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Abstract

Background

Drug-coated balloons (DCB) are used for vascular access interventional therapy (VAIVT). However, few studies on patients with repeated short-term restenosis after VAIVT using a standard balloon (SB) have been reported, and the effect of DCB use on patency in these patients remains unclear.

Purpose

This study aimed to evaluate the efficacy of DCB in patients with repeated short-term restenosis after VAIVT with SB.

Materials and Methods

This was a single-center retrospective study. We enrolled 50 consecutive patients who suffered two consecutive restenosis episodes within 6 months after VAIVT with SB. In the third session, patients were treated with DCB or SB. Target lesion revascularization (TLR) was evaluated for 1 year after the third session, with the primary endpoint being the TLR-free rate at 6 months after VAIVT.

Results

At the third procedure, 24 patients were treated with DCB (DCB group), whereas 26 were treated with SB (SB group). The TLR-free rates at 6 months and 1-year were significantly higher in the DCB group than in the SB group (79.2% vs 26.9%, p < .001; and 41.7% vs 7.7%, p = .005). In the DCB group, a significant correlation was observed between the TLR duration from VAIVT with DCB and the prerestenosis duration before DCB treatment.

Conclusions

Among patients with repeated short-term restenosis after VAIVT, DCB use significantly improved short-term patency compared with that after SB use. DCB may help extend the period between sessions, which are repeated in the short term, to an acceptable length.

Keywords

dialysis arteriovenous fistula percutaneous transluminal angioplasty drug-coated balloon short-term restenosis patency rate

Introduction

In recent years, the increase in the number of patients with end-stage renal failure has become a matter of global concern, with approximately 4 million people receiving renal replacement therapy, including hemodialysis.^1,2 The most common approach site for dialysis is through an arteriovenous fistula (AVF) constructed in the upper limb, rather than a central venous dialysis catheter inserted into the internal meridian vein or subclavian vein, due which is associated with risks such as infection.^3,4 Patients on dialysis can suffer from a variety of problems, including heart failure and infection; in particular, stenosis of the AVF is a major cause of dialysis failure, which can lead to a worsened quality of life and threaten the patient’s life.⁵ According to national guidelines, reconstructing the AVF or vascular access intervention therapy (VAIVT) is recommended as a treatment for the stenosis, with VAIVT often being the treatment of choice due to its low degree of invasiveness and associated medical costs and patient burden.⁶ Thus, although VAIVT plays an important role, the patency prognosis of the procedure with a standard balloon (SB) is not good, exhibiting a restenosis rate of approximately 50% at 6 months after the session.^7–9 Especially, cases requiring frequent interventions due to repeated restenosis over a short period of time are the most problematic in daily practice. The main cause of restenosis is thought to be excessive neointimal tissue formation during the healing process after repeated VAIVT. To address this, a drug-coated balloon (DCB) is typically used to inhibit neointimal tissue formation. DCB delivers drugs such as paclitaxel to the intima, preventing tissue overgrowth in the intima and allowing the maintenance of the lumen.^10,11

To date, it has been used in various vascular regions, including coronary and peripheral artery diseases, with good patency prognosis.^12–14 Recently, DCB has been used in VAIVT, and its usefulness has been reported in a number of cases, contributing to improved patency prognosis.^9,15,16

However, no studies have reported patients with repeated short-term restenosis after VAIVT with SB, and whether the procedure with DCB is also useful for these patients remains unclear. Therefore, this study aimed to investigate the short-term efficacy of DCB in patients with recurrent restenosis after VAIVT using SB.

Methods

Study design and patient population

In this single-center, retrospective, observational study, we included consecutive patients on maintenance dialysis who had undergone VAIVT for stenosis recurrence at our hospital between January 2020 and December 2023 and had previously experienced restenosis within 6 months on two consecutive occasions after the procedure with SB. Prerestenosis duration was defined as the mean duration of the first to second and second to third session (Fig. 1). Among these patients, we excluded those on maintenance dialysis through an artificial venous graft and those who died within 1 year after the final session. This study was approved by the Ethics Committee of our hospital (Approval No. 24-2, Date: 2024/4/15) and was conducted in accordance with the provisions of the Declaration of Helsinki. The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000056288).

Figure 1.

Study design. Repeated short-term restenosis was defined as restenosis within 6 months on two consecutive occasions after vascular access interventional therapy (VAIVT) with a standard balloon. Pre-restenosis duration was defined as the mean duration of the first to second and second to third session.

VAIVT procedures

AVF angiography was performed in patients with suspected dialysis shunt failure, including those with poor debridement, recirculation, and elevated venous pressure. If angiography showed stenosis of >50%, shunt failure was suspected; subsequently, VAIVT was performed on the lesion. The access site was determined by the operator, and either the distal radial artery or AVF was chosen as the approach site. A 6-French-size sheath (Ultra High Flow, Medikit, Tokyo, Japan) was used. After sheath insertion, anticoagulation therapy was administered to all patients according to the standard hospital protocol of 60 units/kg heparin, with a maximum dose of 5000 international units. A 0.014-inch wire was advanced through the lesion and the vessel diameter was estimated angiographically before dilation using a scoring balloon. After these SB treatments, if the operator decided to use a DCB, a three-minute inflation was performed. Treatment endpoints included lesion stenosis of ≤30% and good blood flow as indicated in angiography. A skilled cardiologist at our hospital performed each step of the procedure. The DCB used in the procedure was the IN.PACT™ AV (Medtronics, Fridley, Minnesota, United States), which carries a paclitaxel dose of 3.5 µg/mm² with a urea excipient. Treatment effectiveness was determined by confirming adequate shunt thrill and successful dialysis within 48 h.

Qualitative arteriovenous fistula angiography

Angiograms of the AVF taken before and after the third session were analyzed using a computer-assisted system that employed edge-detection methods (QCA-CMS5.1, Medis Imaging Systems, Leiden, Netherlands).

Clinical follow up

After the final session with either DCB or SB, the patient continued dialysis at a regular hospital. Primary patency was defined as the duration before a second session was required due to dialysis shunt dysfunction, such as poor blood outflow, increased venous pressure, or the presence of ≥50% AVF stenosis, as detected by ultrasound imaging, and was observed over a 1-year follow-up period.

Statistical analysis

Statistical analysis was performed using the SPASS software (version 29.0; IBM Corp., Armonk, NY, USA). Qualitative data are presented with frequencies, while quantitative data are shown as the mean values ±SD. For continuous variables, comparisons between the two groups were performed using a two-tailed, unpaired t test or Wilcoxon test. Discrete variables are presented as percentages, and comparisons were performed using chi-square analysis or Fisher’s exact test. Survival curves were constructed using Kaplan–Meier estimates and compared using the log-rank test. Variables that showed statistical significance in the univariate analyses were entered into multivariate analysis using backward stepwise selection to obtain the final model. At each step, the least significant variable was discarded from the model until all variables in the model reached p < .20. A p-value < .05 was considered statistically significant.

Results

Patient and lesion characteristics

Between January 2020 and December 2023, a total of 57 consecutive patients were enrolled in this study. After selection using excluding criteria, 50 patients were included in the present study (Fig. 2). A total of 24 patients were treated with DCB (DCB group), whereas the remaining 26 were treated with an SB (SB group). The groups did not significantly differ in terms of baseline patient characteristics or medications. In addition, no significant differences were observed in the treatment process, including AVF location, stenotic site, or balloon diameter (Table 1).

Figure 2.

Patient population.

Table 1.

Clinical characteristics.

Variables	Drug-coated balloon group (n = 24)	Standard balloon group (n = 26)	p value
Clinical characteristic
Age (years)	72.4±11.0	74.4±11.0	0.51
Female, n (%)	7 (29.2)	7 (26.9)	0.86
Hypertension, n (%)	18 (75.0)	23 (88.5)	0.22
Diabetes mellitus, n (%)	14 (13.9)	15 (15.1)	0.96
Dyslipidemia, n (%)	6 (25.0)	4 (15.4)	0.40
CAD, n (%)	11 (45.8)	8 (30.8)	0.27
LEAD, n (%)	7 (29.2)	10 (38.5)	0.49
CVD, n (%)	5 (20.8)	5 (19.2)	0.89
CHF, n (%)	6 (25.0)	9 (34.6)	0.46
Smoking			0.72
No smoking, n (%)	11(45.8)	9 (34.6)
Current, n (%)	3 (12.5)	4 (15.4)
Past, n (%)	10 (41.7)	13 (50.0)
Hemodialysis history	82.7±113.8	100.2±111.3	0.44
Medication
Aspirin, n (%)	10 (41.7)	10 (38.5)	0.82
P2Y12 inhibitor, n (%)	5 (20.8)	5 (19.2)	0.89
Cilostazol, n (%)	1 (4.2)	1 (3.8)	0.95
Warfarin, n (%)	2 (2.4)	3 (11.5)	0.71
Arteriovenous fistulas and VAIVT procedure status
TLR-free period from first-second VAIVT (day)	102.0±52.5	98.9±46.8	0.83
TLR-free period form first second-third VAIVT (day)	100.9±57.7	119.1±57.4	0.27
Location			0.65
Upper arm, n (%)	6 (25.0)	8 (30.8)
Forearm, n (%)	18 (75.0)	18 (69.2)
Culprit lesion			0.98
Anastomotic part, n (%)	13 (54.2)	14 (53.8)
Body part, n (%)	11 (45.8)	12 (46.2)
Qualitative arteriovenous fistulas angiography
Lesion length (mm)	40.9±13.9	46.6±26.1	0.55
Reference vessel diameter (mm)	4.9±1.0	6.4±7.2	0.39
% Stenosis (%)	70.9±3.44	80.1±12.0	0.01
Post % stenosis (%)	13.0±1.6	17.0±5.5	0.02
Diameter of balloon (mm)	5.3±0.8	5.7±1.0	0.21

Patient characteristics of the conventional balloon and DCB groups. Data are expressed as n (%), mean ±standard deviation, or median. CAD: Coronary artery disease; LEAD: Lower extremity artery disease; CVD: Cerebral vascular disorder; CHF: Chronic heart failure; VAIVT: Vascular access intervention therapy

Clinical outcomes

Among the 50 patients, 39 experienced TLR during the 1-year clinical follow-up. The TLR-free rates at 6 months and 1-year were significantly higher in the DCB group compared with those in the SB group (79.2% vs 26.9%, p < .001; and 41.7% vs 7.7%, p = .005, respectively; Fig. 3 and Table 2). Univariate and multivariate Cox regression analyses of the determinants of TLR within 6 months revealed that DCB use and pre-restenosis duration were independent risk factors (DCB: HR 0.041, p < .001; pre-restenosis mean duration: HR 0.969, p < .010; Table 3). However, in the landmark analysis 6 months after the third session, no significant difference was observed between the two groups (Fig. 4). In addition, in the DCB group, a significant correlation was identified between the duration of TLR after the procedure with DCB and the pre-restenosis duration before DCB treatment (Fig. 5).

Figure 3.

Survival analysis according to vascular access interventional therapy (VAIVT) with drug-coated balloon (DCB) or standard balloon (SB). Kaplan–Meier survival curves of target lesion revascularization stratified according to VAIVT with DCB or SB.

Table 2.

TLR-free rates at 6 months and 1-year from final VAIVT.

Variables	Drug-coated balloon group (n = 24)	Standard balloon group (n = 26)	p value
TLR-free rates during 6 months follow-up, n (%)	19 (79.2)	19 (26.9)	<0.001
TLR-free rates during 1 year follow-up, n (%)	9 (37.5)	2 (7.7)	0.005

Data are expressed as n (%).

TLR: target lesion revascularization.

Table 3.

Univariate and multivariate Cox hazard regression analysis for the Determinants of TLR within 6 months.

Variables	Univariate			Multivariate
Variables	HR	95% CI	p value	HR	95% CI	p value
Hypertension	2.32	11.69–89.39	0.04
Use of DCB	0.01	0.03−0.36	<0.001	0.04	0.01–0.25	<0.001
Mean duration	0.98	0.97−1.00	0.04	0.97	0.95–0.99	0.01
Multiple lesion	6.00	1.13−31.99	0.04
Lesion length	1.02	1.00-1.05	0.10

CI: confidence interval; HR: hazard ratio; DCB: drug-coated balloon.

Figure 4.

Landmark analysis (>6 months) of target lesion revascularization stratified according to vascular access interventional therapy (VAIVT) with drug-coated or standard balloon.

Figure 5.

The association between target lesion revascularization duration from vascular access interventional therapy (VAIVT) with drug-coated balloon (DCB) and the pre-restenosis duration before VAIVT with DCB.

Discussion

Summary of key findings

The main findings of this study are as follows. (1) VAIVT with DCB improved patency within a short period even in cases of repeated restenosis. (2) For cases of repeated restenosis within a short period, a limit to the improvement in long-term patency after the procedure with DCB was noted. (3) The duration between TLR and the procedure with DCB significantly correlated with pre-restenosis duration.

Current use and rationale of DCB in VAIVT

The primary cause of restenosis is thought to be the excessive formation of neointimal tissue during the healing process following repeated VAIVT. DCBs were used to inhibit the neointimal cell proliferation. DCBs deliver drugs such as paclitaxel directly to the intima, preventing tissue growth and maintaining vascular lumen patency. Several recent studies have demonstrated that compared with SBs, DCB improves patency rates in cases of AVF stenosis.¹⁶ However, few studies focusing on repeated short-term restenosis cases have reported improved patency outcomes.

Impact of prior restenosis interval on DCB effectiveness

In our study, DCB use was associated with improved patency rates at 6 months in cases of repeated short-term restenosis. Previous studies have also suggested that the use results in greater benefits in restenotic than de novo lesions.¹⁷

While studies on the efficacy of DCB for repeated short-term restenosis remain limited, Shintaku et al. reported the efficacy of it in 29 cases with short-term restenosis within approximately 3 months (mean 92 ± 21 d). In this study, the authors demonstrated a patency rate of 92% at 3 months but only 36% at 6 months.¹⁸ Conversely, a large-scale clinical trial reported a 6-month patency rate of 86.1% after VAIVT with DCB, comparable to the findings in the present study.¹⁶ One of the reasons for the difference in the 6-month patency rate may be the difference in the pre-restenosis duration before DCB treatment. In the reference study, restenosis occurred on average 92 d after treatment, whereas in the present study, it occurred 107 d after treatment. Our study demonstrated that along with DCB use, pre-restenosis duration was an independent factor influencing TLR within 6 months, TLR duration after procedure with DCB, and pre-restenosis duration before DCB treatment. Considering these results, it can prolong restenosis duration; however, this may depend on the previous restenosis duration. In addition, pre-expansion using cutting or scoring balloons instead of high-pressure balloons may have contributed to improved outcomes. Previous studies have reported that compared with high-pressure balloons, cutting balloons yield superior patency, and that the combination of scoring balloons and DCB is particularly effective.^17,19 Based on these findings, our research results suggest that even in cases of repeated restenosis in a short period of time, the treatment effect of DCB can be maximized by preparing the lesion site appropriately using a cutting or scoring balloon, improving the 6-month patency rate.

Limitations in long-term patency

In contrast, landmark analysis at 6 months revealed no significant differences in the patency rates between the DCB and SB groups. This indicated that DCB do not offer long-term patency advantages. Similar limitations in long-term efficacy have been highlighted in previous studies, emphasizing the need for further research.¹⁶ Despite the limited long-term benefits, the medium-term improvement in patency observed in this study is likely to enhance the quality of life of patients and reduce healthcare costs, even in cases of repeated short-term restenosis.

Clinical implications

In conclusion, our study suggests that compared with standard balloon angioplasty alone, drug-coated balloon angioplasty may improve short-term patency in patients with repeated short-term restenosis. However, we did not observe any long-term improvements in patency after procedure with DCB. Considering the correlation between the mean TLR duration from procedure with DCB and the mean restenosis duration before DCB treatment, DCB may help extend the period between VAIVT, which are repeated in the short term, to an acceptable length.

Limitations

This study had several limitations. First, this was a single-center, nonrandomized, retrospective study. Thus, a potential risk of patient selection bias exists. Second, no clear criteria exist for deciding whether the drug is applied to the lesion using a DCB during the VAIVT, leaving the decision to the operator. Therefore, a prospective randomized study involving larger numbers of patients and centers is warranted.

Footnotes

Acknowledgments

We would like to thank Editage () for English language editing.

Author contributions

Takanori Maeda: Investigation, Writing—Original Draft. Koji Kuroda: Conceptualization, Data Curation, Formal Analysis, Writing—Review and Editing.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical considerations

This study was approved by the Ethics Committee of our hospital and was conducted in accordance with the provisions of the Declaration of Helsinki. The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000056288).

Consent to participate

Informed consent was obtained in the form of an opt-out on the website of the Hyogo Prefectural Awaji Medical Center.

Consent for publication

As no personally identifiable data or images are included in this publication, consent for publication was not required. All data have been anonymized, and no information that could potentially identify individual participants is included in the study results.

ORCID iD

Koji Kuroda

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. The data will not be publicly available due to privacy or ethical concerns. Specific data may be shared upon request, and access will be granted in compliance with institutional and ethical guidelines.

References

Appendix

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Efficacy of drug-coated balloon for repeated short-term restenosis of dialysis arteriovenous fistulas

Abstract

Background

Purpose

Materials and Methods

Results

Conclusions

Keywords

Introduction

Methods

Study design and patient population

VAIVT procedures

Qualitative arteriovenous fistula angiography

Clinical follow up

Statistical analysis

Results

Patient and lesion characteristics

Clinical outcomes

Discussion

Summary of key findings

Current use and rationale of DCB in VAIVT

Impact of prior restenosis interval on DCB effectiveness

Limitations in long-term patency

Clinical implications

Limitations

Footnotes

Acknowledgments

Author contributions

Declaration of conflicting interests

Funding

Ethical considerations

Consent to participate

Consent for publication

ORCID iD

Data Availability Statement

References

Appendix

References