The growth in the number of patients with end-stage renal disease (ESRD) is continuing at a higher rate than the increase in general population, with a consequent increase in the number patients receiving hemodialysis. At the end of 2017, the number of patients receiving renal replacement therapy in Korea was 98746, with 73059 (73.9%) of those receiving hemodialysis.1 This rise in hemodialysis patients is considered to be due to an increase not only in the elderly population but also in those with chronic illnesses such as diabetes and hypertension. Indeed, more than two-thirds of ESRD cases are attributed to chronic diseases such as diabetes and hypertension.

Permanent vascular access is important in patients requiring hemodialysis. Unfortunately, maturation failure, which occurs in 30%–55% of patients undergoing arteriovenous fistula (AVF) surgery for hemodialysis, hinders the utility of AVF.2–4 Delayed complications of mature fistulas result in reinterventions and hospital admissions as well as a one-year fistula failure rate of 30%–40%.4–8

Intimal hyperplasia (IH) is a vasculopathy characterized by the differentiation of smooth muscle cells that form a multilayer compartment in the tunica intima of blood vessels. Direct endothelial damage is the most important cause of IH in coronary artery disease and peripheral arterial disease.9–11 Conversely, both direct vascular damage due to hypertension and indirect vascular injury due to uremia, anemia, or chronic inflammation are responsible for IH in chronic kidney disease.12 The effects of cilostazol on direct vascular injury-induced IH have been previously demonstrated,9–11 whereas the impact of cilostazol on indirect vascular injury-induced IH in patients with chronic kidney disease remains unclear.12 In the present retrospective study, we tested the hypothesis that cilostazol might improve the maturation rate and durability of vascular access for hemodialysis.

The patient demographics were similar between the cilostazol and control groups (Table 1). Specifically, the mean ages of the cilostazol and control groups were 64.3 and 65.0 years, respectively, which was not significantly different (p=0.726). Furthermore, there were no differences in comorbidities, other medications including antiplatelet agents and anticoagulation agents, and cause of ESRD between the two groups.

Table 2 shows the patient outcomes between the cilostazol and control groups. The vascular complications were significantly lower in the cilostazol group than in the control group (36.4% [n=39] vs. 51.7% [n=45]; odds ratio [OR] 0.535, 95% confidence interval [CI] 0.301–0.952, p=0.033). The analysis of the vascular complications by subgroups revealed that the rate of maturation failure was significantly lower in the cilostazol group than in the control group (2.8% [n=3] vs. 11.5% [n=10], OR 0.222, 95% CI 0.059–0.834, p=0.016) and that the number of patients undergoing hemodialysis for reoperation after fistula maturation was significantly lower in the cilostazol group than in the control group (7.5% [n=8] vs. 28.7% [n=25], OR 0.200, 95% CI 0.085–0.472, p<0.001). The rate of radiological interventions (PTA) to maintain fistula patency was also lower in the cilostazol group than in the control group, although the difference was not statistically significant (35.5% [n=38] vs. 44.8% [n=39], OR 0.678, 95% CI 0.380–1.209, p=0.187). Furthermore, the number of PTA procedures was not significantly different between the cilostazol (1.7±1.1) and control (2.2±2.0) groups (p=0.157). Finally, there were no statistically significant differences the interval between AVF surgery and PTA between the two groups (p=0.300). The incidence of vascular complication was a significant difference in maturation failure and reoperation after maturation, but there was no statistically significant difference in survival analysis (Fig. 1).

Fig. 1.

AVF survival curves for patients the cilostazol group versus control group. (a) Maturation failure; (b) reoperation after maturation; (c): PTA. PTA, percutaneous transluminal angioplasty.

(0.23MB).

Of the 194 AVF surgical patients, 100 patients underwent radiocephalic (RC) fistula surgery, 93 patients underwent brachiocephalic (BC) fistula surgery, and 1 patient underwent brachiobasilic fistula surgery. When comparing the cilostazol group and the control group in patients that underwent RC fistula surgery, vascular complications were significantly lower in the cilostazol group than in the control group (39.3% [n=22] vs. 61.4% [n=27], p=0.028), and reoperation after fistula maturation was also significantly lower in the cilostazol group than in the control group (5.4% [n=3] vs. 27.3% [n=12], p=0.002). The rates of maturation failure (p=0.249) and PTA (p=0.081) were not significantly different between the cilostazol group and the control group. When comparing the cilostazol group and control group in patients that underwent BC fistula surgery, there was no significant difference in the rate of vascular complications between the two groups (33.3% [n=17] vs. 42.9% [n=19], p=0.345). However, the rates of maturation failure (2.0% [n=1] vs. 14.3% [n=6], p=0.043) and reoperation after fistula maturation (9.8% [n=5] vs. 31.0% [n=13], p=0.010) were significantly lower in the cilostazol group than in the control group. The rate of PTA to maintain fistula patency was not significantly different between the two groups (p=0.840) (Table 3).

The present single-center, retrospective study was designed to evaluate the potential benefit of cilostazol in patients with hemodialysis access. Several common mechanisms underlie the pathophysiology of AVF maturation failure and vascular complications for all vascular access types, particularly those involved in neointimal hyperplasia.17–20 Studies have consistently demonstrated that changes in the extracellular matrix, which occur early during vascular remodeling, can lead to failed fistula dilation and subsequent stenosis and thrombosis of the access point. A large randomized controlled trial has demonstrated that thrombosis plays only a limited role in failed fistula maturation and vascular remodeling and that IH is a more prominent mechanism.17

The pathophysiology of IH is complex, but one central hemodynamic-related mechanism involves the upregulation of mitogen-activated protein kinases.18 Experimental studies suggest that this pathway may be controlled by cilostazol,19–21 a phosphodiesterase (PDE)-3 inhibitor that is used for the treatment of intermittent claudication.13,15,16,22-24 PDE-3A and PDE-3B are two members of the PDE-3 enzyme family. PDE-3A is expressed in platelets, vascular smooth muscle cells, and cardiomyocytes, whereas PDE-3B is found in adipocytes, hepatocytes, pancreatic β-cells, and macrophages.14,25 Therefore, the pharmacological effects of cilostazol include vasodilation, inhibition of platelet activation and aggregation, inhibition of thrombosis, increased blood flow to extremities, improvement in serum lipids, and inhibition of vascular smooth muscle cell growth; these effects of cilostazol contribute to the reduction of AVF maturation failure.17 The use of cilostazol after vascular surgery may reduce the incidence of maturation failure and subsequent intervention or reoperation by influencing vascular remodeling, in agreement with the results of the present study.17

The main finding of the present study was the reduction in vascular complications among hemodialysis patients treated with cilostazol. Specifically, the incidence of maturation failure was significantly lower in the cilostazol-treated patients who underwent hemodialysis without maturation failure after vascular surgery. Additionally, the incidence of reoperation was also significantly lower in the patients treated with cilostazol. However, there was no significant difference in vascular complication in survival analysis using Kaplan-Meier curve analysis. It is thought that maturation failure was mostly determined within 2 months after surgery, so it seems that there was no difference in the time factor.

When comparing the vascular complications according to the fistula location, patients that underwent RC fistula surgery experienced fewer vascular complications when taking cilostazol. The analysis of the vascular complications by subgroups revealed that the rate of reoperation after fistula maturation was significantly lower in the cilostazol group than in the control group. However, there were no significant differences in the rates of maturation failure and PTA between the cilostazol and control groups. Patients that underwent BC fistula surgery did not experience fewer vascular complications when taking cilostazol. However, the analysis of the vascular complications by subgroups revealed that the rates of maturation failure and reoperation were significantly lower in the cilostazol group than in the control group. The rate of PTA was not significantly different between the two groups in patients that underwent BC fistula surgery. When cilostazol was administered, the rate of reoperation after fistula maturation was significantly lower in both RC fistula surgery and BC fistula surgery, the rate of maturation failure was significantly lower in BC fistula surgery, not RC fistula surgery. In our study, it is difficult to analyze the preoperative vein diameter because there was no measurement and vascular ultrasound reports, but in the previous study, the vein diameter was found to be an independent predictor of maturation.26 Therefore, in patients that underwent RC fistula surgery, the vein diameter was generally smaller than in patients that underwent BC fistula surgery, so it is expected that these factors may have influenced maturation failure. Therefore, when the vein diameter is large, the effect of cilostazol can be more clearly evaluated, and when the vein diameter is small, it might be difficult to compare the effects of cilostazol because the vein diameter can be a risk factor for maturation failure. In patients that underwent BC fistula surgery, the rates of both maturation failure and reoperation were lower in the cilostazol group, although the rate of vascular complications was not different between the cilostazol group and the control group. In our study, vascular complications were defined as serious vascular access events, including maturation failure, PTA, and reoperation after fistula maturation. In patients who underwent BC fistula surgery, there was no difference in the rate of PTA between the cilostazol group and the control group, and this effect showed no difference in vascular complications.

As cilostazol is a PDE-3 inhibitor, it is expected to reduce the incidence of maturation failure and reoperation by inhibiting IH by reducing vascular smooth muscle cell growth after AVF surgery.9–11 However, if PTA is performed owing to stenosis or thrombosis of AVF after maturation, it may occur due to mechanical trauma from venipuncture or shear stress due to turbulent blood flow rather than IH.27,28 Therefore, administration of cilostazol is considered to not have a significant influence on PTA.

The present study has several limitations that should be acknowledged. First, the patient population was relatively small in this single-institution study. However, the study cohort was larger than that of a previously published similar study.17 Additionally, between January 2012 and June 2018, only one surgeon performed AVF and AVG surgeries which might reduce bias due to differences in surgical skills among different surgeons. The present study did not reveal a difference in the number of PTA procedures between the cilostazol and control groups. Since vascular conditions that require PTA can cause endothelial damage and IH, cilostazol administration might affect the final number of patients undergoing PTA. However, the cilostazol and control groups did not exhibit differences in the efficacy of cilostazol after PTA in the present study and a future controlled study is warranted.

In conclusion, the present retrospective, single-surgeon, single-center study found that there were differences in vascular complications between the patients treated with cilostazol and those who were not administered cilostazol; however, a definitive conclusion requires a larger study cohort. Future well-designed prospective studies with larger populations are necessary to address these issues.

Authors declare no conflict of interest.