STUDY PROTOCOL OF SIROLIMUS-COATED BALLOON VERSUS PACLITAXEL-COATED BALLOON ANGIOPLASTY FOR THE TREATMENT OF DYSFUNCTIONAL ARTERIOVENOUS FISTULA ...

Study Protocol of Sirolimus-coated bAlloon Versus
pAclitaxel-coated balloon angioplasty for the
treatment of dysfunctional ArterioVenous Fistula
(SAVE AVF)
Chee Wooi Tan (  tan.chee.wooi@singhealth.com.sg )
 Singapore General Hospital https://orcid.org/0000-0001-9735-3010
Ru Yu Tan
 Singapore General Hospital
Suh Chien Pang
 Singapore General Hospital
Alvin Ren Kwang Tng
 Singapore General Hospital
Nick Zhi Peng Ng
 Singapore General Hospital
Alfred Bingchao Tan
 Singapore General Hospital
Ankur Patel
 Singapore General Hospital
Apoorva Gogna
 Singapore General Hospital
Tze Tec Chong
 Singapore General Hospital
Chieh Suai Tan
 Singapore General Hospital
Tjun Yip Tang
 Singapore General Hospital

Research Article

Keywords:

Posted Date: June 13th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-1632344/v1

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License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
Background
Dysfunction of arteriovenous fistula (AVF) remains a significant morbidity for patients who are suffering
from end-stage-kidney-disease (ESKD). The primary cause of dysfunction in AVF is due to stenosis from
neointimal hyperplasia. Plain old balloon angioplasty (POBA) has been the standard of care for the
treatment of AVF stenosis however the average patency rates remain poor. Drug-coated balloon (DCB)
represents an emerging alternative to POBA in prolonging the patency of AV access. Paclitaxel-coated
balloon (PCB) is currently the most widely studied DCB as compared to second generation DCB,
sirolimus-coated balloon (SCB).

Methods
This is a single center, prospective and retrospective double arm registry study that is investigator driven
to compare the efficacy and safety of the two DCBs in the real-world setting in Singapore. A total of 200
eligible participants will be recruited and followed-up for 12-months. The primary endpoint is the patency
rates at 6-month while the secondary endpoints are the patency rates and the number of repeat
interventions needed to maintain patency at 6-and 12-months.

Discussion
Drug-coated balloon is an emerging device in endovascular intervention of AV access. PCB was the most
used DCB, until its safety concern was raised recently due to the findings of increasing risk of death
following application of PCB in femoro-popliteal artery of the leg. Compared to paclitaxel, sirolimus is
cytostatic in its action with a high safety margin and has anti-inflammatory effects. It has a high transfer
rate to the vessel wall and effectively inhibits neointimal hyperplasia. There have not been head-to-head
comparison of PCB and SCB in the treatment of dysfunctional AV access; hence through this study, we
will be able to study the safety and efficacy of the two DCBs in the real-world setting.

Trial registration:
ClinicalTrials.gov Identifier: NCT05333640 on 19 April 2022

Background
Dysfunction of arteriovenous (AV) access remains a significant morbidity for patients who are suffering
from end-stage-kidney-disease (ESKD). Arteriovenous fistula (AVF) is the preferred AV access for its better
durability, lower infection rates and maintenance costs compared to arteriovenous grafts and catheters.
[1] However, AVF still has almost 50% failure rate after a median lifetime of 3–7 years.[2]
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The primary cause of dysfunction in AVF is due to stenosis from neointimal hyperplasia.[3] Treatment of
AVF stenosis by percutaneous transluminal angioplasty (PTA) was first reported in 1981.[4] Since then,
plain old balloon angioplasty (POBA) has been the standard of care. The average patency rates after
POBA were reported to be 42% at 1 year. [5]

Drug-coated balloon (DCB) represents an emerging alternative to POBA in prolonging the patency of AV
access. Local delivery of antiproliferative agent to targeted vessel wall to combat neointimal hyperplasia
and prevent re-stenosis has been a promising strategy. Paclitaxel-coated balloon (PCB) is currently the
most widely studied DCB. To date, a substantial number of large-scale randomized-control-trials have
demonstrated the superiority of PCB over POBA. [6–10] As a second-generation DCB, sirolimus-coated
balloon (SCB) has also been demonstrated to be effective in the treatment of dysfunctional AVF and AVG.
[11–13] However, there have been no direct comparison between the two types of DCB. We aim to collect
all data pertaining to the use of SCB and PCB in our institution to compare the efficacy and safety of the
two DCBs in the real world setting in Singapore.

Materials And Methods
Hypothesis, aims and design

Singapore General Hospital (SGH) is the oldest hospital in Singapore with many vascular access salvage
procedures performed per year (~ 1400 cases per year).

We hypothesize that the 6-month circuit primary patency rates are not inferior in AVF treated with SCB
compared to PCB. This single center, prospective and retrospective double arm registry study is a multi-
investigator study that is conducted in accordance with the ethical principles in the Declaration of
Helsinki and is approved by the hospital’s Centralized Institutional Review Board. Informed consent will
be obtained from all subjects recruited to this dual parallel registry.
Case selection

Retrospective analysis of consecutive patients with dysfunctional AVF who underwent PCB and SCB
angioplasty from May-2021 to February-2022 will be undertaken (Study 1). From March-2022, all new
patients referred and treated with PCB and SCB will be subsequently included (Study 2). Informed
consent will be obtained.

A total of 200 participants (100 participants in SCB-arm and 100 participants in PCB-arm) from SGH that
fulfil the inclusion and exclusion criteria (Table 1) will be recruited. Participants will be followed-up for 12
months after the index intervention.

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Table 1
                                     Inclusion and Exclusion Criteria
 Inclusion Criteria                                                           Exclusion Criteria

 Age 21–85 years                                                              Patient unable to provide
                                                                              informed consent

 Patient who requires balloon angioplasty for dysfunctional or                Presence of symptomatic
 thrombosed AVF                                                               or angiographically
                                                                              significant central vein
                                                                              stenosis who require
                                                                              treatment, with more than
                                                                              30% residual stenosis
                                                                              post angioplasty

 Matured AVF, defined as being in use for at least 1 month prior to           Patients who had
 angioplasty                                                                  underwent stent
                                                                              placement within the AVF
                                                                              circuit

 Successful thrombolysis and angioplasty of the underlying stenosis,          Patient who are currently
 defined as less than 30% residual stenosis on Digital Subtraction            enrolled in other DCB trials
 Angiography (DSA) based on visual assessment of the operator and
 restoration of thrill in the AVF on clinical examination. (For concurrent
 asymptomatic or angiographically not significant central vein stenosis,
 patients can be included if no treatment is required.)

 Received either PDCB or SDCB for the treatment of the stenosis               Sepsis or active infection

                                                                              Recent intracranial bleed
                                                                              or gastrointestinal bleed
                                                                              within the past 12 months

                                                                              Allergy to iodinated
                                                                              contrast media, heparin,
                                                                              paclitaxel or sirolimus

                                                                              Pregnancy

                                                                              Inadequate treatment of
                                                                              underlying stenosis,
                                                                              defined as ≥ 30% residual
                                                                              stenosis of the underlying
                                                                              lesions.

Investigational devices

Drug-coated balloon that will be used in this study consists of sirolimus drug-coated balloon (Selution
Sustained Limus Release (SLR); M.A. MedAlliance SA, Nyon, Switzerland), with is coated with 1µg/mm2
of sirolimus and paclitaxel drug-coated balloon (Lutonix 035 DCB Catheter; Lutonix, Maple Grove,
Minnesota), that is coated with 2µg/mm2 of paclitaxel.

Study procedure
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All procedures will be performed in interventional suite equipped with fluoroscopy system according to
center protocol by credentialled operators. Minimum diameter of each stenotic lesion will be determined
pre-procedure.

Thrombosed AVF

Thrombosed AVF is treated with pharmaco-mechanical thrombolysis as per center protocol. Briefly,
vascular sheaths or cannulas are placed in both antegrade and retrograde directions. Thrombolytic
agents are then instilled. Through the sheath, a central venogram is performed followed by pull back
venogram. Following that, balloon angioplasty and maceration of clots are performed. Once all stenoses
are adequately treated (defined as ≤ 30% stenosis), the stenosis lesion will be treated with either SCB or
PCB at the operator’s discretion or patients’ preference. Completion venograms are then obtained. The
type and dose of the thrombolytic agent, administration of anti-coagulants, type, size, and length of
balloon and thrombectomy devices used during the procedure are also at the operator’s discretion.

Non-thrombosed AVF

Initial angiogram will be performed via vascular sheaths, cannula, or angiographic catheter. All clinically
significant stenosis will be treated with POBA. Should there be more than 1 stenosis, all the lesions will be
labelled and treated (from the AV anastomosis up to, but not including, the subclavian vein). Lesions are
considered separate if they are separated by a gap of at least 2 cm. The lesion will be dilated with POBA
that is sized like the adjacent reference vessel. Inflation time will be at least 2 minutes per inflation. In the
event of resistant stenosis, high-pressure conventional plain balloon or cutting balloon may also be used.
In stenotic segment adjacent to aneurysmal segment, where percentage of stenosis is difficult to
determine, the treated segment should reach at least 6mm in diameter.

Drug-coated balloon angioplasty

All the lesions will be treated with SCB or PCB that is sized like the adjacent reference vessel and will
cover the geographical zone with at least 1cm proximal and distal overlap. The balloon will be inflated to
an appropriate inflation pressure. Inflation time will be at least 2 minute per inflation. A final fistulogram
will be obtained at the end of procedure.
Follow Up

The patients will be follow-up at 6- and 12-month after the intervention to assess the primary and
secondary outcomes. Participants who are indicated for repeat intervention (Table 2) are considered to
have reached primary endpoint.

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Table 2
                      Indications of clinically significant lesions for repeat intervention
      Indications

      1.Thrombosed or partially thrombosed AVF

      2.Ipsilateral extremity edema

      3.Alteration in pulse, thrill or bruit

      4.Clinical features of inflow stenosis: lack of pulse augmentation

      5.Clinical features of outflow stenosis: failure of fistula to collapse when the arm is elevated

      6.Excessive collapse of venous segment upon arm elevation

      7.New difficult in cannulation

      8.Aspiration of clots

      9.Inability to achieve the target dialysis blood flow

      10.Prolonged bleeding beyond usual for 3 consecutive dialysis sessions

      11.Unexplained (> 0.2 units) decreased in delivered Kt/V on a constant dialysis prescription

Endpoints and definitions
Study’s primary and secondary endpoints are listed in Table 3.

                                                   Table 3
                                       Primary and Secondary Endpoints
 Primary Endpoint          Secondary Endpoints

 Primary patency           Primary patency rate of the circuit at 12-month
 rate of the circuit at
 6-month.

                           Treated lesion restenosis rate at 6- and 12-month (defined as incidence of
                           stenosis > 50% diameter of adjacent reference vessel segment from
                           angiography images)

                           Number of repeat interventions to treated lesion at 6- and 12-months

                           Number of repeat interventions to maintain access circuit (including
                           interventions to treated lesion) at 6-and 12-months

                           Treated lesion revascularisation free interval (defined as the interval from
                           intervention to repeat clinically driven target lesion intervention)

                           Complication rates of the procedure

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The patency outcomes are classified according to the Society of Interventional Radiology. [14]
Postintervention primary patency is defined as interval following intervention until the next required
intervention (angioplasty, thrombolysis, or surgical revision) or time of measurement of patency.
Postintervention assisted primary patency is defined as interval after intervention until subsequent
access thrombosis or time of measurement of patency. Secondary patency was defined as interval after
intervention until the access is abandoned or time of measurement of patency.

Sample size calculation and statistical analysis

This is prospective and retrospective double arm registry study to compare the effectiveness of SCB
against PCB angioplasty. From the results of PCB in published RCTs, the 6-month circuit patency was
58.3% while SCB results in 68% primary patency in our pilot study [10]. Based on Alpha of 0.05 and Beta
of 0.2 and assuming a dropout rate of 10%, a sample size of 200 patients at 1:1 ratio has 80% power to
detect a difference between the 2 group at 6 months.

The data analyses will be performed with STATA and SPSS version 23 by an independent biostatistician
who will be blinded. Kaplan-Meier survival analyses will be used to estimate primary, assisted primary
and secondary patency rates.

Discussion
While unremitting efforts have been made to prolong the patency of AVF, many are mechanical solutions
without addressing the underlying biological mechanism. The role of high-pressure balloons and cutting
balloons were limited by post-intervention recoil and accelerated neointimal hyperplasia from endothelial
injury. [15, 16] The high restenosis rates have precluded the use of bare metal stenting in the treatment of
AVF stenosis. [17] Although the use of stent grafts has been encouraging, the evidence has only been for
specific lesions such as the graft-vein anastomosis of AVG and cephalic arch stenosis. [17–20]
Furthermore, deployment of stent in AVF will make the stented segment unavailable for cannulation and
may impede future surgical revision or new access creation within the same vessel.

DCB is an emerging device in endovascular intervention of AV access. PCB was the most used DCB, until
its safety concern was raised when Katsanos et al. reported risk of death following application of PCB in
femoro-popliteal artery of the leg. [21] Although this has not been proven in AV access, the findings from
Katsanos et al. may provoke restricted use of PCB, resulting in clinical disadvantages for ESKD patients
who rely on AV access to perform life-saving haemodialysis.

SCB, the newer generation DCB may serve as viable alternative option. Compared to paclitaxel, sirolimus
is cytostatic in its action with a high safety margin and has anti-inflammatory effects. It has a high
transfer rate to the vessel wall and effectively inhibits neointimal hyperplasia in the porcine coronary
model. [22] The initial studies on the effectiveness of SCB in maintaining the patency of AVF and AVG
have been promising. Tang et al. reported target lesion patency of 71.8% at 6-month for dysfunctional

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AVF that underwent SCB angioplasty [13] while Tan et al. reported access circuit primary patency of 65%
for thrombosed AVG. [11]

There have not been head-to-head comparison of PCB and SCB in the treatment of dysfunctional AV
access, hence the results of this study will help in hypothesis generating and fine-tuning of protocol in a
larger scale, multicenter-randomized-controlled-trial. The advantages of this registry study from a high-
volume Asian centre are that it is practical i.e., assessing circuit assess patency as the endpoint and is a
study that is not industry driven, with its potential inherent biases and one of the first head-to-head DCB
comparison studies of its nature. It may not be a RCT but the cost of doing something like this is
prohibitive and will take time to recruit.

Conclusion
The study protocol of SAVE AVF has been described as above.

Abbreviations
AVF: Arteriovenous fistula; DCB: Drug-coated balloon; SCB: Sirolimus-coated balloon; AV: Arteriovenous;
PCB: Paclitaxel-coated balloon; ESKD: End stage kidney disease; DSA: Digital Subtraction Angiography;
PTA: Percutaneous transluminal angioplasty; SGH: Singapore General Hospital; POBA: Plain old balloon
angioplasty

Declarations
Acknowledgements

The authors wish to thank Charyl Yap Jia Qi and Khoo Bao Xian, study coordinators who help in
completion of this study.

Authors’ contributions

RYT, TYT, AG, TTC and CST conceptualized this study. RYT and TYT wrote the protocol. RYT, CWT, and
SCP recruited the patients, RYT, CWT, CST will perform statistical analysis of the data. RYT, CWT, TYT
prepared this manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to
confidentiality of the data but are available from the corresponding author on reasonable request.

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Ethics approval and consent to participate

This study was approved by our Centralized Institutional Review Board (CIRB number: 2022/2014)
Informed consent will be obtained from all subjects participating in the study.

Consent for publication

Not applicable.

Competing interests

Not applicable

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Figures

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Figure 1

Study 1

Prospective Study

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Figure 2

Study 2

Retrospective Study 

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