Cilostazol May Improve Maturation Rates and Durability of Vascular Access for Hemodialysis

Abstract

Cilostazol is effective in controlling pathophysiological pathways similar or identical to those involved in nonmaturation and failure of the arteriovenous access. This case–control study examined whether cilostazol would improve maturation rates and durability of vascular access for hemodialysis. The treatment group included 33 patients who received cilostazol for ≥30 days prior to creation of a dialysis access and continued with cilostazol therapy for ≥60 days after surgery. The matched (gender, age, race, diabetes, and the year of surgery) control group included 116 patients who underwent the same procedure but did not receive cilostazol prior to and at least 3 months after surgery. Primary outcomes were maturation and, for those that matured, time of functioning access, defined as the time from the first use to irreparable failure of the access. Secondary outcomes were time to maturation, complications, and time to first complication. Study group patients were 3.8 times more likely to experience fistula maturation compared to the controls (88% vs 66%, RR = 3.8, 95% confidence interval: 1.3-11.6, P = .016). Fewer patients in the study group had complications (76% vs 92%, P = .025), and the time from construction of the fistula to the first complication was longer (345.6 ± 441 days vs 198.3 ± 185.0 days, P = .025). Time to maturation was similar in both groups (119.3 ± 62.9 days vs 100.2 ± 61.7 days, P = .2). However, once matured, time to failure was significantly longer in the treatment group (903.7 ± 543.6 vs 381.6 ± 317.2 days, P = .001). Multivariate analysis confirmed that the likelihood of maturation was significantly higher in the treatment group patients. These results suggest that dialysis access patients may benefit from preoperative and postoperative cilostazol therapy. If confirmed by a randomized trial, this treatment will have a major beneficial impact on patients dependent on a well-functioning access for their hemodialysis.

Keywords

cilostazol AV fistula hemodialysis access

Get full access to this article

View all access options for this article.

References

Dember

Beck

Allon

; Dialysis Access Consortium Study Group. Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA. 2008;299(18):2164–2171.

Feldman

Joffe

Rosas

Burns

Knauss

Brayman

. Predictors of successful arteriovenous fistula maturation. Am J Kidney Dis. 2003;42(5):1000–1012.

Huijbregts

HJT

Bots

Wittens

CHA

Schrama

Moll

Blankestijn

; CIMINO study group. Hemodialysis arteriovenous fistula patency revisited: results of a prospective, multicenter initiative. Clin J Am Soc Nephrol. 2008;3(3):714–719.

Allon

Robbin

. Increasing arteriovenous fistulas in hemodialysis patients: problems and solutions. Kidney Int. 2002;62(4):1109–1124.

Lee

. Novel paradigms for dialysis vascular access: downstream vascular biology—is there a final common pathway? Clin J Am Soc Nephrol. 2013;8(12):2194–2201.

Feldman

Held

Hutchinson

Stoiber

Hartigan

Berlin

. Hemodialysis vascular access morbidity in the United States. Kidney Int. 1993;43(5):1091–1096.

Brahmbhatt

Remuzzi

Franzoni

Misra

. The molecular mechanisms of hemodialysis vascular access failure. Kidney Int. 2016;89(2):303–316.

Allon

Litovsky

Young

. Medial fibrosis, vascular calcification, intimal hyperplasia, and arteriovenous fistula maturation. Am J Kidney Dis. 2011;58(3):437–443.

Abeles

Kwei

Stavrakis

Zhang

Wang

García-Cardeña

. Gene expression changes evoked in a venous segment exposed to arterial flow. J Vasc Surg. 2006;44(4):863–870.

10.

Gross

Massy

Henaut

. Para-cresyl sulfate acutely impairs vascular reactivity and induces vascular remodeling. J Cell Physiol. 2015;230(12):2927–2935.

11.

Zhang

Huang

Xia

. Suppression of experimental abdominal aortic aneurysm in a rat model by the phosphodiesterase 3 inhibitor cilostazol. J Surg Res. 2011;167(2):e385–e393.

12.

Begum

Shen

Manganiello

. Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility. Curr Opin Pharmacol. 2011;11(6):725–729.

13.

Begum

Hockman

Manganiello

. Phosphodiesterase 3A (PDE3A) deletion suppresses proliferation of cultured murine vascular smooth muscle cells (VSMCs) via inhibition of mitogen-activated protein kinase (MAPK) signaling and alterations in critical cell cycle regulatory proteins. J Biol Chem. 2011;286(29):26238–26249.

14.

Hashimoto

Tanaka

Takeda

Ito

Nagano

. Cilostazol induces PGI(2) production via activation of the downstream Epac-1/Rap1 signaling cascade to increase intracellular calcium by PLC∊ and to activate p44/42 MAPK in human aortic endothelial cells. PLoS One. 2015;10(7): e0132835.

15.

Chen

Lin

Hsuan Ting

Yeh

. Cilostazol promotes vascular smooth muscles cell differentiation through the cAMP response element-binding protein-dependent pathway. Arterioscler Thromb Vasc Biol. 2011;31(9):2106–2113.

16.

Dawson

Cutler

Meissner

Strandness

. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. Circulation. 1998;98(7):678–686.

17.

Ishizaka

Taguchi

Kimura

. Effects of a single local administration of cilostazol on neointimal formation in balloon-injured rat carotid artery. Atherosclerosis. 1999;142(1):41–46.

18.

Lee

Mokrzycki

Moist

Maya

Vazquez

Lok

; North American Vascular Access Consortium. Standardized definitions for hemodialysis vascular access. Semin Dial. 2011;24(5):515–524.

19.

Wong

Ward

Taylor

Selvakumar

How

Bakran

. Factors associated with early failure of arteriovenous fistulae for haemodialysis access. Eur J Vasc Endovasc Surg. 1996;12(2):207–213.

20.

Kimura

Tani

Kanbe

Watanabe

. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung. 1985;35(7A):1144–1149.

21.

Tanaka

Gotoh

Fukuuchi

. Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia. Stroke. 1989;20(5):668–673.

22.

Takigawa

Matsumaru

Hayakawa

Nemoto

Matsumura

. Cilostazol reduces restenosis after carotid artery stenting. J Vasc Surg. 2010;51(1):51–56.

23.

Douglas

Holmes

Kereiakes

; Cilostazol for Restenosis Trial (CREST) Investigators. Coronary stent restenosis in patients treated with cilostazol. Circulation. 2005;112(18):2826–2832.

24.

Iida

Nanto

Uematsu

Morozumi

Kitakaze

Nagata

. Cilostazol reduces restenosis after endovascular therapy in patients with femoropopliteal lesions. J Vasc Surg. 2008;48(1):144–149.

25.

Ishii

Kumada

Toriyama

. Cilostazol improves long-term patency after percutaneous transluminal angioplasty in hemodialysis patients with peripheral artery disease. Clin J Am Soc Nephrol. 2008;3(4):1034–1040.

26.

Hong

Kim

Shin

. Cilostazol prevents tumor necrosis factor-alpha-induced cell death by suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and activation of Akt/cyclic AMP response element-binding protein phosphorylation. J Pharmacol Exp Ther. 2003;306(3):1182–1190.

27.

Kim

Shin

Choi

Hong

. Inhibition of lipopolysaccharide-induced apoptosis by cilostazol in human umbilical vein endothelial cells. J Pharmacol Exp Ther. 2002;300(2):709–715.

28.

Kim

Park

Lee

. Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F. Hypertension. 2005;45(4):552–556.

29.

Remuzzi

Ene-Iordache

Mosconi

. Radial artery wall shear stress evaluation in patients with arteriovenous fistula for hemodialysis access. Biorheology. 2003;40(1-3):423–430.

30.

Ene-Iordache

Semperboni

Dubini

Remuzzi

. Disturbed flow in a patient-specific arteriovenous fistula for hemodialysis: multidirectional and reciprocating near-wall flow patterns. J Biomech. 2015;48(10):2195–2200.

31.

Sun

Lin

. New mechanism of action for cilostazol: interplay between adenosine and cilostazol in inhibiting platelet activation. J Cardiovas Pharmacol. 2002;40(4):577–585.

32.

Zangan

Falk

. Optimizing arteriovenous fistula maturation. Semin Intervent Radiol. 2009;26(2):144–150.

33.

Peterson

Barker

Allon

. Disparities in fistula maturation persist despite preoperative vascular mapping. Clin J Am Soc Nephrol. 2008;3(2):437–441.

34.

Leake

Yuo

. Arteriovenous grafts are associated with earlier catheter removal and fewer catheter days in the United States Renal Data System population. J Vasc Surg. 2015;62(1):123–127.