Sirolimus Coated Angioplasty Balloon in the Salvage of Thrombosed Arteriovenous Graft
Condition: End Stage Renal Failure on Dialysis; Arteriovenous Graft Occlusion
MeSH terms: Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 2

Summary: 
      End stage renal disease is on increasing trend. Haemodialysis is the main dialysis modality
      among these patients which accounts for the incidence of 81.3% in 2015 based on data from
      Singapore renal registry. Thus, A functioning dialysis vascular access (either arteriovenous
      Fistula or graft) is critical to the delivery of life-saving haemodialysis treatment to these
      patients.

      The main focus in our study is thrombosed (blocked) AVG as it has higher thrombosis rate and
      poorer patency rate. Conventionally, to restore the function of the dialysis access, the
      thrombus (clot) will be lysed with the use of lytic agent; followed by treatment of the
      underlying stenosis (narrowing) with plain balloon angioplasty (dilatation). However
      narrowing often recur and multiple repeated angioplasty procedures are needed keep the AVG
      flowing to prevent clots formation.

      Recently developed balloons called drug eluting balloons, are coated with medications to
      prevent the narrowing from recurring after angioplasty. With these drug balloons, the AVG can
      potentially continue to have good flow for a longer period of time, hence, decreasing the
      chance of clotting. A newer generation of drug-eluting balloon, called sirolimus coated
      balloon, are coated with a medicine called sirolimus. It has been successfully used in the
      treatment of narrowing of vessels in the leg and heart and it were superior than conventional
      paclitaxel coated balloon angioplasty.

      We hypothesis that sirolimus coated balloon is superior to conventional plain balloon
      angioplasty with decreased re-stenosis of target lesion, improved access circuit and target
      lesion patency, and decreased number of interventions needed to maintain patency.
    

Detailed description: 
      Dialysis vascular accesses such as Arteriovenous Fistula (AVF) and Arteriovenous Grafts (AVG)
      are surgically created vasculatures used for hemodialysis in patients with End Stage Renal
      Disease (ESRD). A functioning dialysis vascular access is critical to the delivery of
      life-saving hemodialysis (HD) treatment to these patients. Unfortunately, neointimal
      hyperplasia frequently occurs within the dialysis vascular access, resulting in stenosis,
      poor flow and thrombosis with loss of function. The durability of both AVF and AVG are poor,
      with an almost 50% failure rate after a median lifetime of 3 to 7 years for AVF and 12 to 18
      months for AVG. Vascular access failure is the most common reason for hospitalization among
      HD patients. The global healthcare costs for treating vascular access-related complications
      amount to USD 18 billion, and in USD 1 billion in the US alone. These figures are set to
      increase, due to the increase in prevalence of access interventions and hemodialysis patients
      globally. Singapore has one of the highest ESRD rates in the world and investigators are
      facing an increasing number of patients with ESRD and majority of the patients opting for
      hemodialysis as their treatment modality. As such, vascular access related complication is
      set to be a major contribution of healthcare cost in our nation.

      Thrombosis of dialysis access is a catastrophic event in patients with ESRD as it results in
      a loss of access to hemodialysis. Thrombosis is often as a result of underlying stenosis in
      the dialysis circuit. To restore the function of the dialysis access, the thrombus is lysed
      with the use of lytic agents; followed by treatment of the underlying stenosis. The current
      gold standard therapy for treatment of stenosis in dialysis access is plain balloon
      angioplasty (BA). Despite its widespread availability and minimally invasive nature, the mid-
      and long-term patency with BA in patients with ESRD is poor. The reported average primary
      patency after BA is around 40-50% at 1 year. Multiple repeated angioplasty are required to
      maintain the patency of the vascular access. Hence, there is an urgent clinical need to
      improve the patency of dialysis vascular access.

      Recently, the use of stents, in particular stent graft, has been shown to be superior to
      angioplasty for stenosis occurring at the site of venous anastomoses of an AVG. The incidence
      of patency of the treatment area was significantly greater in the stent-graft group than in
      the balloon-angioplasty group (51% vs. 23%, P<0.001), as was the incidence of patency of the
      access circuit (38% vs. 20%, P=0.008) at 6 months. For cephalic arch stenosis in AVF, the use
      of stent graft has also been shown to be superior to bare metal stent. The 6 month primary
      patency for stent graft and bare stent was 81.8 and 39.1%, respectively. One-year primary
      patency for stent graft and bare stent was 31.8 and 0.00%, respectively (P = 0.002). However,
      the use of stent graft for the management of dialysis vascular access is not without any
      concern. In particular, re-stenosis can occur within the stented segment (post stent 12-month
      primary patency is 46%), resulting in the need for repeat angioplasty. Future stent
      deployment in the re-stenotic segment may also not be feasible due to the presence of the
      stent. Moreover, the presence of a stent can impede future surgical revision or new access
      creation within the same vessel.

      Paclitaxel-coated balloon angioplasty (PCBA) has also been shown recently to be superior to
      plain BA in the treatment of stenosis in dialysis vascular access. This is because the very
      intervention used to treat the underlying stenosis by plain BA can induce vascular injury and
      accelerate intimal hyperplasia, resulting in rapid restenosis and need for repeated
      procedures to maintain vessel patency. By releasing Paclitaxel, which is an
      anti-proliferative drug, locally into the vessel wall during balloon contact, it will blunt
      the acceleration of intimal hyperplasia response, resulting in improved primary patency after
      angioplasty. Additionally, unlike stents, PCBA does not leave a permanent structure that may
      impede future surgical revision. In a small 40 patient pilot study, the primary unassisted
      patency in the PCBA group was significantly better than the plain BA group at 6 (70 % versus
      25 %) and 12 months (35 % versus 5 %, p <0.001) respectively.

      Sirolimus coated balloon (SCB) is the new generation of drug eluting balloons that are
      available in the market. Compared to Paclitaxel, sirolimus is cytostatic in its mode of
      action with a high margin of safety. It has a high transfer rate to the vessel wall and
      effectively inhibit neointimal hyperplasia in the porcine coronary model. In the coronary
      artery interventions, preliminary clinical studies using SCB have also shown excellent
      procedural and 6 month patency.

      The effectiveness of SCB in patients with dialysis access dysfunction has not been previously
      investigated. As thrombosis frequently occur as a result of underlying stenosis from
      neointimal hyperplasia, investigators postulate that the application of SCB after successful
      thrombolysis will inhibit the onset of neointimal hyperplasia and result in better vascular
      access patency. Specifically for AVG, where thrombosis episodes are frequent and the 3 month
      patency rate after successful thrombolysis is only 40%, investigators hypothesize that the
      application of SCB after successful thrombolysis in AVG may be the key to improving the mid
      and long term patency of the AVG after successful thrombolysis.

      Investigators intended to perform this single centre study with a planned total of 20
      patients enrolled from Singapore General Hospital. The patient pool will be from adult renal
      failure patients with successfully thrombolysis of thrombosed AVG admitted to SGH between
      June 2018 and December 2018. Adult patients of both genders and all races may be included in
      this study. Children and pregnant women will not be included in this study as they are
      considered a vulnerable population and are also not representative of the population at risk.

      Patients who are admitted to the hospital for thrombosed AVG will be screened and offered
      enrollment if they meet the inclusion criteria. Patients will be consented and pre-procedure
      blood tests (full blood count, renal panel and PT/PTT) performed as per standard hospital
      criteria. Patients who have successful thrombolysis will be recruited into the study and
      receive the sirolimus coated balloon in the same setting. Patients who have unsuccessful
      thrombolysis will be considered as screen failures and will not be recruited into the trial.

      Thrombolysis of the AVG will be performed as per standard hospital protocol in the
      Interventional Nephrology suite (INS). Briefly, an antegrade and retrograde vascular sheath
      will be placed in the thrombosed AVG under ultrasound guidance. Thrombolytic agents will be
      delivered into the thrombosed AVG via the vascular sheaths or infusion catheters. The culprit
      venous stenosis will be treated using plain BA and thrombus within the AVG macerated using
      the same angioplasty balloon. The arterial plug will be dislodged by using a 5.5Fr Fogarty
      balloon. Following successful thrombolysis of the AVG, the number and location of lesions
      within the dialysis circuit will be documented. After adequate angioplasty of the culprit
      lesion (defined as <30% residual stenosis after treatment at rated burst pressure of the
      angioplasty balloon), SCB will be applied at the culprit lesion after appropriate sizing
      using the diameter of the graft or the outflow vein as reference. To ensure adequate contact,
      the SCB should be of the same or oversized by 1mm the diameter of the reference vessel. An
      inflation device with a pressure gauge will be used to inflate up to manufacturers' stated
      burst pressure. The duration of balloon inflation will be 2 minutes at the rated burst
      pressure. Post angioplasty with SCB, a completion graftogram will be done to document the
      results. The size of the balloon used, inflation pressure, the transit time of balloon,
      number of inflation, procedure complications (if any), and residual stenosis will be
      recorded.

      Post procedure, all patients will received daily dose aspirin (100mg) and clopidogrel (75mg)
      orally for 1 month, followed by treatment with aspirin alone for 6 months. For patients who
      are already on Aspirin prior to the procedure, they will continue on aspirin after the trial.
      For patients who are already on clopidogrel before the trial, they will continue on
      clopidogrel after 1 month of combination therapy with aspirin.

      As patients with ESRD are at increased risk of bleeding, proton pump inhibitors will be
      prescribed during the period that they are receiving dual anti-platelet therapy. Patients
      will also be informed of the risk of bleeding and to seek immediate medical attention should
      they develop any bleeding episodes. The patients will be followed up via monthly phone call
      from the principle investigator while they are on dual anti-platelet therapy.

      Investigators define patency based on SIR reporting standards (Gray et al., 2003):

      Post-intervention target lesion patency:

      Interval after intervention until the next re-intervention at or adjacent to the original
      treatment site or until the access is abandoned. Percutaneous or surgical treatments of a new
      arterial or venous outflow stenosis/occlusion (including access thrombosis) that do not
      involve or exclude the original lesion from the access circuit are compatible with lesion
      patency. Creation of a new access that incorporates the target lesion into the new access
      circuit is also compatible with target lesion patency.

      Post-intervention access circuit primary patency:

      Interval following intervention until the next access thrombosis or repeated intervention. It
      ends with the treatment of a lesion anywhere within the access circuit, from the arterial
      inflow to the superior vena cava-right atrial junction.

      Post-intervention access circuit assisted primary patency:

      Interval after intervention until access thrombosis or a surgical intervention that excludes
      the treated lesion from the access circuit. Percutaneous treatments of either
      restenosis/occlusion of the previously treated lesion or a new arterial or venous outflow
      stenosis/occlusion (excluding access thrombosis) are compatible with assisted primary
      patency.

      Post-intervention access circuit secondary patency:

      Interval after intervention until the access is surgically declotted, revised or abandoned.
      Thrombolysis and percutaneous thrombectomy are compatible with secondary patency.

      With regards to the potential complication, it will be categorised according to SIR
      definitions of minor or major complications (Aruny et al., 2003):

      A major complication is defined as one that:

        1. require therapy, minor hospitalisation (< 48 hours),

        2. require major therapy, unplanned increase in level of care, prolonged hospitalisation
           (>48 hours),

        3. leads to permanent adverse sequelae, or

        4. death

      A minor complication is one that:

        1. requires no therapy with no consequence,

        2. requires nominal therapy with no consequence; includes overnight admission for
           observation only.

      All participants will be followed-up after intervention to assess the patency clinically and
      radiologically as well as complications and whether able to achieve prescribed haemodialysis.

      All participants will be received call from principal investigator or site-investigator or
      study members monthly to assess the compliance to antiplatelet therapy as well as assess
      whether any adverse effects associated with antiplatelet therapy.

      The participant is seen for assessment of primary outcome. The window period for this
      scheduled post-intervention visit is 3 month post-intervention ± 1 weeks.

      The participant returns for a 6-month follow-up to assess the patency rate of AVG as well as
      any intervention needed to maintain patency.
    

Intervention name(s): Sirolimus Coated Balloon
Intervention type(s): Device
Intervention description(s): Sirolimus has been used in organ transplantation as well as coronary stent due to its antiproliferative properties. It has been proven to has better outcome in animal studies compared to paclitaxel, which is about 22% in the sirolimus group versus 75% re-stenosis rate in paclitaxel group.
Sirolimus is coated on the surface of the angioplasty balloon and is transferred to the vessel wall when balloon is inflated and in contact with the vessel wall.
The following table compare sirolimus to paclitaxel. In which sirolimus works by cytostatic mechanism with a ten thousand fold of safety margin. And sirolimus's anti-restenosis effect is optimal with the benefit of lower level of competition and lesser tissue absorption and elution.
Other intervention name(s): Drug eluting device
Intervention MeSH terms: Sirolimus
Intervention model: Single Group Assignment
Intervention model description: This is a phase 2, pilot clinical trial to investigate the effect of SCB on thrombosed AVG. Specifically, we are focusing on AVG as they have a higher thrombosis rate than AVF and the patency rate even after successful thrombolysis is much lower than AVF. As neointimal hyperplasia is the predominant cause for stenosis at the graft vein junction, treatment with Sirolimus will intuitively delay the recurrence of neo-intimal hyperplasia and result in better patency of the AVG after successful thrombolysis.
Patients with ESRD presenting with a thrombosed AVG between June 2018 and December 2018 will be screened for suitability. Eligible patients of at least 21 years of age will be offered participation. The potential benefits and risks of SCB will be explained and informed consent obtained from participants. A total of 20 patients will be recruited for the trial and they will be followed up for 6 months after the interventions.
Masking: None (Open Label)
Primary purpose: Treatment