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:

1. Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux

Guidelines Panel summary report on the management of primary

vesicoureteral reflux in children. J Urol. 1997;157(5):1846-1851.

2. Hughes PD. Ureteric reflux in adults and children treated exclusively by

endoscopic Teflon injection: A 10-year experience. Aust N Z Surg. 1999;69

(12):856-859.

3. Kershen RT, Atala A. New advances in injectable therapies for the

treatment of incontinence and vesicoureteral reflux. Urol Clin North Am.

1999;26(1):81-94.

4. Puri P, Granata C. Multicenter survey of endoscopic treatment of

vesicoureteral reflux using polytetrafluoroethylene. J Urol. 1998;160(3 Pt

2):1007-1011.

5. Kumon H, Tsugawa M, Ozawa H, et al. Endoscopic correction of

vesicoureteral reflux by subureteric Teflon (polytetrafluoroethylene)

injection: Review of 6-year experience. Int J Urol. 1997;4(6):541-545.

6. Belman AB. Vesicoureteral reflux. Pediatr Clin North Am. 1997;44(5):1171

1190.

7. Yasui T, Akita H, Sasaki S, et al. Endoscopic injection of Teflon for

correction of primary vesicoureteral reflux in children. Int J Urol. 1997;4

(4):349-351.



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8. Engel JD, Palmer LS, Cheng EY, Kaplan WE. Surgical versus endoscopic

correction of vesicoureteral reflux in children with neurogenic bladder

dysfunction. J Urol. 1997;157(6):2291-2294.

9. Skoog SJ, Belman AB, Majd M. A nonsurgical approach to the management

of primary vesicoureteral reflux. J Urol. 1987;138(4 Pt 2):941-946.

10. Kaplan WE, Dalton DP, Firlit CF. The endoscopic correction of reflux by

polytetrafluoroethylene injection. J Urol. 1987;138(4 Pt 2):953-955.

11. Atala A, Keating MA. Vesicoureteral reflux and megaureter. In: Campbell's

Urology. Vol. 2. 7th ed. PC Walsh, et al., eds. Philadelphia, PA: WB Saunders

Co.; 1999; Ch. 61: 1859-1916.

12. O'Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic

injection of Teflon. J Urol. 1984;167(4):1808-1809; discussion 1810.

13. Chertin B, Colhoun E, Velayudham M, et al. Endoscopic treatment of

vesicoureteral reflux: 11 to 17 years of followup. J Urol. 2002;167(3):1443

1445; discussion 1445-1446.

14. Chertin B, De Caluwe D, Puri P. Endoscopic treatment of primary grades IV

and V vesicoureteral reflux in children with subureteral injection of

polytetrafluoroethylene. J Urol. 2003;169(5):1847-1849; discussion 1849.

15. Moran Penco JM, Gomez Fraile A, Rodriguez Alarcon J, et al. Evolution of

the treatment of vesicoureteral reflux in Spain. J Urol. 2004;171(2 Pt

1):834-837.

16. Wheeler D, Vimalachandra D, Hodson EM, et al. Antibiotics and surgery for

vesicoureteric reflux: A meta-analysis of randomised controlled trials. Arch

Dis Child. 2003;88:688-694.

17. Hodson EM, Wheeler DM, Vimalachandra D, et al. Interventions for

primary vesicoureteric reflux. Cochrane Database Syst Rev. 2007;

(3):CD001532.

18. Sugiyama T, Hanai T, Hashimoto K, et al. Long-term outcome of the

endoscopic correction of vesico-ureteric reflux: A comparison of injected

substances. BJU Int. 2004;94(3):381-383.

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131.

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subureteral collagen injection (SCIN): Combined one-stage correction of

high-grade bilateral vesicoureteral reflux (VUR) in children. Eur J Pediatr

Surg. 2004;14(1):45-50.



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21. Heidenreich A, Ozgur E, Becker T, Haupt G. Surgical management of

vesicoureteral reflux in pediatric patients. World J Urol. 2004;22(2):96-106.

22. Aaronson IA. Does Deflux alter the paradigm for the management of

children with vesicoureteral reflux? Curr Urol Rep. 2005;6(2):152-156.

23. Kobelt G, Canning DA, Hensle TW, et al. The cost-effectiveness of

endoscopic injection of dextranomer/hyaluronic acid copolymer for

vesicoureteral reflux. J Urology. 2003;169(4):1480-1484.

24. U.S. Food and Drug Administration, Deflux injectable gel. Summary of

Safety and Effectiveness Data. Premarket Approval Application (PMA) No.

P000029. Rockville, MD: FDA; September 24, 2001.

25. Keating MA. Role of periureteral injections in children with vesicoureteral

reflux. Curr Opin Urol. 2005;15(6):369-373.

26. Dean GE, Doumanian LR. The extended use of Deflux

(dextranomer/hyaluronic acid) in pediatric urology. Curr Urol Rep. 2006;7

(2):143-148.

27. Tsai CC, Lin V, Tang L. Injectable biomaterials for incontinence and vesico

ureteral reflux: Current status and future promise. J Biomed Mater Res B

Appl Biomater. 2006;77(1):171-178.

28. Elder JS, Shah MB, Batiste LR, Eaddy M. Part 3: Endoscopic injection versus

antibiotic prophylaxis in the reduction of urinary tract infections in

patients with vesicoureteral reflux. Curr Med Res Opin. 2007;23 Suppl

4:S15-S20.

29. Harper L, Boutchkova S, Lavrand F, et al. Postoperative cystography and

endoscopic treatment of low-grade vesicoureteral reflux. J Laparoendosc

Adv Surg Tech A. 2008;18(3):461-463.

30. Cabezalí Barbancho D, Gómez Fraile A, López Vázquez F, et al. Our

experience using various injectable materials for the endoscopic

treatment of vesicoureteral reflux. Arch Esp Urol. 2008;61(2):269-277.

31. Seibold J, Werther M, Sievert KD, Stenzl A. Long-term results after

endoscopic subureteral injection for VUR using dextranomer/hyaluronic

acid copolymer: A five years experience. Urologe A. 2010;49(4):536-539.

32. Bae YD, Park MG, Oh MM, Moon du G. Endoscopic subureteral injection

for the treatment of vesicoureteral reflux in children: Polydimethylsiloxane

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(Deflux(R)). Korean J Urol. 2010;51(2):128-131.



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33. Aubert D. Vesico-ureteric reflux treatment by implant of

polydimethylsiloxane (Macroplastique): Review of the literature. Prog Urol.

2010;20(4):251-259.

34. Ormaechea M, Ruiz E, Denes E, et al. New tissue bulking agent

(polyacrylate polyalcohol) for treating vesicoureteral reflux: Preliminary

results in children. J Urol. 2010;183(2):714-717.

35. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric

vesicoureteral reflux: Systematic review. Pediatrics. 2010;125(5):1010

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36. Peters CA, Skoog SJ, Arant BS Jr, et al. Summary of the AUA guideline on

management of primary vesicoureteral reflux in children. J Urol. 2010;184

(3):1134-1144.

37. Nagler EV, Williams G, Hodson EM, Craig JC. Interventions for primary

vesicoureteric reflux. Cochrane Database Syst Rev. 2011;(6):CD001532.

38. Ionescu S, Tîrlea S. Endoscopic treatment of vesicoureteral reflux in

children. Chirurgia (Bucur). 2011;106(2):259-263.

39. Routh JC, Bogaert GA, Kaefer M, et al. Vesicoureteral reflux: Current trends

in diagnosis, screening, and treatment. Eur Urol. 2012;61(4):773-782.

40. Tekgül S, Riedmiller H, Hoebeke P, et al. EAU Guidelines on Vesicoureteral

Reflux in Children. Eur Urol. 2012;62(3):534-542.

41. Alizadeh F, Mazdak H, Khorrami MH, et al. Postoperative ureteral

obstruction after endoscopic treatment of vesicoureteral reflux with

polyacrylate polyalcohol copolymer (Vantris(®)). J Pediatr Urol. 2013;9

(4):488-492.

42. Kim JW, Oh MM. Endoscopic treatment of vesicoureteral reflux in pediatric

patients. Korean J Pediatr. 2013;56(4):145-150.

43. Stredele RJ, Dietz HG, Stehr M. Long-term results of endoscopic treatment

of vesicoureteral reflux in children: Comparison of different bulking

agents. J Pediatr Urol. 2013;9(1):71-76.

44. Cloutier J, Blais AS, Moore K, Bolduc S. Prospective study using a new

bulking agent for the treatment of vesicoureteral reflux: Polyacrylamide

hydrogel. J Urol. 2013;190(3):1034-1037.

45. Moore K, Bolduc S. Prospective study of polydimethylsiloxane vs

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48. Lee S, Jeong SC, Chung JM, Lee SD. Secondary surgery for vesicoureteral

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Investig Clin Urol. 2016;57(1):58-62.

49. Asgari SA, Asl AS, Safarinejad MR, Ghanaei MM. High success rate with new

modified endoscopic treatment for high-grade VUR: A pilot study with

preliminary report. J Pediatr Urol. 2016;12(2):100.e1-e4.

50. Karakus SC, User IR, Kılıc BD, et al. The comparison of

dextranomer/hyaluronic acid and polyacrylate-polyalcohol copolymers in

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51. Yap TL, Chen Y, Nah SA, et al. STING versus HIT technique of endoscopic

treatment for vesicoureteral reflux: A systematic review and meta-

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52. Blais AS, Bolduc S, Moore K. Vesicoureteral reflux: From prophylaxis to

surgery. Can Urol Assoc J. 2017;11(1-2 Suppl1):S13-S18.

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55. Warchoł S, Krzemień G, Szmigielska A, et al. Endoscopic correction of

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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.



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

http://www.aetnabetterhealth.com/pennsylvania

0534 vesicoureteral reflux treatment by endoscopic injection of … · 2020. 9. 3. ·...

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