efficacy of 13 cilostazol in preventing restenosis and in promoting the long-term outcome of revascularization 14 interventions In fact, the anti-proliferative effects on smooth muscle cells, the anti-inflammatory 15 effects, and the endothelium protection can counter the complex events underlying restenosis and 16 prevent reocclusion of the vessel On the other hand, antiplatelet agents are well known to reduce fatal 17 or non-fatal CVD events in patients with coronary or peripheral artery disease 18 Starting from the late ’90s, cilostazol has also been studied in a large number of randomized, controlled, 19 clinical trials - mainly carried out in Asian countries or USA - for the prevention of restenosis after 20 coronary, carotid and lower limb revascularization 21 EP TE D M AN U SC RI PT Clinical efficacy 23 Table shows the results of the main metanalysis on the use of cilostazol after percutaneous coronary 24 or peripheral revascularization 25 3.1 Coronary revascularization 26 Studies that proved the efficacy of cilostazol for preventing a restenosis and improving the clinical 27 outcome after percutaneous revascularization enrolled the following patients: patients with stable or 28 unstable angina or silent myocardial ischemia [10], patients with acute coronary syndrome [11], AC C 22 ACCEPTED MANUSCRIPT diabetic patients with angina pectoris [12], patients with long lesions [13], patients who underwent elective balloon PTCA [14] A metanalysis including more than 5,000 patients randomized to receive cilostazol plus single or dual antiplatelet treatment vs single or dual antiplatelet treatment alone, with a follow-up from to 36 months, has shown the efficacy of cilostazol for preventing angiographic restenosis and improving the clinical outcome after a stent implantation with or without eluting drugs These results suggest a significant reduction of restenosis incidence (-40%; p≤0.001) and a decreased need for repeat revascularization (-31%; p≤0,001) [15] Another metanalysis was carried out to evaluate the clinical effects of a cilostazol treatment in more 10 than 14,000 patients randomized to receive cilostazol plus a dual antiplatelet treatment vs dual 11 antiplatelet treatment alone, after a stent implantation with or without eluting drugs, with a follow-up 12 from to 25 months Results show that the cilostazol treatment has efficiently and significantly 13 reduced the incidence of major cardiovascular events (-32%; p