Deflux ® clinical update Addendum as of 2nd November 2007

List of new key references 1.Swerkersson S,*Jodal U, Sixt R, Stokland E, Hansson E. Relationship Among Vesicoureteral Reflux, Urinary Tract Infection and Renal Damage in Children. J Urol 2007; Conway P H, Cnaan A, Zaoutis T, Henry B V, Grundmeier R W, Keren R. Recurrent Urinary Tract Infections in Children: Risk Factors and Association With Prophylactic Antimicrobials. JAMA 2007; Wadie GM, Tirabassi MV, Courtney RA, Moriarty KP. The Deflux procedure reduces the incidence of urinary tract infections in patients with vesicoureteral reflux. J Laparoendosc Adv Surg Tech A Jun;17(3): Current Medical Research and Opinion. Volume 23, Supplement 4, 2007: Challenges surrounding vesicoureteral reflux: fuel for a paradigm shift in treatment 1.Vesicoureteral reflux treatment: the past, present, and future. Terry W. Hensle and Amy L. Grogg 2.Examining pediatric vesicoureteral reflux: a real- world evaluation of treatment patterns and outcomes. Terry W. Hensle, Grace Hyun, Amy L. Grogg and Michael Eaddy 3.Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux. Jack S. Elder, Manan B. Shah, LaKeasha R. Batiste and Michael Eaddy 4.Considerations regarding the medical management of VUR: what have we really learned? Martin A. Koyle and Anthony A. Caldamone

What these articles tell us; take home messages There is a relationship between VUR and permanent renal damage −...related to UTI with VUR as a reinforcing factor Antimicrobial prophylaxis −is not associated with decreased risk of recurrent UTI, even after adjusting for propensity to receive prophylaxis −but is a risk factor for antibimicrobial resistance among children with recurrent UTI Adherence with prophylactic antibiotic therapy was less then 50%. −The effectiveness of antibiotic therapy is greatly diminished by poor antibiotic adherence. The Deflux procedure was effective −not only in eliminating VUR on radiologic studies −but also in reducing the incidence of UTIs and antibiotic use in children with VUR Patients on Deflux had lower number of UTIs within one year of treatment when compared to patients on prophylactic antibiotics. The disadvantage of antibiotic therapy is antibiotic resistance and wasted resources as patients are nonadherent to therapy −Clinical practice guidelines should be revisited

Relationship Among Vesicoureteral Reflux, Urinary Tract Infection and Renal Damage in Children (1/3) Authors: −Swerkersson S −Jodal U −Sixt R −Stokland E −Hansson E. Published: J Urol Date: August 2007 Purpose of this study: −to study the relationship among VUR, UTI and permanent renal damage in children.

Relationship Among Vesicoureteral Reflux, Urinary Tract Infection and Renal Damage in Children (2/3) Study Methods Highlights −Retrospectively analysis of 303 children younger than 2 years with a first time, nonobstructive, culture verified UTI −The protocol included -Ultrasonography and VCUG within 3 months after urinary tract infection - 99m technetium dimercapto-succinic acid scintigraphy after 1 to 2 years. Results −VUR was found in -36 of 163 boys (22%) -44 of 140 girls (31%). −Of the 303 patients 80 (26%) had permanent renal damage according to dimercapto-succinic acid scintigraphy. −The rate of abnormality increased significantly with grade of VUR in boys and girls. −The relative risk of renal damage was significantly increased in patients with VUR grade II and higher. −Factors significantly related to permanent renal damage: -Maximum C-reactive protein concentration -Maximum temperature during UTI -Presence of VUR -Febrile recurrences of urinary tract infection

Relationship Among Vesicoureteral Reflux, Urinary Tract Infection and Renal Damage in Children (3/3) Conclusion −There was a significant relationship between grade II VUR and higher and permanent renal damage in boys and girls. −These findings support the concept that renal damage is associated with VUR and is often congenital in boys, while in girls it is more related to UTI with VUR as a reinforcing factor.

Recurrent Urinary Tract Infections in Children Risk Factors and Association With Prophylactic Antimicrobials (1/3) Authors: −Conway P H −Cnaan A −Zaoutis T −Henry B V −Grundmeier R W −Keren R. Published: JAMA Date: July 2007 Purpose of this study: −to identify risk factors for recurrent UTI in a pediatric primary care cohort, to determine the association between antimicrobial prophylaxis and recurrent UTI, and to identify the risk factors for resistance among recurrent UTIs.

Recurrent Urinary Tract Infections in Children Risk Factors and Association With Prophylactic Antimicrobials (2/3) Background −The evidence regarding risk factors for recurrent urinary tract infection (UTI) and the risks and benefits of antimicrobial prophylaxis in children is scant. Main Outcome Measures −Time to recurrent UTI −Antimicrobial resistance of recurrent UTI pathogens. Study Methods Highlights −From a network of 27 primary care pediatric practices in urban, suburban, and semirural areas spanning 3 states... −... a cohort of children aged 6 years or younger... −...who were diagnosed with first UTI between July 1, 2001, and May 31, 2006, was assembled. −Time-to-event analysis was used to -determine risk factors for recurrent UTI -the association between antimicrobial prophylaxis and recurrent UTI −A nested case-control study was performed among children with recurrent UTI to identify risk factors for resistant infections.

Recurrent Urinary Tract Infections in Children Risk Factors and Association With Prophylactic Antimicrobials (3/3) Results −Among children in the network, 611 had a first UTI and 83 had a recurrent UTI. −In multivariable Cox time-to-event models, factors associated with increased risk of recurrent UTI included white race, age 3 to 5 years and grade 4 to 5 VUR −Sex and grade 1 to 3 VUR were not associated with risk of recurrence. −Antimicrobial prophylaxis... -was not associated with decreased risk of recurrent UTI, even after adjusting for propensity to receive prophylaxis -but was a risk factor for antibimicrobial resistance among children with recurrent UTI Conclusion −Among the children in this study, -antimicrobial prophylaxis was not associated with decreased risk of recurrent UTI, -but was associated with increased risk of resistant infections.

The Deflux Procedure Reduces the Incidence of UTIs in Patients with VUR (1/2) Authors: −Wadie −Tirabassi −Courtney −Moriarty Published: Journal of Laparoendoscopic & Advanced Surgical Techniques Date: June 2007 Purpose of this study: −to review the experience of a single institution with the Deflux procedure and assess its effectiveness in reducing the incidence of urinary tract infections (UTIs) in children with Vesico Ureteric Reflux (VUR).

The Deflux Procedure Reduces the Incidence of UTIs in Patients with VUR (2/2) Study Methods Highlights −Charts of 100 patients with VUR, who presented between June 2003 and June 2005, were prospectively reviewed. −Data collected included: -Demographics -Number of preoperative and postoperative UTIs -A radiologic grade of VUR on VCUG -Presence of VUR on a radionuclide VCUG 3 months after the procedure. −Patients were continued on oral antibiotics until urine culture at 3 months was negative and no reflux was demonstrated on VCUG. −The student’s t test was used for data analysis. Results −155 ureters treated -10 had Grade I reflux, 42 Grade II, 76 Grade III, 25 Grade IV, and 2 Grade V. -A second injection was required in 22 ureters (14.2%). −Overall success rate of the procedure (Grade 0 reflux at 3 months): -77.4% after the first injection -83.9% after a second injection −The success rate per grade: -100% for Grade I % for Grade II % for Grade III - 64% for Grade IV - 50% for Grade V. −Thirteen (13) patients had UTIs after the procedure, compared to 75 before. −There was a 5-fold reduction in the incidence of UTIs/year, from a mean of 0.68 pre- to 0.12 postinjection (P 0.001). −The majority of UTIs were caused by Escherichia coli Conclusion −We conclude that the Deflux procedure is effective -not only in eliminating VUR on radiologic studies -but also in reducing the incidence of UTIs and antibiotic use in children with VUR

Authors: −Terry W. Hensle −Amy L. Grogg Published: Current Medical Research and Opinion. Volume 23, Supplement 4, 2007 Vesicoureteral reflux treatment: the past, present, and future (1/2) Article Purpose: −A brief overview of VUR, while highlighting current diagnostic, and treatment patterns. −An introduction of the topics of the supplement, which are 1.poor adherence to prophylactic antibiotic regimens, 2.the potential for resistance given prophylactic non- adherence and efficacy issues, and 3.the effectives of Deflux at preventing UTIs when compared to prophylactic antibiotics in patients with VUR.

Background: −Vesicoureteral reflux (VUR) occurs in 1% of children. −VUR is typically diagnosed after a UTI; in fact 1/3 of children with a UTI will have VUR Diagnostic and Management: −After diagnosing VUR, the primary goal of treatment is to prevent pyelonephritis and long- term renal complications −Treatment is dependent on VUR grade, with prophylactic antibiotics being recommended for grades 1 and 2, and moderate grade 3. However, AUA guidelines acknowledge that prophylactic therapy is not supported by well- designed, randomized controlled trials. −Open surgery is reserved for bilateral grade 3 and grades 4-5. −Deflux, which came to market after AUA guidelines were established, has more favorable resolution rates when compared to prophylactic antibiotics (77% vs. 33%, respectively). Vesicoureteral reflux treatment: the past, present, and future (2/2) First-line Prophylactic Antibiotic Therapy −The goal of prophylactic antibiotic therapy is to prevent UTIs and renal scarring; but the treatment is not curative. −There is no evidence that antibiotics prevent UTIs or renal scarring when compared to a placebo group. −Studies report up to 40% of patients have breakthrough UTIs while on prophylactic antibiotics. −In spite of the lack of efficacy, antibiotic resistance is becoming a huge problem for prophylactic antibiotic patients. AUA guidelines (1997) −Recommends that parental preferences be honored when treating VUR −The Cochrane Collaboration identified a need for the guidelines to compare prophylactic antibiotics to endoscopic injection

Examining pediatric vesicoureteral reflux: a real-world evaluation of treatment patterns and outcomes (1/3) Authors: −Terry W. Hensle −Grace Hyun −Amy L. Grogg −Michael Eaddy Published: Current Medical Research and Opinion. Volume 23, Supplement 4, 2007 Article Purpose: −This article describes the current treatment paradigm for patients diagnosed with VUR, focusing on patient adherence to prophylactic antibiotics therapy.

Examining pediatric vesicoureteral reflux: a real-world evaluation of treatment patterns and outcomes (2/3) Background: −Uncomplicated VUR patients traditionally placed on prophylactic antibiotics −The goal of therapy is to prevent UTIs while waiting for VUR to spontaneously resolve. −There is a tremendous potential to under use treatment through non- adhrence. −This study evaluates the treatment patterns of VUR patients focusing on adherence to treatment. Study Methods Highlights: −The study uses a managed care database to evaluate treatment patterns of patients diagnosed with VUR -included are data from 82 US healthcare plans, representing 45 million lives. −Pediatric patients ( years of age) newly diagnosed with VUR were included in the study. −Patients were evaluated over the first year after diagnosis for the use of -prophylactic antibiotic therapy -open surgery -endoscopic injection with Deflux. −For patients who filled at least one antibiotic prescription, adherence to antibiotic therapy was measured from the date of diagnosis to the end of the one year follow-up period for each patient; assuming antibiotic therapy prophylactically for at least one year. −Adherence was measured by dividing the total days of antibiotic acquired over one year by 365 days.

Examining pediatric vesicoureteral reflux: a real-world evaluation of treatment patterns and outcomes (3/3) Key Study Results: −There were 10,975 patients with a diagnosis of VUR under 11 years of age -76% were placed on prophylactic antibiotics as initial treatment -0.38% on Deflux -1.5% open surgery −Patients on antibiotic therapy only filled enough medication to last 41.4% of the year, indicating a very poor level of compliance (80% is considered adherent with therapy) −Only 17% of patients were greater than 80% adherent to therapy Conclusions: −On average adherence with prophylactic antibiotic therapy was less then 50%. −The effectiveness of antibiotic therapy is greatly diminished by poor antibiotic adherence. Antibiotic Nonadherence Antibiotic Resistance N=10,975

Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux (1/3) Authors: −Jack S. Elder −Manan B. Shah −LaKeasha R. Batiste −Michael Eaddy Published: Current Medical Research and Opinion. Volume 23, Supplement 4, 2007 Article Purpose: −This article compares patients given Deflux as first-line therapy to those given prophylactic antibiotics as first line therapy.

Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux (2/3) Background: −Uncomplicated VUR patients have been traditionally placed on prophylactic antibiotics as first-line therapy −The goal of therapy is to prevent UTIs while waiting for VUR to spontaneously resolve −However, the literature shows that prophylactic antibiotic therapy is not effective in reducing UTIs −Even if antibiotics were 100% efficacious, the benefit of therapy would be reduced because patients are not taking the medication. −Clinical trials have shown that Deflux has better resolution rates than prophylactics. −As such, this study evaluates first-line prophylactic antibiotic therapy versus first- line Deflux therapy in terms of UTI rates. Study Methods Highlights: −The study uses a managed care database to evaluate treatment patterns of patients diagnosed with VUR; included are data from 82 US healthcare plans, representing 45 million lives. −Pediatric patients ( years of age) newly diagnosed with VUR were included in the study −Patients with neuropathic bladder, posterior urethral valves, and bladder exstrophy were excluded. −3 antibiotic patients were matched to each Deflux patient on age, gender, the number of UTIs prior to index and diagnosing physician specialty. −UTIs were defined as a diagnosis of UTI + an antibiotic (other than their first antibiotic after diagnosis or an antibiotic with a days supply of < 15 days) + a urinalysis/culture.

Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infections in patients with vesicoureteral reflux (3/3) Key Study Results: −There were 152 patients in this study (114 antibiotic patients to 38 Deflux patients) −13% of all patients had a UTI, with Deflux patients trending to have a lower rate of UTIs than prophylactic antibiotic patients 7.9% vs. 14.9%, respectively (p=0.0953) −When evaluating the average number of UTIs after index, the Deflux group averaged 0.08 vs 0.28 in the prophylactic antibiotic group (p=0.029). Conclusions: −Patients on Deflux had lower number of UTIs within one year of treatment when compared to patients on prophylactic antibiotics.

Considerations regarding the medical management of VUR: what have we really learned? (1/2) Authors: −Martin A. Koyle −Anthony A. Caldamone Published: Current Medical Research and Opinion. Volume 23, Supplement 4, 2007 Article Purpose: −This article seeks to put the information presented in the supplement in perspective, with a focus on antibiotic resistance and lack of efficacy with prophylactic antibiotic therapy.

Considerations regarding the medical management of VUR: what have we really learned? (2/2) Introduction: −Uncomplicated VUR patients have been traditionally placed on prophylactic antibiotics −Although prophylactic therapy gained popularity 4 decades ago, questions of resistance, efficacy and nonadherence to the prophylactic regimen forces clinicians to review this common practice. Background: −Antibiotic resistance has increased substantially due the misuse of antibiotics; such misuse increases the risk for resistance in urinary pathogens and normal bacterial flora. −In VUR patients, therapies commonly used for prophylactic therapy have the highest rates of resistance. -Patients given antibiotics for more than 4 weeks were 23 times more likely to have resistant E-Coli -Resistance to SMZ/TMP is increasing in children on prophylactic therapy −Given the threat resistance strains of bacteria pose to society, clinicians should re-consider the risk versus benefits. Value of Prophylactic Antibiotic Therapy in Children with VUR −A meta-analysis of clinical studies showed 30-50% of prophylactic antibiotic patients have UTIs −A comparison of no antibiotics vs antibiotics showed no difference in UTI rates −The Elder study within this supplement showed rates of UTIs at 14.9% for antibiotic therapy vs 7.9% for Deflux −Data concluded that long-term antibiotic therapy does not reduce renal scarring Implication of Non-Adherence to Prophylactic Therapy −Only 17% of VUR patients take their prophylactic antibiotic therapy more than 80% of the time. −This suggest that giving prophylactic treatment is cumbersome or inconvenient −Non-adherence further increases the risk of antibiotic resistance Potential Solutions/Conclusion −The disadvantage of antibiotic therapy is antibiotic resistance and wasted resources as patients are nonadherent to therapy −Clinical practice guidelines should be revisited

AUA policy statement as of October 31st 2007 Use of Deflux® in the Management of Vesicoureteral Reflux It is the current position of the American Urological Association that endoscopic injection of the dextranomer/hyaluronic compound Deflux® is an option in the management of pediatric vesicoureteral reflux (VUR). The absence of inclusion of Deflux in the 1997 Pediatric Reflux Guidelines simply reflects the fact that it had not been introduced at that time and therefore could not have been evaluated. The contention that Deflux has not been proven to reduce urinary infections associated with reflux is inappropriate to the same extent that no other treatment modality has been shown to reduce all urinary tract infections. The resolution of reflux has been shown to reduce the incidence of pyelonephritis. Therefore to the extent that Deflux can correct VUR, it will reduce the incidence of pyelonephristis. The significantly lower morbidity associated with the use of Deflux, compared to open surgery, indicates Deflux must be considered as an important option in VUR management. The choice of management options remains with the informed family and the physician, based upon multiple factors including age, sex, reflux grade, voiding patterns, risk of renal injury, and parental preferences. To attempt to dictate specific treatment modality based upon concrete evidence is simply impossible based upon the current state of evidence. Any claim that current evidence can guide such a decision reflects a lack of understanding of the state of current evidence. As more evidence emerges, selection of specific therapy for specific patients may become more appropriate. At present, Deflux must be considered an option in the care of the pediatric patient with VUR. Board of Directors, October