Effectiveness of cilostazol in prevention of restenosis after endovascular reconstructive procedures on the lower extremity arteries
AbstractObjective: to evaluate effectiveness of Cilostazol in prevention of restenosis in the reconstruction area in patients undergoing endovascular reconstructive procedures on the lower extremity arteries.
Patients and methods. Our prospective study included 80 patients with stage IIb–III chronic lower limb ischemia due to atherosclerotic peripheral arterial disease. They were divided into two groups, 40 patients each (using the envelope randomization method). The study was approved by the local ethics committee. All patients after roentgenendovascular interventions received conservative therapy (acetylsalicylic acid at a dose of 75 mg once daily, Atorvastatin 10 mg QD with lipid spectrum control, and Clopidogrel 75 mg QD). One month after, the study group patients were switched from Clopidogrel to Cilostazol (Aducil®) taken at a dose of 100 mg twice daily for 2 months. The control group patients continued receiving therapy with Clopidogrel for 3 months. All subjects underwent laboratory (assessment of endothelial nitric oxide synthase (eNOS), prostacyclin, endothelin-1, and interleukin-6) and instrumental diagnostic procedures prior to operation and 1, 3, 6 and 12 months thereafter.
Results. There was a statistically significant increase in the level of eNOS in the study group patients after 3 (р=0.001), 6 (р=0.002), and 12 months (р<0.001) as compared with the control group. At 3, 6, and 12 months after the interventions, there was a statistically significant decrease of interleulin-6 and endothelin-1 levels in the study group as compared with the control (р<0.001).
According to the findings of duplex scanning of lower limbs at 3 months, 13 (32.5%) patients in the control group and 7 (17.5%) patients in the study group developed neointimal hyperplasia and restenosis (>30%) in the arterial reconstruction zone (p<0.05). 15 (37.5%) patients in the control group and 10 (25%) patients in the study group had restenosis at 6 months (p=0.04). By 12 months, the number of patients with restenosis increased up to 26 (65%) and 18 (45%) in the control and study group, respectively (p=0.04).
Conclusion. Including Cilostazol 100 mg B.I.D. in the study group patients resulted in an increased level of endothelial nitrogen oxide synthase (p<0.05), decreased levels of endothelin-1 (p<0.001) and interleukin-6 (p<0.001) as compared with the control group patients. Prescription of Cilostazol after endovascular interventions on lower limb arteries decreased possibility of developing restenosis in the reconstruction zone.
Keywords:peripheral arterial disease; endovascular interventions; cilostazol; restenosis; endothelial nitric oxide synthase (eNOS); prostacyclin; endothelin-1; interleukin-6
Funding. The study had no financial support.
Conflict of interest. The authors declare no conflicts of interest.
Authors’ contribution. Study conception and design – Kalinin R.E., Suchkov I.A.; methodology development – Suchkov I.A., Porsheneva E.V.; statistical processing – Porsheneva E.V., Nikiforova L.V., Povarov V.O.; draft manuscript preparation – Porsheneva E.V., Mzhavanadze N.D.; manuscript revision – Suchkov I.A., Porsheneva E.V.
For citation: Porsheneva E.V., Kalinin R.E., Nikiforova L.V., Povarov V.O., N.D. Mzhavanadze N.D., Suchkov I.A. Effectiveness of cilostazol in prevention of restenosis after endovascular reconstructive procedures on the lower extremity arteries. Angiology and Vascular Surgery. Journal named Academician A.V. Pokrovsky. 2022; 28 (3): 23–31. DOI: https://doi.org/10.33029/1027-6661-2022-28-3-23-31 (in Russian)
References
1. Kalinin R.E., Suchkov I.A., Chobanyan A.A. Prospects for forecasting the course of obliterating atherosclerosis of lower limb arteries. Science of the young. Eruditio Juvenium. 2019; 7 (2): 274–282. DOI: https://doi.org/10.23888/HMJ201972274-282. (in Russian)
2. Kalinin R.E., Suchkov I.A., Mzhavanadze N.D., et al. Rognostic markers of restenosis in patients with peripheral artery disease after endovascular procedures. Surgery news. 2022; 30 (1): 12–19. DOI: https://doi.org/10.18484/2305-0047.2022.1.12. (in Russian)
3. Hiramoto J.S., Teraa M., de Borst G.J., Conte M.S. Interventions for lower extremity peripheral artery disease. Nature Reviews Cardiology. 2018; 15 (6): 332–350. DOI: https://doi.org/10.1038/s41569-018-0005-0
4. Stoner M.C., Calligaro K.D., Chaer R.A. Reporting standards of the Society for Vascular Surgery for endovascular treatment of chronic lower extremity peripheral artery disease. Journal of Vascular Surgery. 2016; 64 (1): e1–e21. DOI: https://doi.org/10.1016/j.jvs.2016.03.420
5. Klein A.J., Ross C.B. Endovascular treatment of lower extremity peripheral arterial disease. Trends in Cardiovascular Medicine. 2016; 26 (6): 495–512. DOI: https://doi.org/10.1016/j.tcm.2016.02.007
6. Kherallah R.Y., Khawaja M., Olson M., et al. Cilostazol: a Review of Basic Mechanisms and Clinical Uses. Cardiovascular Drugs and Therapy. 2022; 36 (4): 777–792. DOI: https://doi.org/10.1007/s10557-021-07187-x
7. Natsional’nye rekomendatsii po diagnostike i lecheniyu zabolevanii arterii nizhnikh konechnostei. М. 2019; 89. (in Russian)
8. Lee M.S., Banka G. In-stent Restenosis. Interventional Cardiology Clinics. 2016; 5 (2): 211–220. DOI: https://doi.org/10.1016/j.iccl.2015.12.006
9. Ho K.J., Owens C.D. Diagnosis, classification, and treatment of femoropopliteal artery in-stent restenosis. Journal of Vascular Surgery. 2017; 65 (2): 545–557. DOI: https://doi.org/10.1016/j.jvs.2016.09.031
10. Kalinin R.E., Suchkov I.A., Mzhavanadze N.D., et al. Von Willebrand factor in patients with peripheral artery disease who undergo invasive treatment. I.P. Pavlov Russian Medical Biological Herald. 2021; 29 (3): 389–396. DOI: https://doi.org/10.17816/PAVLOVJ79099. (in Russian)
11. Laird J.R., Katzen B.T., Scheinert D., et al.; RESILIENT Investigators. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circulation: Cardiovascular Interventions. 2010; 3 (3): 267–276. DOI: https://doi.org/10.1161/CIRCINTERVENTIONS.109.903468
12. Iida O., Soga Y., Hirano K., et al. Long-term outcomes and risk stratification of patency following nitinol stenting in the femoropopliteal segment: retrospective multicenter analysis. Journal of Endovascular Therapy. 2011; 18 (6): 753–761. DOI: https://doi.org/10.1583/11-3581.1
13. Bangalore S., Singh A., Toklu B., et al. Efficacy of cilostazol on platelet reactivity and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: insights from a metaanalysis of randomised trials. Open Heart. 2014; 1 (1): e000068. DOI: https://doi.org/10.1136/openhrt-2014-000068
14. Derkacz A., Protasiewicz M., Poręba R., et al. Plasma asymmetric dimethylarginine predicts restenosis after coronary angioplasty. Archives of Medical Science. 2011; 7 (3): 444–448. DOI: https://doi.org/10.5114/aoms.2011.23410
15. Iida O., Yokoi H., Soga Y.; STOP-IC investigators. Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. Circulation. 2013; 127 (23): 2307–2315. DOI: https://doi.org/10.1016/j.jvs.2013.09.019
16. Koutakis P., Ismaeel A., Farmer P., et al. Oxidative stress and antioxidant treatment in patients with peripheral artery disease. Physiological Reports. 2018; 6: e13650. DOI: https://doi.org/10.14814/phy2.13650
17. Ismaeel A., Brumberg R.S., Kirk J.S., et al. Oxidative Stress and Arterial Dysfunction in Peripheral Artery Disease. Antioxidants (Basel). 2018; 7 (10): 145. DOI: https://doi.org/10.3390/107100145
18. Huynh D.T.N., Heo K.S. Therapeutic targets for endothelial dysfunction in vascular diseases. Archives of Pharmacal Research. 2019; 42 (10): 848–861. DOI: 10.1007/s12272-019-01180-7
19. Medina-Leyte D.J., Zepeda-García O., Domínguez-Pérez M., et al. Endothelial Dysfunction, Inflammation and Coronary Artery Disease: Potential Biomarkers and Promising Therapeutical Approaches. International Journal of Molecular Sciences. 2021; 22 (8): 3850. DOI: https://doi.org/10.3390/ijms22083850
20. Simeone S.M., Li M.W., Paradis P., Schiffrin E.L. Vascular gene expression in mice overexpressing human endothelin-1 targeted to the endothelium. Physiological Genomics. 2011; 43 (3): 148–160. DOI: https://doi.org/10.1152/physiolgenomics.00218.2009
21. Tyrrell D.J., Goldstein D.R. Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6. Nature Reviews Cardiology. 2021; 18 (1): 58–68. DOI: https://doi.org/10.1038/s41569-020-0431-7
22. Stoica A.L., Stoica E., Constantinescu I., et al. Interleukin-6 and interleukin-10 gene polymorphism, endothelial dysfunction, and postoperative prognosis in patients with peripheral arterial disease. Journal of Vascular Surgery. 2010; 52 (1): 103–109. DOI: https://doi.org/10.1016/j.jvs.2010.01.088
23. Donato G., Benedetto F., Stilo F.; RIVALUTANDO Collaborators. Evaluation of Clinical Outcomes After Revascularization in Patients With Chronic Limb-Threatening Ischemia: Results From a Prospective National Cohort Study (RIVALUTANDO). Angiology. 2021; 72 (5): 480–489. DOI: https://doi.org/10.1016/j.jvs.2021.02.009