|Year : 2021 | Volume
| Issue : 1 | Page : 118-127
|Paclitaxel-Coated Balloons Compared to Plain Balloon Angioplasty in the Management of Dysfunctional Arteriovenous Fistulae: A Single-Center Randomized Clinical Trial
Mohammad Arabi1, Refaat Salman1, Abdulaziz Alharbi1, Yousof Alzahrani1, Omar Bashir1, Shahbaz Qazi1, Mubarak Abdallah2, Mahfooz Farooqui2, Fayez Hejaili2, Mohammad Almoaiqel1
1 Department of Medical Imaging, Division of Vascular and Interventional Radiology, Ministry of National Guard Health Affairs; King Abdullah International Medical Research Center; King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 King Abdullah International Medical Research Center; King Saud bin Abdulaziz University for Health Sciences; Department of Internal Medicine, Division of Nephrology, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
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|Date of Web Publication||16-Jun-2021|
| Abstract|| |
The study aimed to compare paclitaxel-coated balloons (PCB) to percutaneous transluminal plain balloon angioplasty (PTA) in the management of dysfunctional arteriovenous fistulae. This single institution randomized controlled trial was approved by the institutional and local review boards and is registered in the ClinicalTrials.gov website. The study was initially designed to recruit a total of 92 patients. However, recruitment was terminated after the release of the meta-analysis that raised concerns about the potential increased risk of death associated with PCB. A total of 23 patients with nonthrombosed dysfunctional fistulae (mean age 67 years, 12 females) were recruited (PCB = 12) from October 2017 to September 2018. The fistulae were radiocephalic (n = 5), brachiocephalic (n = 12), brachiobasilic (n = 6), and seven immature fistulae. After a 2-min predilatation of the target lesions, patients were randomized to receive an additional 2-min of angioplasty with either a plain balloon or PCB (Lutonix). The primary endpoint was fistula patency at 12 months. The secondary endpoints included technical and clinical success, time-to-reintervention, survival at 12 months, and complications. The primary endpoint of fistula patency at 12 months was met in three patients treated with PCB and two patients treated with PTA. The all-cause mortality at one year was 8% (n = 2), both were in the PTA group. Treatment failed in restoring adequate fistula function in four patients [2 PCB with immature arteriovenous fistula (AVF) and two PTA with mature AVF]. Three patients were lost to follow-up (1 PCB, 2 PTA). Of the remaining patients (6 PCB and 4 PTA), there was no significant difference in the median time-to-reintervention between the two groups (148 vs. 174 days). Two minor complications were recorded which did not require any additional treatment. Although this trial was terminated prematurely, there appears to be no significant difference between PCB and PTA in maintaining fistula patency and reducing the time-to-reintervention. No mortality was recorded in the PCB group during the study period.
|How to cite this article:|
Arabi M, Salman R, Alharbi A, Alzahrani Y, Bashir O, Qazi S, Abdallah M, Farooqui M, Hejaili F, Almoaiqel M. Paclitaxel-Coated Balloons Compared to Plain Balloon Angioplasty in the Management of Dysfunctional Arteriovenous Fistulae: A Single-Center Randomized Clinical Trial. Saudi J Kidney Dis Transpl 2021;32:118-27
|How to cite this URL:|
Arabi M, Salman R, Alharbi A, Alzahrani Y, Bashir O, Qazi S, Abdallah M, Farooqui M, Hejaili F, Almoaiqel M. Paclitaxel-Coated Balloons Compared to Plain Balloon Angioplasty in the Management of Dysfunctional Arteriovenous Fistulae: A Single-Center Randomized Clinical Trial. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2021 Dec 4];32:118-27. Available from: https://www.sjkdt.org/text.asp?2021/32/1/118/318513
| Introduction|| |
An arteriovenous fistula (AVF) is the dialysis access of choice. However, stenosis remains a major concern resulting in access dysfunction or failure. While angioplasty improves circuit patency, target lesion restenosis requires repeated interventions despite the use of different techniques such as high-pressure balloons (HPB), cutting balloons, or stents. Recent trials and retrospective studies comparing the conventional to a paclitaxel-coated balloon (PCB) angioplasty in dialysis access demonstrated variable comparative effectiveness at six and 12 months and potentially reduced the rate of reinterventions.,,,,,,,,,,,,,,,,,, In a meta-analysis of six randomized control trials (RCTs) and four cohort studies including 911 patients, there was no statistically significant improvement in the target lesion restenosis rate in the RCTs. However, the PCBs resulted in an improved target lesion restenosis rate in the cohort studies. Recent RCT demonstrated that PCB is superior to standard balloon angioplasty at six months with similar safety profile. Another meta-analysis of 8 RCTs, comparing PCB angioplasty (n = 327) to PTA (n = 331), showed no difference in short or mid-term mortality. This variation in reported outcomes in different studies may be explained by the differences in the patient population, underlying pathology, severity and extent of lesions, and the variability of techniques in performing balloon angioplasty between institutions and operators. In our center, conventional angioplasty followed by PCB angioplasty with different devices was variably used. There was no uniform protocol to allow for comparison of outcome measures. This RCT was designed to assess the patency rate and time-to-reintervention after PCB versus PTA in patients with native dialysis fistulae.
| Materials and Methods|| |
This single institution RCT was approved and funded by the King Abdullah International Medical Research Center (KAIMRC) and approved by the Saudi Food and Drug Authority (SFDA). The trial is registered in the ClinicalTrials.gov website (NCT03189667). All participants signed an IRB approved Arabic language consent form before enrolment and initial angiographic assessment.
The study was designed to compare the effectiveness of PCBs to PTA in reducing the restenosis rate in native dialysis AVFs. The optimal sample size at the time of the initial design was 84 participants (42 participants per group) assuming a restenosis proportion of 70% and 40% in PCB and PTA groups, respectively, an alpha level of 0.05, a two-sided test, an odds ratio of 0.286, and a power of 80%. Accounting for a 10% drop-out rate, the final sample size was 92 subjects (46 subjects per group). However, enrollment was terminated due to slow recruitment and after the release of the meta-analysis that raised concerns about a potential increased risk of death associated with PCB following peripheral interventions. A total of 23 patients (12 females) with nonthrombosed dysfunctional fistulae (mean age 67 years, range 47–84 years) were recruited (PCB = 12) from October 2017 to September 2018. During the same period, a total of 188 participants presented for dialysis fistula interventions as shown in the flow diagram of the study [Figure 1]. The participants were screened using the inclusion and exclusion criteria [Table 1]. The 12-month follow-up was completed in September 2019. Fistulae were radiocephalic (n = 5), brachiocephalic (n = 12), brachiobasilic (n = 6), and seven immature fistulae. Patients presented with weak thrill (n = 6), failed dialysis (n=9), failed recirculation (n=5), and abnormal pulsation (n = 3) [Table 2]. A one-to-one randomization sequence was generated by the biostatistics department. The principal investigator and coinvestigators were blinded to the randomization sequence. The randomized sealed envelope was opened after the initial angiographic confirmation of a stenotic lesion of more than 50%. All procedures were performed or directly supervised by one of the five interventional radiologists with experience ranging from 2 to 10 years.
The initial fistulogram was done using ultrasound-guided brachial artery access with a 3 Fr cannula to assess the severity, number, length, and location of lesions. No direct fistula access was done on the initial fistulogram to minimize spasm. Stenosis was defined as more than 50% luminal loss compared to adjacent normal appearing non-aneurysmal segments (reference vessel diameter) according to the following formula:
- Stenosis percentage = 1-(Target lesion diameter/[(pre+poststenotic vessel diameter)/2)]×100. The stenosis was evaluated using manual or automatic vessel analysis on an AlluraXper Philips compression or using a purse-string suture with a Slip-Not® Suture Retention Device (MeritMedical, UT, USA). If the stenosis Was >50%, the patient was randomized to either two additional minutes of PTA at nominal pressure using the same pre-dilatation balloon or an additional 2 min of dilatation with PCB (Lutonix®, Bard peripheral vascular, AZ, USA). The balloon size was not to exceed the reference vessel diameter by more than 25% [Table 3]. A weight-based bolus of intravenous heparin was administered. Multiple adjacent lesions were treated with a single balloon if possible. Multiple PCBs (n = 16) were used if lesions could not be covered with a single balloon. Two PCB patients required central venoplasty, and a patient in the PTA group required coil embolization of a competing collateral during the index procedure.
Hemostasis was achieved with either manual post-procedure anticoagulation or postprocedure protocol was prescribed.
The monitoring of clinical and functional parameters was done by the dialysis and clinical teams during each dialysis session for 12 months after the index procedure. The study protocol did not include scheduled fistulography or ultrasound for flow assessment. Patients were referred for reintervention whenever they met the initial inclusion criteria based on the functional or clinical parameters.
The primary functional endpoint was access circuit patency based on functional and clinical criteria at 12 months, and the primary safety endpoint was the periprocedural complication rate, based on the Society of Interventional Radiology guidelines. The secondary end-points included technical success (<30% residual stenosis without postdilatation) and access circuit dysfunction-free survival (time to re-intervention) based on functional or clinical criteria. Survival at 12 months was included as a secondary endpoint after the amendment of the study protocol following the termination of recruitment due to the safety concerns linked to the PCBs.
The categorical variables are summarized as frequency and percentage and the numerical variables (continuous variables) as the mean and standard deviation. The normality assumptions were assessed for all numerical variables using a statistical test (i.e., Shapiro–Wilk test) and also graphical representation (i.e., histograms and Q-Q plots). Categorical variables were compared with the chi-squared or Fisher’s exact test, normally distributed numerical variables with the t-test, and other quantitative variables with the Mann–Whitney U-test. The baseline characteristics, baseline severity, and outcome variables were com-pared between the two groups. A P<0.05 was considered as statistical significance. All the statistical analyses were done using SAS software, version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).
| Results|| |
The primary endpoint of fistula patency at 12 months was met in 27.3% (3/11) of patients treated with the PCB and 22.2% (2/9) of patients treated with PTA (P >0.9) [Table 4]. Two minor complications were recorded which did not require any additional treatment (one small self-limited extravasation and one non-occlusive brachial artery embolus). There was no difference in the maximum pressure delivered to the lesions with either the PCB or PTA arms (15.8 atm vs. 20.4 atm; P = 0.10). Treatment failed in restoring adequate fistula function in four patients (2 PCB patients with immature AVF and 2 PTA patients with mature AVF). The all-cause mortality at one year was 8% (n = 2), due to other co-morbidities and both were in the PTA group. Three patients were lost to follow-up [1 PCB (8%)and 2 PTA (18%)]. In the remaining 10 patients (6 PCB and 4 PTA), there was no statistical difference (P = 0.60) in the median time-to-reintervention between the two groups(148 vs. 174 days) [Figure 2]. At the time-of-reintervention, the target lesion restenosis was present in all lesions previously treated with PCB and PTA. Additional stenotic lesions along the dialysis circuit were found in (1/6) PCB patients and (2/4) PTA patients.
|Figure 2: Participants at risk for reinterventions at 3-month intervals. Baseline numbers indicate the participants who have competed follow-up. Patients who were lost to follow-up were removed from the analysis.|
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| Discussion|| |
Early clinical studies and trials investigating the use of PCBs in the management of dialysis circuits showed variable results regarding the time-to-reintervention and the patency rate at different time points. Katsanos et al randomized 40 patients to PCBs versus plain HPB angioplasty of dialysis fistula or AV graft. The primary patency at six months was 70% in the active treatment group versus 25% for the conventional HPB. Another trial randomized 20 lesions shorter than 2 cm in 10 patients and found that the target lesion revascularization duration was significantly longer with PCB compared to PTA (251.2 d vs. 103.2 d; P <0.01). The primary patency rate of the target lesion at six months was significantly higher in the PCB group (70% vs. 0%; P <0.01) but not significantly different at 12 months (20% vs.0%; P<0.05). Kitrou et al randomized 40 patients to PCB versus HPB angioplasty for the treatment of dysfunctional AVF. Additional dilatation with a HPB was required in twothirds of the PCB group to achieve anatomic success. Nevertheless, PCBs significantly prolonged the target lesion restenosis-free survival (PCB, 308 d; HPB, 161 d; P = 0.03). The access circuit primary patency was significantly in favor of the PCB angioplasty (PCB, 270 d; HPB, 161 d; P = 0.04). In a different trial, 14 patients were randomized to PCBs compared to 16 patients to PTA. The PCBs did not improve the target lesion or circuit patency at six months (50% for PCB vs. 68% for PTA) despite the improved restenosis rate (33% for PCB vs. 75% for PTA).
In a multicenter RCT of 285 patients with dysfunctional AVF, the target lesion and access circuit primary patency rate at six months did not differ between PCB (Lutonix) and PTA. However, the number of interventions required to maintain the target lesion patency at six months was lower in the PCB group (0.31 versus 0.44 per patient, P = 0.03). In the long-term analysis of this trial, the target lesion primary patency (TLPP) at nine months was statistically better in the PCB group (58% ± 4% vs. 46% ± 4%; P = 0.02) but not statistically better at 18 or 24 months. The access circuit patency rate was not different between the groups; however, PCB was associated with a shorter mean time-to-reintervention (322 vs. 207 d; P <0.0001) and fewer interventions to maintain the TLPP at nine months but not at 12, 18, or 24 months. Both PCB and PTA treatments were equally safe.
A recent multicenter trial involving 136 patients with dysfunctional fistulae and grafts randomized to PCB versus HBP showed no significant difference in the primary patency at six and 12 months, and both treatment arms were associated with similar safety profiles and mortality rates. On the contrary, a single-center RCT of 39 patients showed a worse time-to-reintervention and the target lesion revascularization rate at 12 months with PCBs. A meta-analysis of six RCTs concluded that the PCBs did not result in statistically significant improvement in the target lesion primary patency at all-time points between one to 24 months. However, the effect of the PCBs on the primary patency was significant at six, 12, and 24 months in the analyzed cohort studies. Another meta-analysis of 8 RCTs (PCB = 327, PTA = 331), specifically examining all-cause mortality as the primary endpoint, showed no significant difference in the short and mid-term mortality when using PCBs compared to PTA. A recent RCT of 330 patients showed that PCB is superior to standard balloon angioplasty in maintaining six-month patency (82.2% vs. 59.5%, P <0.0001).
In this present RCT, the initial study protocol was powered to include 92 patients; however, enrollment was terminated due to slow recruitment and the safety concern raised by the meta-analysis of Katsanos et al with subsequent advisories by several international and national regulatory authorities to use PCBs with caution in participants with a risk of restenosis. This trial, although under-powered, suggested that PCBs did not result in improved time-to-reintervention and primary patency at 12 months. The survival analysis was included after the amendment of the initial study protocol to assess all-cause mortality at 12 months after the index procedure. There was no observed mortality in the PCB group during the study period, and two participants died in the PTA group due to other comorbidities.
The findings of this trial are limited by the premature termination and the small sample size, limiting its statistical power and validity of conclusions. Slow recruitment was related to the exclusion of a large proportion of the screened patients due to fistula thrombosis or known isolated central vein stenosis. Our center accepts referrals from several satellite dialysis clinics, and the initial baseline referral data at presentation were insufficient. In addition, three patients were lost to follow-up. The available data do not allow for accurate subgroup analysis or a correlation between the lesion characteristics and the defined outcomes. However, the strength of the study design is that it attempted to treat all lesions in both groups, using the same duration of inflation to limit the difference between the two arms to the drug application only. Both arms received a total of 4 min inflation including 2 min of initial predilatation to eliminate the waist and prepare the vessel for drug delivery, which may mitigate the potential bias that can be introduced by the prolonged inflation time during PCB application.
In conclusion, although this trial was terminated prematurely, there appears to be no significant difference between the PCB and PTA in maintaining fistula patency and reducing the time-to-reintervention. No mortality was recorded in the PCB group during the study period.
| Acknowledgment|| |
We thank the Vascular Interventional Radiology unit for their assistance and contribution to the data collection and the Biostatistics Department their assistance in the statistical analysis.
| Compliance with Ethical Standards|| |
This single institution RCT was approved and funded by the King Abdullah International Medical Research Center. The trial is registered and approved by the SFDA. The trial is registered in the ClinicalTrials.gov website (NCT03189667).
| Funding|| |
This single institution RCT was approved and funded by the King Abdullah International Medical Research Center (KAIMRC).
| Patient consent|| |
All participants signed an IRB approved Arabic language consent form before enrolment and initial angiographic assessment.
Conflict of interest: None declared.
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Department of Medical Imaging, Division of Vascular and Interventional Radiology, Ministry of National Guard-Health Affairs, Riyadh
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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