Drug Eluting Balloon for Early Fistula Failure Trial
Drug Eluting Balloon for Early Fistula Failure Trial
Hemodialysis (HD) remains the most prevalent form of renal replacement therapy (RRT) for
 patients with End Stage Renal Disease (ESRD). Loss and dysfunction of vascular access is a
 significant contributor to morbidity in ESRD patients on HD. The National Kidney Foundation's
 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest that all ESRD patients
 should initiate dialysis with a functioning permanent vascular access with arteriovenous
 fistulas (AVF) preferred over arteriovenous grafts (AVG). Central venous catheters (CVC) are
 the least preferred vascular access for HD due to the complications associated with them.
 Despite these recommendations, up to 80% patients start dialysis with a CVC. One of the
 reasons for low AVF rates is early fistula failure (EFF). The most important causes for EFF
 amenable to intervention is stenosis anywhere in the circuit. Endovascular approach has shown
 a high rate of technical success in the treatment of stenotic lesions related to HD
 arteriovenous access. Percutaneous balloon angioplasty (PBA) is considered the treatment of
 choice for these lesions. Despite good technical and immediate success PBA has poor long term
 outcomes with recurrence rates of 60-70% at 6 months. One of the reasons could be the damage
 caused by angioplasty itself leading to intima-media rupture promoting the cascade of events
 leading to further development of neo intimal hyperplasia (NIH). Recently the use of covered
 stents at the time of angioplasty has shown better patency rates at 6 months but still not
 optimal. Lately the development of drug eluting stents and drug eluting balloons (DEB) have
 shown considerable advantage in clinical trials related to coronary and peripheral arterial
 disease angioplasty. In a randomized control trial, the researchers are planning to assess
 the efficacy of DEB angioplasty as compared to standard PBA in AVF's with EFF.
Hemodialysis (HD) remains the most prevalent form of RRT for patients with End Stage Renal
 Disease (ESRD). Just in the United States there are more than 380,000 patients with ESRD on
 hemodialysis (HD) and the number is expected to increase to 500,000 by the year 2020. Recent
 data provided by Saudi Centre for Organ Transplantation (www.scot.org.sa) shows that there
 are just over 13000 patients with End-stage renal disease (ESRD) on hemodialysis in the
 Kingdom of Saudi Arabia. This number is expected to rise at a rate of 7-8% annually reaching
 18000 by year 2018. Establishing a viable vascular access is crucial and is considered the
 'life-line' for such patients. Loss and dysfunction of vascular access is a significant
 contributor to morbidity in ESRD patients on HD. In the United States <50% of all
 hemodialysis accesses remain patent at 3 years with the economic burden of maintaining
 vascular access patency calculated to exceed $1 billion with a >6% annual trend. The National
 Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest
 that all ESRD patients should initiate dialysis with a functioning permanent vascular access
 with arteriovenous fistulas (AVF) preferred over arteriovenous grafts (AVG). Central venous
 catheters (CVC) are the least preferred vascular access for HD due to the complications
 associated with them. Despite these recommendations and clear benefits of using arteriovenous
 access for hemodialysis, up to 80% patients start dialysis with a CVC. One of the reasons for
 low AVF rates is early fistula failure (EFF). EFF is defined as an AVF that never develops
 adequately for dialysis (failure to mature) or which fails within 3 months of starting
 dialysis. An adequate AVF for dialysis according to KDOQI guidelines is the one which a) Has
 a flow of greater than 600ml/min, b) Has a diameter of 0.6cm or greater and c) Is
 approximately not deeper than 0.6cm from the skin surface. Between 23%-46% of newly
 constructed AVF have problems with early failure resulting in a dismal one year patency of
 60-65%.

 In order to devise a strategy to prevent EFF, one needs to understand the physiology of
 fistula maturation. Creation of an AVF leads to an immediate increase in flow through the
 vein due to the pressure gradient created. This increase in flow leads to increase wall shear
 stress which is defined mathematically by the formula 4ηQ/πr3, where η is blood viscosity, Q
 is blood flow and r is vessel radius. Shear stress thus is directly proportional to blood
 flow while inversely proportional to vessel diameter. After the creation of the AVF, the flow
 mediated increase in shear stress is mitigated by vessel dilatation through biological
 mediators. Consequently the shear stress is brought back to pre-anastomosis levels leading to
 vessel dilation. It seems that this positive remodeling of the vein leading to AVF maturation
 is dependent on increase in blood flow rather than the increase in pressure. Any pathology
 affecting the blood flow through the newly constructed AVF can thus lead to failure to
 mature.

 The two most important causes for EFF amenable to intervention are stenosis anywhere in the
 circuit (present in around 80% of EFF) and/or presence of accessory veins. While stenosis
 development is pathological and accessory vein presence is natural, both lead to decreased
 blood flow through the main AVF circuit, which may be responsible for failure to mature.
 Addressing these two entities in a timely fashion can lead to salvage of many AVF, which
 otherwise would have been abandoned.

 Development of neo-intimal hyperplasia (NIH) is the main pathology causing stenosis in the
 AVF circuit. There are many factors thought to be responsible for the development of this
 NIH. These include turbulent flow with wall shear stress disturbances, uremic endothelial
 dysfunction, repeated venipunctures, and unique anatomic factors. The pathogenesis includes
 migration of smooth muscle cells and myofibroblasts from media to intima, neoangiogenesis of
 microvessels inside neointima, and high levels of inflammatory blood markers.

 Since its introduction, endovascular approach has shown a high rate of technical success in
 the treatment of stenotic lesions related to HD arteriovenous access. Percutaneous balloon
 angioplasty (PBA) is considered the treatment of choice for these lesions. Despite good
 technical and immediate success PBA has poor long term outcomes with recurrence rates of
 60-70% at 6 months. One of the reasons could be the damage caused by angioplasty itself
 leading to intima-media rupture promoting the cascade of events leading to further
 development of NIH. Recently the use of covered stents at the time of angioplasty has shown
 better patency rates at 6 months but still not optimal. Lately the idea of delivering
 loco-regional pharmacological agents at the time of angioplasty to prevent NIH from happening
 has been extensively studied mostly in coronary arteries. This lead to the development of
 drug eluting stents and drug eluting balloons (DEB). These therapies have shown considerable
 advantage in clinical trials related to coronary and peripheral arterial disease. Although
 promising but advantages in coronary and peripheral arteries may not be applicable to
 arteriovenous access where the lesions are mostly venous with different characteristics. The
 role of these more costly interventions needs to be addressed in stenosis related to AVF,
 before wide spread use can be recommended. In a recent randomized non-blinded study involving
 40 patients, Kostanos et al showed better 6 month patency rates (70% vs 25%) with DEB
 angioplasty as compared to standard PBA. The study is non-blinded and involved both AVG and
 AVF with target lesion spread all over the arteriovenous access circuit. Patane et al
 recently performed a study on 26 failing radiocephalic AVF's with juxta-anastamosis stenosis,
 defined as stenosis within 3 cm of arteriovenous anastamosis. In this study DEB angioplasty
 showed a 6 month primary patency of 96.1% which is much higher than historical conventional
 balloon angioplasty. The investigators targeted a lesion which resembles more closely
 arterial lesions where DEB has been shown to be effective, which seems more reasonable but
 there were no controls in the study. Due to the lack of a control group such high patency
 rates become questionable. Nevertheless this study highlights the importance of doing a
 randomized control trial targeting a specific lesion. In a controlled pilot study of
 radio-cephalic AVF with inflow stenosis Lai et al from Taiwan showed short term patency
 benefits with DEB angioplasty as compared to standard PBA. This being a pilot study had only
 20 patients and was not adequately powered to answer the question. If these results are
 indeed proven to be true, this can lead to great improvement in patency of AVF's. In a
 randomized control trial the researchers are planning to assess the efficacy of DEB
 angioplasty as compared to standard PBA in AVF's with EFF.
Inclusion Criteria:

 -  Age >18 years

 -  Patients with EFF

 -  Stenosis anywhere in the AVF being the only identifiable cause of EFF.

 Exclusion Criteria:

 -  Patients with AVF which is deeper than 0.8cm from the skin.

 -  AVF which is tortuous and lacks adequate straight segment for cannulation with 2
 needles.

 -  Patients with allergy to paclitaxel

 -  Patients on anti-coagulation and those with bleeding disorders.

 -  Severe thrombocytopenia i.e platelet count< 50,000.

 -  Life expectancy less than 12 months.

 -  Documented severe contrast allergy.

 -  Inability to come for timely and adequate follow up.

 -  Patients undergoing transplantation work up and expected to be transplanted within 6
 months.

 -  EFF secondary to accessory veins or causes other than stenosis.