Impact of Clinical Guidelines on Voiding Cystourethrogram Use and Vesicoureteral Reflux Incidence

Author's Accepted Manuscript Impact of Clinical Guidelines on Voiding Cystourethrogram Utilization and Vesicoureteral Reflux Incidence Ted Lee , Chandy Ellimoottil , Kathryn A. Marchetti , Tanima Banerjee , Vesna Ivančić , Kate H. Kraft , David A. Bloom , John M. Park , Julian Wan

PII: DOI: Reference:

S0022-5347(17)77416-2 10.1016/j.juro.2017.08.099 JURO 14956

To appear in: The Journal of Urology Accepted Date: 24 August 2017 Please cite this article as: Lee T, Ellimoottil C, Marchetti KA, Banerjee T, Ivančić V, Kraft KH, Bloom DA, Park JM, Wan J, Impact of Clinical Guidelines on Voiding Cystourethrogram Utilization and Vesicoureteral Reflux Incidence, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.08.099. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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Title Impact of Clinical Guidelines on Voiding Cystourethrogram Utilization and Vesicoureteral Reflux Incidence

Affiliations Department of Urology, Michigan Medicine, Ann Arbor, MI

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Institute for Healthcare Policy and Innovation, Michigan Medicine, Ann Arbor, MI

Corresponding author: Ted Lee, M.D. Department of Urology University of Michigan Medical School

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Authors Ted Lee, M.D.1, Chandy Ellimoottil, M.D.1,2, Kathryn A Marchetti B.S.1, Tanima Banerjee, M.S.2, Vesna Ivančić, M.D.1, Kate H Kraft, M.D.1, David A Bloom, M.D.1, John M Park, M.D. 1, Julian Wan, M.D.1

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Address: 1500 E Medical Center Drive, Ann Arbor, MI 48109 [email protected] Phone: 201-543-7520 Fax: 734-615-0886

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Abstract

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Background

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To prevent overdiagnosis and overtreatment of vesicoureteral reflux, the 2007 British National Institution of Clinical Excellence (NICE) and 2011 American Academy of Pediatrics (AAP) guidelines both recommended against routine voiding cystourethrogram in children presenting with first febrile urinary tract infections. The impact of these guidelines on clinical practice is unknown. Methods

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Using an administrative claims database (CliniformaticsTM Data Mart), children with voiding cystourethrogram or diagnosis of vesicoureteral reflux between 2001 and 2015 were identified. The cohort was divided into children 0-2 and 3-10 years of age. Single and multiple group interrupted time series analyses (difference-in-difference) were performed with guidelines as intervention points. Vesicoureteral reflux incidence was compared across each time period. Results

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Conclusions

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Of 51,649 children with voiding cystourethrograms, 19,422 (38%) were diagnosed with vesicoureteral reflux. In children 0-2 years old, voiding cystourethrogram utilization did not decrease after the 2007 NICE guidelines were announced (-0.37, 95% CI -1.50 to 0.77, p = 0.52) but did significantly decrease after the 2011 AAP guidelines were announced (-2.00, 95% CI 3.35 to -0.65, p = 0.004). In children 3-10 years old, voiding cystourethrogram utilization decreased during the entire study period. There was a decrease in vesicoureteral reflux incidence in both groups that mirrored patterns of voiding cystourethrogram utilization.

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The 2011 AAP guidelines led to a concurrent decrease in voiding cystourethrogram utilization and incidence of vesicoureteral reflux among children 0-2 years of age. Further studies are needed to assess the risks and benefits of reducing the diagnosis of vesicoureteral reflux among young children.

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Introduction Twenty-five to 40% of young children presenting with a febrile urinary tract infection have an underlying diagnosis of vesicoureteral reflux.[1] Since majority of vescioureteral reflux resolves with time and growth, there is controversy over the ideal time to obtain screening

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studies.[2,3] The 2007 British National Institute of Clinical Excellence (NICE) and 2011

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American Academy of Pediatrics (AAP) issued guidelines on pediatric urinary tract infection that recommended against routine use of voiding cystourethrogram in children presenting with a febrile urinary tract infection, instead recommending only a routine renal ultrasound and reserving the voiding cystourethrogram for specific circumstances.[4, 5] Supporters believed that these changes would mitigate overdiagnosis and overtreatment of vesicoureteral reflux, while

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others were concerned that the diagnosis of vesicoureteral reflux will be delayed or missed in some patients, resulting in recurrent urinary tract infections, pyelonephritis, and renal scarring

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episodes that would have been preventable.[6, 7] The effect of these guidelines on rates of voiding cystourethrogram utilization and

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incidence of vesicoureteral reflux remain undefined. Previous investigators have studied the impact of these guidelines on voiding cystourethrogram utilization and vesicoureteral reflux detection rates at an institutional level.[8, 9] Herein, we build on this work by examining the impact of major guidelines at a national level by using a large administrative claims database. We hypothesized that the 2007 NICE and 2011 AAP guidelines decreased voiding cystourethrogram utilization and vesicoureteral reflux incidence within the United States following their publication.

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Material sand Methods

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Data and study population The data was obtained using an administrative claims database composed of members of a national managed care company affiliated by CliniformaticsTM Data Mart (Optuminsight, Eden

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Prairie, MN). The CliniformaticsTM Data Mart database includes deidentified enrollment

information of more than 111 million unique members across the United States since 1993. The

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database is capable of following subjects longitudinally, providing access to all inpatient and outpatient claims data from both community and tertiary referral centers. The geographic diversity of the database allowed us to assess trend across the nation. This study was deemed exempt from review by our university Institutional Research Board.

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We included all children less than 10 years of age who underwent voiding cystourethrogram with principle diagnosis of urinary tract infections and/or pyelonephritis as defined by claims-based definitions in the International Classification of Diseases, Ninth

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Revision (see supplement table 1). Among these patients, we identified those with principle diagnosis of vesicoureteral reflux. We excluded children with co-existing diagnoses that involve

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voiding cystourethrogram as part of standard evaluation or diagnoses that may predispose them to urinary tract infections (see supplement table 2). Outcomes

Our outcomes of interest were the quarterly rate of voiding cystourethrogram utilization per 100,000 and the incidence of vesicoureteral reflux per 100,000 children per year before and after the release of the 2007 NICE and 2011 AAP guidelines. The 2011 AAP guideline were

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intended to affect children from 2 months to 24 months of age less than 2 years of age; hence, our cohort was divided into children 0 to 2 years of age and children 3 to 10 years of age. We included the 2007 NICE and 2011 AAP guidelines as intervention time points of our analysis.

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Time periods were defined as: pre-NICE (2001 – 2007), pre-AAP (2007 – 2011), and post-AAP (2011 – 2015).

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Statistical Analysis

A single group interrupted time series analysis was performed to assess voiding

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cystourethrogram utilization trend in each age group from January 2001 to June 2015.[10] Since the intended target group of the 2011 AAP guidelines was children less than 2 years of age, we expected that any decline due to the guidelines would be more pronounced in the 0 – 2 year group. Therefore, we used a multiple group interrupted time series analysis (difference-in-

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difference) to examine the impact of the guidelines on rates of voiding cystorurethgoram utilization for children 0 – 2 years age compared to those 3 – 10 years of age.[11] Only the first voiding cystourethrogram ordered for a child was included for interrupted time series models.

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In addition to the above analysis, the incidence of vesicoureteral reflux was captured for each time period. We calculated the incidence of vesicoureteral reflux by quantifying children

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with diagnosis of vesicoureteral reflux and all unique children included in the claims database within each time period. For both children 0 – 2 years and 3 – 10 years of age, t-test was performed between each time period to assess significant change in vesicoureteral reflux incidence.

Baseline demographic characteristics by age groups across each time period were compared using the t-test for continuous variables and Chi-square for categorical variables.

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Statistical analyses were performed using statistical software (STATA 13/SE, College Station, TX). P-values with < 0.05 are considered statistically significant.

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Results There were 51,649 unique children who had at least one voiding cystourethrogram from January 2001 through June 2015. Mean age at time of voiding cystourethrogram was 3.2 years of

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age. 25,706 were obtained in children 0 to 2 years of age and 25,943 were obtained in children 3 to 10 years of age. 82% of the tests were performed on female children. Among all children in

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whom voiding cystourethrogram was performed, 19,422 (38%) were diagnosed with vesicoureteral reflux. Demographics including age, race, geographic location, and gender are detailed in table 1.

The single group interrupted time series analysis among children 0 – 2 years of age

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revealed a decreased quarterly rate of 2.82 voiding cystourethrogram studies per 100,000 children during the post-AAP period (-2.82; 95% CI -4.17 to -1.47; p < 0.0001). There was no decrease in quarterly rates of voiding cystourethgrogram during the pre-NICE or pre-AAP

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periods (0.51; 95% CI -0.56 to 1.59; p = 0.34 and -1.06; 95% CI -2.19 to 0.06; p = 0.06, respectively). The single group interrupted time series analysis among children 3 – 10 years of

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age revealed significantly decreased quarterly rates in all three time periods (pre-NICE, preAAP, post-AAP: -0.49; 95% CI -0.73 to -0.26; p < 0.0001, -0.70; 95% CI -0.91 to -0.49; p < 0.0001, -0.82; 95% CI -1.01 to -0.62; p < 0.0001, respectively). Trends of voiding cystourethrogram utilization among children 0 – 2 and 3 – 10 years of age are demonstrated in figure 1.

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The multiple group time series analysis revealed a greater decrease in quarterly voiding cystourethrogram utilization rates among children 0 – 2 years of age compared to those of children 3 – 10 years of age only after the release of 2011 AAP guidelines (-2.00, 95% CI -3.35

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to -0.65, p = 0.0019). There was no difference in trend after the release of 2007 NICE guidelines (-0.37, 95% CI -1.50 to 0.77, p = 0.52). The difference in difference analysis is demonstrated in figure 2.

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During the pre-NICE guideline, pre-AAP guideline, and post-AAP guideline time

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periods, vesicoureteral reflux incidence among children 0 – 2 years were 41.32, 37.98, and 25.30 per 100,000 children, respectively. Vesicoureteral reflux incidence among children 3 – 10 years were 15.88, 10.31, and 6.02 per 100,000 children, respectively. Among children 0 – 2 years, there was a significant decrease in vesicoureteral reflux incidence between the post-AAP and pre-AAP periods (p < 0.0001). Among children 3 – 10 years, the vesicoureteral reflux incidence

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decreased between the pre-NICE and pre-AAP periods (p < 0.0001) and between the pre-AAP and post-AAP periods (p < 0.0001). Incidence of vescioureteral reflux among children 0 – 2 and

Discussion

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3 – 10 years of age are demonstrated in figure 3.

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After the release of the 2011 AAP guidelines, there has been a significant decrease in

voiding cystourethrogram utilization among children less than 0 – 2 years of age. Likewise, there was a significant decrease in vescioureteral reflux incidence for this same population only after the release of the 2011 AAP guidelines. Among children 3 – 10 years of age, voiding cystourethrogram utilization and vesicoureteral reflux incidence were declining prior to the release of the 2011 AAP guidelines. Collectively, although there was a pre-existing reluctance to diagnose vesicoureteral reflux among older children, these findings suggest that the 2011 AAP

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guidelines effectively decreased vesicoureteral reflux diagnosis among young children less than 2 years of age.

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Previous investigators have reported fewer voiding cystourethrogram studies performed at a local level over the past decade. Vereen et al reported a decreasing trend in voiding

cystourethrogram utilization at a tertiary care center from 2005 to 2013 among children less than 18 years of age.[7] Lee et al reported a steady decrease in the number of voiding

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cystourethrogram studies performed at another large tertiary care center from 2008 to 2015

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among all patients. The time series regression analysis with the 2011 AAP guidelines as the intervention time point did not reveal a significant decrease in trend after the publication of guidelines.[8] Our current study reveals that voiding cystourethrogram utilization rates among older children were trending down prior to the release of 2011 AAP guidelines, while voiding cystourethrogram utilization rates among children 0 – 2 years of age significantly decreased

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following the 2011 AAP guidelines.

With regards to vesicoureteral reflux, Vereen et al reported that the ratio of patients seen

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with vesicoureteral reflux did not change from 2006 to 2013.[7] Lee et al reported that there was no significant difference in vesicoureteral reflux detection rates between 2009 and 2014, but

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there was a threefold increase in the detection of high-grade reflux in 2014 (2.6% vs 8.4%, p 0.03).[8] The current study demonstrates that, among older children, vesicoureteral reflux detection rates have been on the decline since 2001. Among children less than 2 years of age, vesicoureteral reflux detection rates significantly declined only after the release of the 2011 AAP guidelines. Our study does have several limitations. First, the study is limited to only privately insured children, excluding children with lower socioeconomic backgrounds who may have

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higher barriers to healthcare access. Second, although patients are followed longitudinally, not all patients were included in the database since birth. There may be patients who were already diagnosed with vesicoureteral reflux before inclusion in the database. However, the considerable

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size and diversity of the CliniformaticsTM Data Mart database may help account for the relatively small group of subjects that were not reflected in our database and, therefore, unlikely to affect our findings. Third, although the 2011 AAP guidelines were intended to impact children 2 –

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24 months, we divided the groups based on age in years because the database provides only the year of birth for each patient. Considering this limitation, we felt that the two groups of

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0 – 2 and 3 – 10 years of age was most accurate and appropriate. Fourth, we could not differentiate between high-grade and low-grade reflux. Based on recent findings of the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial, however, it may be argued that both children with high and low grade reflux may benefit from

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intervention.[12]

These limitations notwithstanding, our findings help understand the implications of the 2011 AAP guidelines on voiding cystourethrogram utilization and vesicoureteral reflux

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incidence. Relevant to policymakers, our results suggest that the 2011 AAP guidelines have

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achieved its intended effects of decreasing routine voiding cystourethrogram use in young children less than 2 years of age presenting with a first-time febrile urinary tract infection. This in turn decreased vesicoureteral reflux diagnosis in many children that would have been diagnosed with vesicoureteral reflux prior to the release of the guidelines. Some may welcome this paradigm shift in the disease of vesicoureteral reflux. Children presenting with a febrile urinary tract infection without a diagnosis of vesicoureteral reflux are spared a morbid test that involves urethral catheterization and radiation exposure. Those with underlying vesicoureteral reflux that self resolves

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without a repeat episode of febrile urinary tract infection or pyelonephritis are spared long-term prophylactic antibiotics, additional voiding cystourethrogram studies, and potential procedures, such as ureteral reimplantation and/or injection therapies. Conversely, patients with underlying

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vesicoureteral reflux may suffer from repeat urinary tract infections or pyelonephritis episodes that may have been prevented with earlier diagnosis. The missed opportunity for management with prophylactic antibiotics or prompt intervention with surgical or endoscopic procedures may

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result in renal scarring that may have been prevented.

From a health care expenditure perspective, at first glance the guidelines may appear to

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cut cost and conserve resources by decreasing the number of voiding cystourethrogram studies performed and modalities used for management of vesicoureteral reflux. However, episodes of recurrent urinary tract infections, pyelonephritis and renal scarring may pose considerable longterm health care costs.

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Our collective findings suggest that, while there was a pre-existing reluctance to diagnose vesicoureteral reflux among older children, the 2011 AAP guidelines effectively decreased voiding cystourethrogram use and vesicoureteral reflux diagnosis among young children less

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than 2 years of age. Moving forward, research in this area should focus on understanding

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changing management patterns and overall cost in managing vesicoureteral reflux. In addition, it is imperative to examine the rates of recurrent urinary tract infections, pyelonephritis, and renal scarring among patients whose diagnosis was delayed as a result of this paradigm shift in the disease of vesicoureteral reflux. In the end, we must achieve the optimal balance to limit overdiagnosis and overtreatment of vesicoureteral reflux while minimizing children who may suffer as a result.

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Acknowledgements This work was supported by the Bomalaski Michigan Pediatric Urology Scholars fund.

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References

Tullus K, Vesicoureteric reflux in children. Lancet 2015;385:371-9.

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Estrada CR, Passerotti CC, Graham DA, et al. Nomograms for predicting annual resolution rate of primary vesicoureteral reflux: results from 2,462 children. J Urol 2009;182:1535-41.

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Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging Studies after a First Febrile Urinary Tract Infection in Young Children. NEJM;348:195202.

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in Urinary Tract Infections in Children: Diagnosis, Treatment and Long-term Management. 2007: London.

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Subcommittee on Urinary Tract Infection, S.C.o.Q.I., Management, and K.B. Roberts, Urinary tract infection: clinical practice guidelines for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595610.

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Subcommittee On Urinary Tract Infection, Reaffirmation of AAP Clinical Practice Guideline: The Diagnosis and Management of the Initial Urinary Tract Infection in Febrile Infants and Young Children 2-24 Months of Age. Pediatrics 2016: 138.

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Wan J, Skoog SJ, William HC, et al. Section on Urology response to new Guidelines for the diagnosis and management of UTI. Pediatrics 2012;129:1051-3.

8.

Lee LC, Lorenzo AJ, Odeh R, et al. Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System. J Urol 2017;197:951-956.

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Vereen RJ, Kogan BA, and Feustel PJ. Local trends in the evaluation and treatment of urinary tract infections and vesicoureteral reflux in children. Urology Practice 2017;4:549. Linden A. Conducting interrupted time-series analysis for single- and multiple-group comparisons. Stata Jounrnal 2015;15:480-500.

Linden A. Challenges to validity in single-group interrupted time series analysis. Journal of Evaluation in Clinical Practice 2017;23:413-18.

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Investigators RT. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med 2014;370:2367-76.

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Figure Legends

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Figure 1: Trends of voiding cystourethrogram utilization rates among children 0 – 2 and 3 – 10 years of age. Abbreviations: VCUG, voiding cystourethrogram; NICE, National Institute of Clinical

*statistically significant, p < 0.05 Statistical test: single group interrupted time series analysis

Figure 2: Difference in rate of change after major guidelines.

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Excellence; AAP, American Academy of Pediatrics

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Abbreviations: VCUG, voiding cystourethrogram; NICE, National Institute of Clinical Excellence; AAP, American Academy of Pediatrics

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*statistically significant, p < 0.05

Statistical test: multiple group interrupted time series analysis

Figure 3: Incidence of vesicoureteral reflux.

Abbreviations: VUR, vesicoureteral reflux; NICE, National Institute of Clinical Excellence; AAP, American Academy of Pediatrics

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Statistical test: t-test

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*statistically significant, p < 0.05

Table Legends

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Table1: Demographical characteristics Abbreviations: SD, standard deviation; NICE, National Institute of Clinical Excellence; AAP, American Academy of Pediatrics

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Pre-NICE: 2001 to 2007 Q2; Pre-AAP: 2007 Q3 to 2011 Q2; Post-AAP: 2011 Q3 to 2015Q2

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Statistical test: t-test

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Gender FEMALE MALE UNKNOWN

Pre-AAP (N=14775)

Post-AAP (N=6084)

3.3 (2.7) 3.0 (0.0-10.0)

3.0 (2.7) 2.0 (0.0-10.0)

3.2 (2.7) 2.0 (0.0-10.0)

25597 (83.1%) 5184 (16.8%) 9 (0.0%)

12090 (81.8%) 2681 (18.1%) 4 (0.0%)

4716 (77.5%) 1336 (22.5%) 2 (0.0%)

p-value*

Total (N=51649)

<0.0001 3.2 (2.8) 3.0 (0.0-10.0)

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Age Mean (SD) Median Range

Pre-NICE (N=30790)

<0.0001

<0.0001

20900 (76.0%) 2758 (10.0%) 1295 (4.7%) 1016 (3.7%) 1541 (5.6%) 3280 (.%)

10306 (70.0%) 1921 (13.1%) 932 (6.3%) 900 (6.1%) 661 (4.5%) 55 (.%)

4341 (71.8%) 706 (11.7%) 345 (5.7%) 399 (6.6%) 253 (4.2%) 40 (.%)

Census level Division EAST NORTH CENTRAL EAST SOUTH CENTRAL MIDDLE ATLANTIC MOUNTAIN NEW ENGLAND PACIFIC SOUTH ATLANTIC WEST NORTH CENTRAL WEST SOUTH CENTRAL UNKNOWN

5412 (17.6%) 1635 (5.3%) 1745 (5.7%) 2899 (9.4%) 890 (2.9%) 1268 (4.1%) 7174 (23.3%) 4768 (15.5%) 4993 (16.2%) 6 (0.0%)

2047 (13.9%) 562 (3.8%) 906 (6.1%) 1626 (11.0%) 430 (2.9%) 992 (6.7%) 3872 (26.2%) 1656 (11.2%) 2681 (18.1%) 3 (0.0%)

904 (14.9%) 217 (3.6%) 365 (6.0%) 785 (12.9%) 192 (3.2%) 381 (6.3%) 1349 (22.2%) 800 (13.1%) 1083 (17.8%) 8 (0.1%)

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Race WHITE HISPANIC BLACK ASIAN UNKNOWN Missing

42403 (82.2%) 9201(17.8%) 15 (0.0%)

35547 (73.6%) 5385 (11.2%) 2572 (5.3%) 2315 (4.8%) 2455 (5.1%) 3375 (.%)

<0.0001 8363 (16.2%) 2414 (4.7%) 3016 (5.8%) 5310 (10.3%) 1512 (3.0%) 2641 (5.1%) 12395 (24.0%) 7224 (14.0%) 8757 (16.9%) 17 (0.0%)

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Institution of Clinical Excellence (NICE)

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American Academy of Pediatrics (AAP)

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Supplement Table 1: ICD-9–based definitions of demographic and clinical characteristics Definition

Urinary tract infection

599.0

Pyelonephritis

590.11, 590.80, 590.81

Vesicoureteral reflux

593.7x

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Covariate

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Table 2: ICD-9-based definitions of excluded diagnoses. Definition

Other specified cystic kidney disease

753.19

Other obstructive defects of renal pelvis and ureter

753.29

Posterior urethral valve

753.6

Other specified anomalies of bladder and urethra

753.8

Neurogenic bladder NOS

596.54

Atony of bladder

596.4

596.52

Paralysis of bladder

596.53

Detrusor sphincter dyssynergia Spina bifida

596.55 741.x

Prune Belly Syndrome Spinal Cord Injury

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Renal agenesis

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Congenital anomalies of genital organs

752.x

756.71 952.x 753.0

Congenital obstruction of ureteropelvic junction

753.21

Unspecified obstructive defect of renal pelvis and ureter

753.20

Other ureteric obstruction

593.4

Stricture or kinking of ureter

593.3

Other specified disorders of kidney and ureter

593.89

Congenital obstruction of ureterovesical junction

753.22

Other specified disorders of kidney

753.3

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Low bladder compliance

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Covariate

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592.1

Calculus of kidney

592.0

Urinary calculus, unspecified

592.9

Atresia and stenosis of large intestine, rectum, and anal canal

751.2

Epididymitis

604.90, 604.91, 604.99

Exstrophy of urinary bladder

753.5

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Calculus of ureter