Arteriovenous Fistula Maturation Failure Clinical Trial
Official title:
Assessing Clinical Utility of the Criteria for Accessory Vein Obliteration for Failing Arteriovenous Fistula.
Hemodialysis (HD) vascular access dysfunction is a huge clinical problem which results in significant morbidity amongst patients with End Stage Renal Disease (ESRD), causing a severe economic burden on any health care system. Native arteriovenous fistula (AVF) is the preferred form of permanent dialysis access since it is associated with the best long term outcome as compared to other forms of dialysis access. Despite the clinical benefits, many patients on HD do not have AVF as there dialysis access. One of the reasons for low AVF rates is early fistula failure (EFF). The two most important causes for EFF amenable to intervention are stenosis anywhere in the circuit and/or presence of accessory vein (av). Although management of stenosis is well established with relatively clear guidelines, the management of av lacks clear scientific approach. In a recent study researchers recommended a hemodialysis arteriovenous flow quantification-diameter (HAQ) criteria for accessory vein obliteration. The purpose of this controlled, blinded, prospective trial is to assess the clinical utility of the HAQ criteria as compared to current recommendations for av obliteration.
Hemodialysis (HD) vascular access dysfunction is a huge clinical problem which results in
significant morbidity amongst patients with End Stage Renal Disease (ESRD), causing a severe
economic burden on any health care system. Native arteriovenous fistula (AVF) is the
preferred form of permanent dialysis access since it is associated with the best long term
outcome as compared to other forms of dialysis access. Despite the clinical benefits, many
patients on HD do not have AVF as there dialysis access. 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 Dialysis Outcome Quality Initiative
(DOQI) 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 and/or presence of accessory veins. While stenosis development is pathological and
accessory vein (av) 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. Although management of stenosis is well established with relatively clear
guidelines, the management of av lacks clear scientific approach. It has been anecdotally
recommended that any av with a diameter greater than 25% of the AVF diameter should be
considered for ligation. It is also suggested that the significance of an av can be
ascertained by assessing the flow of contrast through the av during an angiogram or by
assessing the augmentation of AVF after manually occluding the av during the procedure.
These current recommendations are very subjective and none have been adequately studied to
date leading to considerable debate on the issue of when to obliterate an av. A scientific
approach to obliteration of av is essential to avoid an unnecessary procedure, which may
even be harmful. Also, obliterating a non-significant av and waiting for AVF to mature may
cause a delay in making a definite decision for the patient. These patients may have other
factors and not av as the cause of EFF. Conversely, not obliterating a significant av may
also delay the use of AVF for dialysis by causing EFF. In a recent study researchers
recommended a hemodialysis arteriovenous flow quantification-diameter (HAQ) criteria for
accessory vein obliteration written below:
1. 60% or greater diameter of the main AVF
2. 50% diameter of AVF with at least one more av>40% in diameter.
3. 50% in diameter and divides into branches of same size.
4. av likely to interfere with cannulation on physical examination.
5. >30% in diameter and associated with stenosis at site of origin.
The HAQ criteria for av obliteration is based on computational flow dynamic (CFD) models of
AVF created using 2 dimensional CFD software. This criteria has not been tested in clinical
trials and its clinical utility has not been established to date. The purpose of this
controlled, blinded, prospective trial is to assess the clinical utility of the HAQ criteria
as compared to current recommendations for av obliteration.
Specific Aim:
The purpose of this controlled, blinded, prospective trial is to assess the clinical utility
of the HAQ criteria as compared to current recommendations for av obliteration.
Method and Materials:
Trial Design: The study will be a single center blinded, controlled and prospective trial.
The study will be conducted according to the ethical standards of King Faisal Specialist
Hospital & Research Center (KFSHRC) for human experimentation and in compliance with the
declaration of Helsinki.
Participants: The study will be conducted at the Interventional Nephrology section at
KFSHRC, Riyadh, Saudi Arabia. All adult patients (Age>18 years) with End Stage Renal Disease
(ESRD) or chronic kidney disease (CKD) with estimated glomerular filtration rate less than
10 approaching ESRD who have had an AVF created and has not matured enough to be used for
dialysis 6 weeks after surgery will be eligible for consideration.
Design: All participants with EFF are currently evaluated for cause of EFF as the standard
of practice at KFSHRC. Patients who agree to participate by providing informed consent will
undergo the same routine evaluation for EFF. As mentioned before, stenosis anywhere in the
AVF circuit and presence of av are the 2 most common causes for EFF. Patients in whom
stenosis is the sole cause of EFF will be excluded from the study. Amongst eligible patients
in whom av is the only cause of EFF will be directly undergo av obliteration. Before and
after any av obliteration assessment of av will be done to ascertain whether it satisfies
current recommendation or the HAQ criteria and to assess the effect of obliteration on
access flows as shown in data collection sheet. Data on av will be interpreted by another
expert, blinded to study details (other than the operator) after the procedure to assure
accuracy. Those patients in which both av and stenosis are present will first undergo
angioplasty of the stenotic region. These patients will be brought back at 4 weeks post
intervention for re-assessment of AVF maturation by staff blinded to intervention details.
av will be managed if indicated at that time. Patients who undergo av obliteration will be
reassessed in 4 weeks for AVF maturation by staff blinded to intervention details. Patients
who are thought to have mature AVF on clinical exam will be scheduled for cannulation. Final
maturity will be defined as an AVF which undergoes 3 consecutive successful HD treatments
using the AVF. Access flows will also be measured. The access flow studies using ultrasound
dilution technique can be done on either of the first three treatment sessions. Ultrasound
dilution technique is an accepted method for assessing access blood flows. Patients with
mature AVF following interventions will be followed for 6 months with monthly evaluation
with access flows and physical examination to assess primary and secondary patency. The
follow up can be extended to another 18 months to assess long term patency but during that
time access management and surveillance will be as per local center practice.
Procedural Details:
Angiograms under fluoroscopy will be performed as standard practice in such procedures. To
assess arteriovenous anastamosis stenosis, arteriograms will be done rather than reflux
angiogram which is more accurate in assessing av. As part of current guidelines for practice
a puff of contrast is injected in the AVF and if there is av present it is assessed
subjectively without any measurement and if it is thought to be significant it is ligated.
But in this study the investigators will take measurements of the av as well as of the AVF
which is the only additional step from the standard of care .In case of av presence,
downstream sheath placement from the origin of av will be avoided as this may cause
functional downstream stenosis leading to slightly high pressure in AVF causing alteration
in the size and flow through the av. Data on the size of av and AVF diameter will be
collected after adequate calibration of the system. This will be collected and sealed before
any intervention and later interpreted by another expert in the field blinded to
intervention to assure accuracy. This interpreter will assign whether the av satisfies the
Standard or HAQ criteria.The investigators currently use a Phillips veradius fluoroscopy
equipment. If the av qualifies for obliteration than obliteration will be performed. For
obliteration of av either the surgical ligation or coil embolization will be used. Both are
established current standards of practice. Successful obliteration will be defined as
complete disappearance of av on repeat angiogram following the procedure. For details of
data collected please see the data collection sheet at the end.
Statistical Design:
Sample Size:
For the purposes of designing this study in terms of sample size, the outcome variable of
interest is whether the fistula matures or not, i.e. a binary outcome. The associated
parameter is the so-called binomial parameter and is denoted here as π. The predictor
variable is whether the patient meets the HAQ criteria or not, i.e. also a binary variable.
The notation for this variable will be X, and that will take on the value one if the patient
meets the HAQ criteria and the value zero if the patient does not meet the HAQ criteria.
Given this notation, then π will be further defined as π0 for those patients that do not
meet the criteria, and π1 for those who do.
In statistical terms, the research hypothesis is H0: π1 - π0 = 0 vs H1: π1 - π0>= δ> 0. Of
clinical interest is to conclude H1 if δ is at least equal to 0.20, i.e. that the
probability that the fistula will mature is at least 20% greater for those meeting the HAQ
criteria than for those not meeting it.
With the research hypothesis framed as such, then the sample size calculation becomes one of
estimating a binomial parameter, i.e.
n = 4(1-πi)πi/M squared, where here M equals 0.05. For varying values of πi, n is maximized
for πi equal to 0.5. At such a maximum, then n equals 25, i.e. 25 patients would be required
of each type (those meeting and those not meeting the HAQ criteria).
Statistical Analysis According to the above description of the statistical design of the
project, the analyses will involve a test between two binomial proportions. Fisher's Exact
test would be carried out and with a size α = 0.05. Additional analyses will also be carried
out to investigate the exact relationship between the size of the accessory vein and the
probability of the fistula maturing. This would be a logistic regression analysis with
repeated covariates and will be analyzed with generalized estimating equations (GEE).
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Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment