0534 vesicoureteral reflux treatment by endoscopic injection of … · 2020. 9. 3. ·...
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Vesicoureteral Reflux Treatment by Endoscopic Injection of BulkingAgents
Clinical Policy Bulletins Medical Clinical Policy Bulletins
Pol icy History
Last
Review
08/09/2018
Effective: 08/21/2000
Next Review:
05/23/2019
Review History
Definitions
Additional
Number: 0534
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
Aetna considers endoscopic injection of dextranomer/hyaluronic acid copolymer
(Deflux), polydimethylsiloxane (Macroplastique), polytetrafluoroethylene (Teflon), or
other bulking agents approved by the U.S. Food and Drug Administration (FDA) for
vesicoureteral reflux (VUR) medically necessary for the treatment of members with
primary or secondary VUR who have any of the following conditions when
conservative treatments (e.g., prophylactic antibiotics and clean intermittent
catheterization) have failed:
Children who have had a previously unsuccessful ureteral re-implantation;
or
Children who have stopped taking their medication as a result of drug
intolerance or parental non-compliance; or
Children whose reflux is associated with a thick-walled neuropathic bladder;
or
Deterioration of renal parameters regardless of reflux severity; or
Lower grades of reflux (grades I to III); or
Persistent reflux in post-pubertal female members; or
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Recurrent, poorly controlled febrile urinary tract infections.
Aetna considers endoscopic injections of bulking agents for VUR experimental and
investigational for members who do not meet these criteria because it has
insufficient evidence ofeffectiveness for persons who do not meet these criteria.
Note: Members whose condition does not improve after 3 treatment sessions are
considered treatment failures and are not likely to respond to this therapy. If the
member fails to respond within 3 treatment sessions, further treatments are not
considered medically necessary.
Aetna considers endoscopic injections of the following experimental and
investigational for the treatment of members with primary or secondary VUR
because their effectiveness has not been established: (not an all-inclusive list)
Autologous blood
Calcium hydroxyapatite
Chondrocytes
Durasphere
Fat
Glutaraldehyde cross-linked bovine dermal collagen (Contigen, C.R. Bard,
Inc., Murray Hill, NJ; Zyplast, Collagen Corporation, Palo Alto, CA)
Myoblasts
Polyacrylamide hydrogel (Bulkamid)
Polyacrylate-polyalcohol copolymer (Vantris).
Background
Vesico-ureteral reflux (VUR) is predominantly a disorder of childhood and occurs
when urine passes backwards from the bladder to the kidneys during micturition. It
is caused by vesico-ureteral sphincter incompetence. Reflux can predispose
patients to urinary tract infections and renal scarring.
Primary VUR is the consequence of a congenital abnormality of the uretero-vesical
junction, in which a deficiency of the longitudinal muscle of the intra-vesical ureter
leads to an insufficient valvular mechanism. Secondary VUR is due to bladder
obstruction and its resultant increased pressures. Obstruction of the bladder can
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be anatomical or functional. The most common anatomical cause of VUR is
posterior urethral valves, which are found in approximately 50 % of VUR-afflicted
boys. On the other hand, anatomical obstructions in females are extremely rare.
Functional causes of VUR are far more common in girls; they include neurogenic
bladder, non-neurogenic bladder, and bladder instability or dysfunction. Urinary
tract infections (bladder infections) and accompanying inflammation can contribute
to the development of VUR by decreasing bladder compliance, increasing intra-
vesical pressures, and by distorting and weakening the uretero-vesical junction.
Approximately 40 % of children with urinary tract infections experience VUR.
Persons who undergo this procedure in the hospital can usually be discharged
within 24 hours. More than 1 day's hospitalization is usually not necessary.
According to the International Classification System of VUR, reflux is graded I to V
on the basis of the appearance of contrast in the ureter and upper collecting duct
system during voiding cystourethrography:
Because of the high rate of spontaneous resolution in patients with grade I to III
VUR, surgical intervention in these patients is rarely indicated. For patients with
grade IV and V reflux, surgical correction (e.g., open ureteral re-implantation or
endoscopic subureteral injection of Teflon) is highly successful.
Endoscopic Teflon therapy for VUR entails injection of polytetrafluoroethylene
(Teflon) paste into the submucosa at the refluxing ureteral orifice to bolster it, thus
eliminating the problem. In most patients, endoscopic injection of Teflon is
performed on an outpatient basis. Hospitalization may be necessary if patient
experiences hematuria, acute urinary retention, or pelvic pain; 1 or 2 repeat
injections may be needed if the initial injection fails to correct reflux. The long-term
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safety of endoscopic Teflon injection has not been clearly established. In particular,
the question of whether there is a significant risk of Teflon particle migration
remains unanswered.
In a recent study comparing the long-term outcome of the endoscopic correction of
VUR of various injected substances, Sugiyama and colleagues (2004) stated that
autologous blood is unsuitable for clinical application because of its poor durability;
and the overall success rate of endoscopic surgery with glutaraldehyde cross-linked
bovine dermal collagen or hyaluronan/dextranomer co-polymer was insufficient
compared with surgical re-implantation. Furthermore, Schlussel (2004) noted that
glutaraldehyde cross-linked bovine dermal collagen and hyaluronan/dextranomer
copolymer do nothave the long-term follow-up of Teflon.
Elder et al (2007) examined the use of endoscopic injection with
dextranomer/hyaluronic acid co-polymer (Dx/HA, Deflux) as a curative option and
as an alternative to antibiotic prophylaxis. The nationally representative
PharMetrics Integrated Medical and Pharmaceutical database was used to conduct
this retrospective analysis. Patients less than 11 years of age who were
continuously eligible and had an International Classification of Diseases (ICD-9-
CM) code for VUR were identified. Resource utilization and outcome measures
were evaluated over a 6-month pre- and 12-month post-index period. Patients
diagnosed with neuropathic bladder, posterior urethral valves, bladder exstrophy,
ureterocele, or duplication anomaly were excluded. Patients were matched 3:1,
antibiotic prophylaxis to Dx/HA, by age, gender, urinary tract infections (UTIs) prior
to index date, and diagnosing physician specialty. The primary outcome assessed
was UTIs. Of the matched patients, 114 received a prescription for antibiotic
prophylaxis and 38 underwent endoscopic injection with Dx/HA. The average
number of UTIs per year was 0.28 in the antibiotic cohort and 0.08 in the Dx/HA
cohort, respectively. The incidence rate ratio (IRR) of 4.826 (p = 0.029) revealed
that the average number of UTIs was 383 % higher for patients receiving antibiotic
prophylaxis compared with patients who underwent endoscopic injection. The
retrospective nature of the analysis did not allow for treatment randomization. Due
to the stringent classification of UTIs, rates of UTIs may be under-estimated in both
cohorts. The authors concluded that treatment with endoscopic injection with
Dx/HA resulted in significantly fewer UTIs compared with children receiving
antibiotic prophylaxis, supporting a role for Dx/HA as a first-line treatment option for
patients with VUR.
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Aaronson (2005) noted that open surgery remains the gold standard for the
treatmentof VUR. For children with grade-I or grade-II reflux, in whom
spontaneous resolution is likely, antibiotic is usually parents' treatment of choice.
On the other hand, for children with grade-IV or grade-V reflux, in which the space
available for the bulking agent is very limited, and in cases of duplex ureters, in
which there is a prolongation of the upper moiety non-refluxing ureter towards the
bladder neck, which limits access to the refluxing orifice, open surgery is the
treatment of choice. For children with grade-III reflux, endoscopic treatment may
be considered as a treatment option. The author also stated that endoscopic
treatment should also be considered for children who have had a previously
unsuccessful ureteral re-implantation; those whose reflux is associated with a thick-
walled neuropathic bladder; those with mild reflux who develop symptomatic break-
through infections because of antibiotic resistance; or children who have stopped
taking their medication as a result of drug intolerance or parental non-compliance.
Aaronson's observations regarding the use of endoscopic treatment for VUR are in
agreement with the findings of other investigators (Stehr et al, 2004; Sugiyama et
al, 2004; and Heidenreich et al, 2004). Stehr et al (2004) stated that ureteral re-
implantation is the operative treatment of choice in cases with high-grade VUR.
Alternatively in cases with lower-grade VUR, injection of bulking agents under the
refluxive orifice can be performed. Sugiyama et al (2004) reported that the cure
rate of endoscopic surgery with bulking agents could be improved by excluding high-
grade VUR from the indications for endoscopic surgery. Heidenreich et al (2004)
stated that the current indications for the surgical correction of VUR depend on the
presence or absence of renal scars. If no scars are present, primary ureteral re-
implantation is only indicated in high-grade bilateral VUR, whereas in the presence of
renal scars surgical correction is indicated in low/high grade reflux at a young age.
Endoscopic subureteral injections are primarily reserved for low-grade VUR with a 1
session success rate of over 90 %. Endoscopic subureteral injections appear to be an
alternative to long-term antibiotics in grade I-III VUR.
Bae and colleagues (2010) compared cure rates and complications of Deflux and
polydimethylsiloxane (Macroplastique) in the treatment of VUR. A total of 29 boys
and 42 girls (total of 115 ureters) with a mean age of 6 years who had undergone
endoscopic subureteral transurethral injection for VUR were enrolled. A single
subureteral injection of Macroplastique was performed in 31 ureters in 23 children
(group I; grade II: n = 4; grade III: n = 12; grade IV: n = 9; grade V: n = 6), and a
single subureteral injection of Deflux was performed in 84 ureters in 48 children
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(group II; grade II: n = 24; grade III: n = 14; grade IV: n = 25; grade V: n = 21).
Renal ultrasound was done 1 day after injection, and voiding cysto-urethrography
(VCUG) was done at 3 months. Successful reflux correction was defined as absent
or grade I reflux on follow-up VCUG. No significant difference in success rates was
observed between group I and group II [80.6 % (25/31) versus 78.6 % (66/84),
respectively, p > 0.05]. The following post-operative complications developed:
ureteral obstruction in 2 ureters of group I and 3 ureters of group II, asymptomatic
urinary tract infection in 3 patients of group I and 2 patients of group II, and bladder
calcification by erosion or mucosal necrosis in 2 patients of group I. The authors
concluded that despite differences in material properties, both Deflux and
Macroplastique were safe for the treatment of children with VUR.
Aubert (2010) carried out a literature review on the use of Macroplastique in VUR.
A PubMed review of the literature since 1996 resulted in the selection of 24 studies
of sufficient level of evidence to assess the effectiveness and tolerance of
Macroplastique in the VUR in adults and children. The overall success rates at 1
year, 2 years and 9-years follow-up were 86 to 93 %, 80 to 92 %, and 77 to 100 %,
respectively, which confirms the maintenance of good results over time, notably in
VUR grade III and above. The success rate was similar for primary and secondary
VUR except for total duplicity. Predictive criterias of success were the surgeon's
experience, the low grade of VUR, and the absence of previous injection. In
comparison with other bulking agents, the higher viscosity and absence of
shrinkage of the product increase its reliability. After more than 12 years of use, no
serious complication has been reported in the literature, reflecting the good
tolerance of Macroplastique on the long-term. The author concluded that published
studies on the use of Macroplastique in VUR confirmed its effectiveness, around 85
% of success for all grades, in both children and adults. The interest of
Macroplastique is linked to its higher viscosity promoting a better reliability and
reproducibility of the technique and its non-resorbable nature providing a
permanent result, especially valuable in high-grade VUR with anatomical anomaly
of the vesicoureteral junction or in VUR secondary to permanent lower urinarytract
dysfunction.
The American Urological Association's guideline on management of primary VUR in
children (Peters et al, 2010) recommended that patients receiving continuous
antibiotic anaphylaxis with a febrile break-through UTI be considered for open
surgical ureteral re-implantation or endoscopic injection of bulking agents for
intervention with curative intent.
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Alizadeh et al (2013) examined the incidence and presentations of ureteral
obstruction following peri-ureteral injection of polyacrylate polyalcohol copolymer
(PPC) for the treatment of VUR. From January 2010 to December 2012, a total of
88 patients (28 males, and 60 females) with 128 renal refluxing units (RRU), 131
ureters and a mean age of 6.7 +/- 5.9 years (range of 4 months to 32 years)
underwent endoscopic correction of their VUR, using PPC. Exclusion criteria were
dysmorphic appearing distal ureter, extra-vesical position of the ureteral orifice,
persistent urethral obstruction (e.g., after previous valve ablation) and severe
bladder trabeculation, making ureteral orifice unidentifiable. Patients were followed-
up by ultrasound 1 month after the injection and then every 3 months.
Cystography was performed 3 months post-operation. Mean follow-up time was
13.1 +/- 6.8 months (range of 3 to 27 months). Two patterns of obstruction were
observed: early, during the first 3 to 4 days post-operation, in 4 patients (4 ureters;
3 %) which was associated with transient hydro-uretero-nephrosis (HUN) in 2
patients (2 ureters; 1.5 %); and late-onset obstruction in 3 patients (4 ureters; 3 %),
which appeared 3 months to 1 year after surgery. It manifested itself by urinary
tract infection and uremia in 1 patient with bilateral obstruction but was
asymptomatic in the other 2. Early obstruction was managed expectantly and
resolved in 3 to 12 months; however, late-onset obstruction needed catheter
placement or open ureteroneocystostomy. The authors concluded that patients
who undergo endoscopic treatment for their VUR using PPC need long-term follow-
up until the safety of this substance is confirmed.
Stredele and colleagues (2013) determined the long-term effect in children of
endoscopic treatment VUR using different bulking agents. Status of VUR,
recurrence of UTI, and recurrence of febrile UTI were evaluated as end-points.
From 1993 to 2005, these investigators injected 229 refluxive ureters (VUR grade II
to IV) in 135 children. Mean age of the children was 55.7 months. These
researchers used collagen in 98 (years 1993 to 2000), polydimethylsiloxane in 32
(years 1999 to 2000), and dextranomer/hyaluronic acid copolymer (Dx/HA) in 99
ureters (years 2000 to 2005). Of the 135 children, 127 underwent a VCUG
(radiologic or nuclid) 3 months after the first injection, and 88 children a second
VCUG (nuclid) after 37 months (mean) post-operatively. Clinically, patients were
monitored for non-febrile or febrile UTI. Data were collected and analyzed
retrospectively by chart review. After first injection with collagen,
polydimethysiloxane and Dx/HA, 52 %, 55 % and 81.5 % of the children were
without VUR, respectively. Repeated injections were successful in only 21 %
(collagen) to 42 % (Dx/HA). Of the 88 with a second VCUG, 48.5 % of the initially
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reflux-free children developed relapse VUR after collagen, 45.5 % after
polydimethylsiloxane and 21.5 % after Dx/HA injection. Clinically, there was a
significant difference in post-operative UTI occurrence in favor of the Dx/HA group.
The authors concluded that clinically and radiologically, Dx/HA exhibited the best
results, giving better protection against UTIs and a better VUR cure rate.
Moreover, there was still a risk of VUR recurrence in successfully treated children
after 3 years of follow-up.
In a single-center, single-surgeon, prospective, off-label study, Cloutier and
colleagues (2013) evaluated the success of endoscopic treatment for VUR using
polyacrylamide hydrogel. All patients underwent endoscopic subureteral double
hydrodistention implantation technique injection followed by renal ultrasound and
VCUG at 3 months post-operatively to confirm the absence of de-novo
hydronephrosis and correction of VUR (grade 0). A total of 40 patients (69 refluxing
ureters) underwent polyacrylamide hydrogel injection. Median age at surgery was
50 months. Bilateral reflux was identified in 29 patients (73 %); 9 patients had
duplex systems, 2 with reflux into both moieties. Reflux was graded using the
International Reflux Study in Children grading system, with grade I seen in 9
ureters, II in 17, III in 20, IV in 18 and V in 5. Mean volume injected was 1.1 ml.
Success rate for grade I to III VUR at 3 months after a single treatment was 87 %,
and the overall success for all grades was 81.2 %. The authors concluded that off-
label use of polyacrylamide hydrogel injection therapy for primarily low-grade VUR
demonstrated that the technique and short-term success rates were comparable to
the most popular bulking agent, dextranomer/hyaluronic acid. Moreover, they
stated that these results suggested that further trials comparing polyacrylamide
hydrogel and dextranomer/hyaluronic acid would be worthwhile. The main
drawbacks of this study were its small sample (40 patients) size, short follow-up (3
months), and the lack of a control group.
Moore and Bolduc (2014) prospectively compared the effectiveness of
polydimethylsiloxane and dextranomer/hyaluronic acid injection for treatment of
VUR. A total of 275 patients with documented VUR (grade I to V) were
prospectively enrolled in a comparative study between April 2005 and February
2011 to be randomly treated endoscopically with either polydimethylsiloxane
(Macroplastique) or dextranomer/hyaluronic acid copolymer (Deflux); 202 were
treated with polydimethylsiloxane and 197 with dextranomer/hyaluronic acid
copolymer. Patients were followed with VCUG at 3 months and renal
ultrasonography at 3 months and at 1 year. Median follow-up was 4.3 years. The
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primary outcome was surgical success (resolution versus non-resolution), and
secondary outcomes included occurrence of adverse events. Vesicoureteral reflux
was fully corrected in 182 of 202 ureters (90 %) treated with polydimethylsiloxane,
compared to 159 of 197 (81 %) treated with dextranomer/hyaluronic acid copolymer
(p <0.05). Obstruction was found in 5 ureters. Uni-variate and multi-variate
analyses did not allow identification of any characteristics that could explain the
significant difference in the success rates except for the type of product used. The
authors presented the largest known prospective evaluation comparing 2 bulking
agents for the treatment of VUR. Endoscopic injection of polydimethylsiloxane
resulted in a better success rate than dextranomer/hyaluronic acid copolymer. The
rate of resolution obtained with the latter is lower than those previously published
due to the inclusion ofhigh-grade reflux.
An UpToDate review on “Management of vesicoureteral reflux” (Matto and
Greenfield, 2015) states that “Subureteric transurethral injection (STING
procedure), an ambulatory day procedure, involves injecting a copolymer
substance, such as dextranomer/hyaluronic acid (Dx/HA or DEFLUX) or
polydimethylsiloxane, beneath the mucosa of the ureterovesical junction through a
cystoscope. This injection changes the angle and perhaps fixation of the
intravesical ureter, thereby correcting reflux. The success rate for correcting VUR
by STING in one or more procedures ranges from 75 to over 90 %. The success
rate for initial correction ofVUR (by ureter) varies by the severity of reflux and
anatomic variables …. The success rate of a second STING procedure after an
initial failed injection is high, ranging from 70 to 90 %. The STING also has been
utilized as a salvage procedure correcting VUR in 65 % of patients who failed a
previous open surgical reimplantation”.
Dogan and colleagues (2015) investigated the parameters which may affect the
outcomes of endoscopic injection and compared the effectiveness of 2 different
bulking agents both composed of dextranomer-hyaluronic acid copolymer. The
data of patients who underwent endoscopic VUR treatment between 2003 and
2012 were retrospectively reviewed. Patients with history of previous open anti-
reflux surgery, more than 1 failed endoscopic treatment for reflux, VUR caused by
posterior urethral valve, duplex system and overt spinal dysraphism were excluded.
Surgical technique was the classical STING method; 1 of the 2 dextranomer-
hyaluronic acid copolymer agents was used (Deflux in 109 and Dexell in 131
patients). Both agents were composed of similar amounts of hyaluronic acid gel
(15 mg in Deflux versus 17 mg in Dexell) but different sized dextranomer
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microspheres (80 to 250 μm in Deflux and 80 to 120 μm in Dexell). During the follow-
up, ultrasonography was performed with 3-month interval, antibiotic prophylaxis was
continued until the control VCUG was taken. Patient based success was defined as
the disappearance of reflux on control VCUG performed 3 to 6 months after the
operation. Data were available for 240 patients. Mean age and mean post-
operative follow-up were 78 ± 41 months and 19 ± 18 months. The overall success
rate was 73.2 %. Gender, laterality, grade of VUR, presence of voiding dysfunction,
renal scar and pre-operative break-through infection (BTI) were not found to affect the
outcome, whereas age younger than 54 months and previous history of failed
endoscopic injection were found to negatively affect the outcome both in uni-variate
and multi-variate analysis. The post-operative UTI (5 febrile and 43 non-febrile) rate
was 20 %. Both uni-variate and multi-variate analysis showed that post-operative
UTI was more common in patients with persisting reflux, with pre-operative BTI and
in girls. Patient characteristics, treatmentoutcome and post-operative UTI rate were
similar regarding the used bulking agent. No ureteral obstruction was experienced
within the follow-up
period. The success rate for 2nd injection was about 60 %, which was significantly
lower than for the patients who underwent 1st injection. These researchers could
not find any affecting factor for this difference. Contrary to the literature, the
success rates in this study were similar in different reflux grades. These
investigators explained this finding that they valued the intra-operative orifice
configuration more than the grade which can be accepted as a patient selection
bias. The lower success rate in children younger than 54 months could be
explained by unstabilized bladder dynamics and higher voiding pressures in this
age group, who are still in the toilet-training phase. Despite successful endoscopic
treatment, UTI might occur. Post-operative UTI was more common in patients with
persisting reflux, pre-operative BTI and girls. The similar success rates of both
bulking agents proved that dextranomer size does not affect the clinical outcome.
The authors concluded that endoscopic treatment of VUR has satisfying outcomes
in properly selected cases. Younger age (less than 54 months) and previous
history of failed injection history were found to be related to unfavorable results.
Post-operative UTI occurs more frequently in patients with persisting reflux, pre-
operative BTI history and girls. The choice of one of the dextranomer-based
substances did not affect the surgical outcome and post-operative UTI
development.
Karakus et al (2016) compared dextranomer/hyaluronic acid (Dx/HA; Dexell) and
polyacrylate-polyalcohol copolymer (PPC; Vantris) in terms of effectiveness,
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injection techniques and complications with special emphasis on vesico-ureteral
junction obstruction (VUJO). A total of 95 patients who underwent endoscopic VUR
treatment between 2009 and 2015 were retrospectively reviewed. Patients were
divided into 2groups: (i) patients underwent endoscopic treatment with PPC (n =
50 patients, 70 renal refluxing units), and (ii) patients underwent endoscopic
treatment with Dx/HA (n = 45 patients, 74 renal refluxing units). The overall
resolution rates based on the number of renal refluxing units studied was 88.6 %
and 70.3 % in group 1 and group 2, respectively. Resolution rates were
significantly better in group 1 compared to group 2. Vesico-ureteral junction
obstruction requiring ureteral re-implantation or stent insertion developed in 7
patients in group 1. No VUJO was observed in group 2; VUJO in group 1 was
markedly higher than that in group 2. The authors concluded that endoscopic
treatment of VUR with PPC provided better resolution rates but higher VUJO rates
compared to Dx/HA.
Periureteral Injection Technique (PIT) for High-Grade Vesico-Ureteral Reflux:
Asgari and colleagues (2016) noted that despite the benefits of the minimally
invasive endoscopic treatment for VUR, it has a major drawback which is low
success rate in high-grade VUR. For overcoming this problem, these researchers
introduced a new modified technique of endoscopic treatment called periureteral
injection technique (PIT). In a pilot study, a total of 37 ureters in 19 boys and 14
girls were treated, including 3 bilateral cases. Of 37 units, 30 (81.1 %) had grade
IV and 7 (18.9 %) had grade V primaryVUR (18 right, 13 left and 3 bilateral units).
Sub-ureteral injection of PPC was done at the 5-o'clock and 7-o'clock positions in
which the direction of injecting needles were almost parallel. Pre- and post-
operative evaluation included urinalysis, urinary tract ultrasonography, voiding
VCUG, dimercaptosuccinic acid scan and urodynamic studies. The median age
was 38 months (range of 8 to 125). At 6 months follow-up confirmed with VCUG,
the VUR disappeared in 34 (91.8 %) units and 3 units [2 (5.4 %) grade II and 1 (2.7
%) had grade III)] had down-graded VUR. Complications included early fever due
to urinary tract infection in 1 children, transient dysuria in 2 patients and low back
pain in 1patient. The authors concluded that the success rate of PIT for treatment
of high grade VUR is high. However, they stated that further studies with more
patients and longer follow-up are needed to draw final conclusion.
Bulking Agents:
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Blais and colleagues (2017) noted that VUR is one of the most common
pathologies encountered in pediatric urology. Better understanding of the evolution
of VUR and new endoscopic surgical techniques in the last decades have led to
major changes in the management of this pathology. However, the treatment
algorithm remains complex and is composed of a wide variety of options, from
active surveillance to surgical treatment. The 3 most popular techniques described
in the literature are: (i) the subureteral Teflon injection (STING), (ii) the
hydrodistention technique (HIT), and (iii) the double hydrodistention technique
(double-HIT). STING technique was the first to be described. The technique
consists of the injection of bulking agent, regardless of the agent, into the detrusor
muscle immediately beneath the ureteral orifice at the 6 o’clock position. With the
HIT, the ureter is distended with irrigation fluid from the cystoscope and the
injection is made within the ureteral orifice, beneath the mucosa. The double-HIT is
similar, but 2 injections are carried out -- a 1st injection is performed more
proximally, within the ureteral tunnel, and a 2nd injection more distally, just under
the ureteral orifice. Cross-linked bovine collagen has been the subject of many
trials, revealing inconsistent success rates and high relapse rates. The variable
degree of ingrowth of native fibroblasts, the shrinkage of the bulking agent, and the
reported immunological reactions after injection of collagen are reasons why cross-
linked bovine collagen has been abandoned by most centers. Injection of
autologous material is appealing, as they behave as free grafts with the absence of
foreign materials. Blood, chondrocytes, fat, and myoblasts were studied. Fat and
chondrocytes showed high rates of long-term VUR recurrence. On the other hand,
blood has not been largely studied and the experimental use of myoblasts in pigs
failed. Calcium hydroxyapatite, a synthetic agent with identical chemical
composition to teeth and bone, was investigated in animals and humans. Only few
studies are available in the literature and reported success rates are widely
variable. The authors stated that further studies with larger cohorts and longer follow-
up are needed. Two agents have been recently introduced for the endoscopic
injection of VUR: (i) polyacrylate-polyalcohol copolymer (PPC,
Vantris), and (ii) polyacrylamide hydrogel (PAHG, Bulkamid). A multi-center
survey showed a success rate of 93.8 % after a single injection of PPC. Patients
were monitored with ultrasound and voiding cystourethrogram. Most renal refluxing
units had higher-grade VUR (55.8 % Grade III and 19.5 % Grade IV) and most
patients (60 %) were followed for more than 2 years. Moreover, PPC and Dx/HA
have been compared in many trials. Endoscopic injection of PPC resulted in higher
success rates. However, concerns have been raised with PPC regarding a high
rate of ur eteral obstruction. Finally, only few published series are available on
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PAHG. These researchers noted that the success rate with this bulking agent
appeared promising, but more trials are needed prior to extensive use.
Polyacrylate-Polyalcohol Copolymer (Vantris):
Warchoł and associates (2017) noted that the endoscopic correction of VUR in
children is a well-accepted therapy in many pediatric urology centers. Polyacrylate-
polyalcohol copolymer (PPC; Vantris) is one of the tissue-augmenting substances
used for endoscopic reflux therapy. These investigators evaluated the results with
PPC in children with VUR. From 2012 to 2016, a total of 125 children (73 girls and
52 boys) aged 0.6 to 17.9 years (mean of 4.9 ± 3.58) were treated with PPC; VUR
was unilateral in 64 and bilateral in 61 patients, comprising 197 RRUs grades: II in
72, III in 50, IV in 33 and V in 42. Of these, primary reflux was present in 132
RRUs and 65 were complex cases; VCUG was performed 3 months after
procedure. Follow-up was completed in 89.6 % of patients (112 children), and 89.8
% of RRUs (177 out of 197). Reflux resolved in 86.4 % of RRUs after single
injection, in 99.4 % after 2nd and in 100 % after the 3rd. The only significant, but
serious complication observed was late ureteral obstruction after PPC injection
correcting high grade reflux, which required ureteral re-implantation. This
complication was found in 9 out of 112 children (8 %), and in 11 out of 177 RRUs
(6.2 %), 1.1 to 2.9 years (mean of 2 ± 0.7) after the PPC injection. The longest
follow-up reached 4.5 years. The authors concluded that these findings showed
that the PPC injection is an effective procedure for treating all grades of VUR with
high success rate. However, because of the possibility of late ureteral obstruction,
which requires uretero-neocystostomy, long-term follow-up is mandatory.
Durasphere:
Ozkuvanci and colleagues (2018) stated that Durasphere EXP (DEXP) is a
compound ofbiocompatible and non-biodegradable particles of zirconium oxide
covered with pyrolytic carbon. These researchers evaluated the durability of off-
label use of DEXP in the treatment of primary VUR in children. Patients who
underwent sub-ureteric injection of DEXP for the correction of primary VUR were
retrospectively reviewed. Patients aged greater than 18 years as well as those who
had grade-I or grade-V VUR, anatomic abnormalities (duplicated system, hutch
diverticulum), neurogenic bladder or treatment refractory voiding dysfunction were
excluded. Radiologic success was defined as the resolutionofVUR at the 3rd
month control. Success was radiographically evaluated at the end of the 1st year.
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A total of 38 patients (9 boys, 29 girls; mean age of 6.3 ± 2.7 years) formed the
study cohort; 46 RRUs received DEXP (grade II: 22; grade III: 18; grade IV: 6).
Mean volume per ureteric orifice to obtain the mound was 0.70 ± 0.16 ml. First
control VCUG was done after 3 months in all patients. After the first VCUG, 6
patients had VUR recurrence. Short-term radiologic success of DEXP was 84.2 %.
Rate of radiologic success at the end of the 1st year was 69.4 % (25/32). Lower
age (p : 0.006) and lower amount of injected material (p : 0.05) were associated
with higher success rates at the end of 1 year. The authors concluded that this was
the first study to ascertain the outcomes of DEXP for treatment of primary VUR in
children. After 1 year of follow-up, DEXP had a 69.4 % success rate. These
preliminary findings need to be validated by well-designed studies.
Furthermore, an UpToDate review on “Management of vesicoureteral reflux” (Matto
and Greenfield, 2018) does not mention Durasphere as a management tool.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
Other CPT codes related to the CPB:
51715 Endoscopic injection of implant material into the submucosal tissue of
the urethra and/or bladder neck
74420 Urography, retrograde, w ith or w ithout KUB
74450 Urethrocystography, retrograde, radiological supervision and
interpretation
74455 Urethrocystography, voiding, radiological supervision and interpretation
78740 Ureteral reflux study (radiopharmaceutical voiding cystogram)
HCPCS codes covered if selection criteria are met:
L8604
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L8606
HCPCS codes not covered for indications listed in the CPB:
Injection, chondrocytes, fat or myoblasts - no specific code:
ICD-10 codes covered if selection criteria are met:
N13.70 - N13.9
The above policy is based on the following references:
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5. Kumon H, Tsugawa M, Ozawa H, et al. Endoscopic correction of
vesicoureteral reflux by subureteric Teflon (polytetrafluoroethylene)
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29. Harper L, Boutchkova S, Lavrand F, et al. Postoperative cystography and
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32. Bae YD, Park MG, Oh MM, Moon du G. Endoscopic subureteral injection
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33. Aubert D. Vesico-ureteric reflux treatment by implant of
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36. Peters CA, Skoog SJ, Arant BS Jr, et al. Summary of the AUA guideline on
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Reflux in Children. Eur Urol. 2012;62(3):534-542.
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47. Dogan HS, Altan M, Citamak B, et al. Factors affecting the success of
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57. Friedmacher F, Colhoun E, Puri P. Endoscopic injection of
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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administer ing plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
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services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in
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for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to
change.
Copyright © 2001-2019 Aetna Inc.
http://www.aetna.com/cpb/medical/data/500_599/0534.html 09/23/2019
AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0534 Vesicoureteral Reflux Treatment by Endoscopic Injection of Bulking Agents
There are no amendments for Medicaid.
www.aetnabetterhealth.com/pennsylvania annual 10/01/2019