1. VUR, UTI, and Antibiotic Prophylaxis How to Use an Article About Therapy or Prevention Journal Club Amy K Evans PGY2 August 15, 2006

2. The Case Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis.

3. The Case Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is admitted to Wd51 for 48hrs of IV abx, then, afebrile, discharged to complete po course. Kali is admitted to Wd51 for 48hrs of IV abx, then, afebrile, discharged to complete po course.

4. The Case Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is admitted to Wd51 for 48hrs of IV abx, then, afebrile, discharged to complete po course. Kali is admitted to Wd51 for 48hrs of IV abx, then, afebrile, discharged to complete po course. She undergoes renal US and VCUG 3 weeks later, which reveal grade II VUR on the left. She undergoes renal US and VCUG 3 weeks later, which reveal grade II VUR on the left.

5. The Question Should we treat her prophylactically? Should we treat her prophylactically? Short-term: Short-term: Will this decrease recurrent infections? Will this decrease recurrent infections? Long-term: Long-term: Will this decrease renal scarring? Will this decrease renal scarring? Why else would it matter? Why else would it matter?

6. Background Vesicoureteral Reflux (VUR) Vesicoureteral Reflux (VUR) Primary – congenital incompetence of VU valve (shortened submucosal tunnel) Primary – congenital incompetence of VU valve (shortened submucosal tunnel) Secondary – multiple anatomic abnormalities Secondary – multiple anatomic abnormalities

7. Background Incidence 1-10% Incidence 1-10% Siblings 30-45% (3/4 asymptomatic) Siblings 30-45% (3/4 asymptomatic) Diagnosed via VCUG Diagnosed via VCUG UTI workup – 40% (girls); 70% (infants <1yo) UTI workup – 40% (girls); 70% (infants <1yo) Antenatal hydronephrosis – 9% (boys) Antenatal hydronephrosis – 9% (boys) Why worry? Why worry? VUR  pyelonephritis  renal scarring  VUR  pyelonephritis  renal scarring  HTN, renal insufficiency, ESRD, pre-eclampsia HTN, renal insufficiency, ESRD, pre-eclampsia

8. Background Natural hx of VUR: spontaneous resolution Natural hx of VUR: spontaneous resolution UTI  VUR? ■ VUR  UTI? UTI  VUR? ■ VUR  UTI? VUR  Pyelo?■ VUR  Scarring? VUR  Pyelo?■ VUR  Scarring?

9. Current Treatment Recs Workup: Workup: Febrile UTI (any age) Febrile UTI (any age) UTI <5yo UTI <5yo UTI x2 in school-age girls UTI x2 in school-age girls UTI in any boy UTI in any boy To treat or not to treat? To treat or not to treat? Imaging: Renal US 40% sensitive (VUR) VCUG Diagnostic! DMSA

10. AUA Treatment Guidelines Grade Age (y) ScarringTreatmentFollow-Up I-IIAny+/- Abx prophy No consensus III-IV0-5+/- Abx prophy Surgery III-IV6-10+/- Unilat: abx Bilat: surgery Surgery V<1+/- Abx prophy Surgery V1-5- Unilat: abx Bilat: surgery Surgery V1-5+Surgery V6-10+/-Surgery

11. Current Treatment Recs AUA Pediatric VUR Guidelines Panel (1997) AUA Pediatric VUR Guidelines Panel (1997) “The panel recommendations to offer continuous abx prophylaxis…are based on limited scientific evidence. To our knowledge controlled studies comparing the efficacy of continuous prophylaxis and intermittent therapy on health outcomes…have not been performed.” “The panel recommendations to offer continuous abx prophylaxis…are based on limited scientific evidence. To our knowledge controlled studies comparing the efficacy of continuous prophylaxis and intermittent therapy on health outcomes…have not been performed.” No controlled studies? No controlled studies? Then what are we basing treatment on? Then what are we basing treatment on?

12. The State of the Art Williams et.al. (2001) Williams et.al. (2001) Systematic review of RCTs on UTI/abx prophy Systematic review of RCTs on UTI/abx prophy Five trials, 1968-1978 Five trials, 1968-1978 Best 2: 71 patients total, normal anatomy, 92% girls Best 2: 71 patients total, normal anatomy, 92% girls Garin et.al. (1998) Garin et.al. (1998) UTI  VUR? no■ VUR  Pyelo? UTI  VUR? no■ VUR  Pyelo? VUR  UTI? no■ Degree VUR  Scars? VUR  UTI? no■ Degree VUR  Scars? VUR  Scarring? no VUR  Scarring? no

13. We Need A Study That… Will help us decide whether or not to prophylax this patient Will help us decide whether or not to prophylax this patient Includes patients with symptomatic VUR Includes patients with symptomatic VUR Compares antibiotic prophylaxis to a control Compares antibiotic prophylaxis to a control Looks at clinically important outcomes Looks at clinically important outcomes

14. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Pediatrics 2006;117:626-632.

15. Study Questions Does VUR correlate with  UTI/renal scarring? Does VUR correlate with  UTI/renal scarring? Does antibiotic prophylaxis correlate with  UTI/renal scarring? Does antibiotic prophylaxis correlate with  UTI/renal scarring?

16. Study Design Randomized, controlled, multicenter trial Randomized, controlled, multicenter trial Inclusion: Inclusion: 3mo-18yo 3mo-18yo Acute pyelonephritis Acute pyelonephritis Exclusion: Exclusion: Grade IV-V VUR Grade IV-V VUR Anatomic abnormalities Anatomic abnormalities Pregnancy Pregnancy

17. Study Design Met inclusion criteria  VCUG Met inclusion criteria  VCUG Pyelo treated: IV abx  po for 14-day course Pyelo treated: IV abx  po for 14-day course Abx: TMP/SMX or nitrofurantoin for 1 year Abx: TMP/SMX or nitrofurantoin for 1 year VURNo VUR Abx No Abx

18. Follow Up At entry: UA/UCx, DMSA, VCUG, Renal US At entry: UA/UCx, DMSA, VCUG, Renal US At Q3mo clinic visit: UA/UCx At Q3mo clinic visit: UA/UCx At 6mo: DMSA At 6mo: DMSA At 12mo: VCUG, Renal US At 12mo: VCUG, Renal US Endpoints: Endpoints: Recurrent UTI Recurrent UTI Renal scarring Renal scarring

19. Study Results

20. Analysis of Results Fisher’s Exact Test Fisher’s Exact Test 2x2 comparison tables 2x2 comparison tables Control vs. variable Control vs. variable Smaller sample size Smaller sample size Gives p value Gives p value Does not give CI Does not give CI Goal: p<.05! Goal: p<.05! http://www.childrensmercy.org/stats/ask/fishers.asp

21. Study Results Recurrence of UTIs Recurrence of UTIs Timing Timing Type Type Recurrent Pyelonephritis & Antibiotics Recurrent Pyelonephritis & Antibiotics Recurrent Pyelonephritis & VUR Degree Recurrent Pyelonephritis & VUR Degree Renal Scarring Renal Scarring VUR VUR Antibiotics Antibiotics

22. Study Results Recurrence of UTI Recurrence of UTI Overall – 20.1% Overall – 20.1% VUR not significant VUR not significant No abx (p=.9999) No abx (p=.9999) VUR – 22.4% VUR – 22.4% No VUR – 23.3% No VUR – 23.3% Abx (p=0.633) Abx (p=0.633) VUR – 23.6% VUR – 23.6% No VUR – 8.8% No VUR – 8.8% Type of Recurrence Cystitis (no p value) VUR – 8.6% No VUR – 13.3% Pyelonephritis (p=.3781) VUR – 7.1% No VUR – 3.8%

23. Study Results Recurrent Pyelo and Antibiotics Recurrent Pyelo and Antibiotics No benefit of abx (p=.0291) No benefit of abx (p=.0291) 7:1 abx:none 7:1 abx:none Recurrent Pyelo and VUR Degree Recurrent Pyelo and VUR Degree 6/8 Grade III (cystitis: 46%) 6/8 Grade III (cystitis: 46%) 2/8 Grade II (cystitis: 40%) 2/8 Grade II (cystitis: 40%) 4/4 pts without VUR 4/4 pts without VUR

24. Study Results Renal Scarring Renal Scarring No evidence VUR  increased scarring (p=.9999) No evidence VUR  increased scarring (p=.9999) VUR (6.2%) = No VUR (5.7%) VUR (6.2%) = No VUR (5.7%) Abx (7.0%) = No Abx (5.1%) Abx (7.0%) = No Abx (5.1%) Grade I VUR – 5.3% with scars Grade I VUR – 5.3% with scars Grade II VUR – 5.2% Grade II VUR – 5.2% Grade III VUR – 13.5% Grade III VUR – 13.5%

25. Study Conclusions Mild/moderate VUR not associated with  UTI, pyelonephritis, or scarring Mild/moderate VUR not associated with  UTI, pyelonephritis, or scarring Antibiotic prophylaxis not associated with  UTI, pyeloneprhitis, or scarring Antibiotic prophylaxis not associated with  UTI, pyeloneprhitis, or scarring

26. Critically Evaluating… (JAMA Users’ Guide) Are the results valid? Are the results valid? What were the results? What were the results? Will the results help me to take care of my patient? Will the results help me to take care of my patient?

27. Are the results valid? Primary Guides Was the assignment of patients to treatment randomized? YES. Was the assignment of patients to treatment randomized? YES. Were all who entered the study accounted for? Were all who entered the study accounted for? Was follow-up complete? Was follow-up complete? NO. Enrolled 236, lost 18 NO. Enrolled 236, lost 18 Lost from what groups? Lost from what groups? Would this change results? Would this change results? Were patients analyzed in the groups assigned to? Were patients analyzed in the groups assigned to? NO. Exclusion of noncompliants NO. Exclusion of noncompliants

28. Are the results valid? Secondary Guides Were pts, clinicians, & study personnel blinded? Were pts, clinicians, & study personnel blinded? NO (no blinding to +/- VUR, abx; no placebos) NO (no blinding to +/- VUR, abx; no placebos) Were groups similar at start, & treated equally? Were groups similar at start, & treated equally? YES (age, gender, degree of reflux) YES (age, gender, degree of reflux)

29. What were the results? How large was the treatment effect? How large was the treatment effect? ARR – risk difference of variable vs. control ARR – risk difference of variable vs. control RRR – variable reduced risk by Z% relative to that occurring in control patients; bigger = better! RRR – variable reduced risk by Z% relative to that occurring in control patients; bigger = better! For example, in presence of VUR: For example, in presence of VUR: 23.6% of those on abx developed UTI (X%) 23.6% of those on abx developed UTI (X%) 22.4% without abx developed UTI (Y%) 22.4% without abx developed UTI (Y%) ARR = X-Y =.236-.224 =.012 ARR = X-Y =.236-.224 =.012 RRR = (1-Y/X)x100% = (1-.224/.236)x100% = 5.1% RRR = (1-Y/X)x100% = (1-.224/.236)x100% = 5.1%

30. What were the results? How large was the treatment effect? How large was the treatment effect? ARR/RRR not reported! ARR/RRR not reported! How precise was the estimated treatment effect? How precise was the estimated treatment effect? Confidence Intervals (CIs) not reported! Confidence Intervals (CIs) not reported! 95% CI: 95% CI: Range that includes the true RRR 95% of time Range that includes the true RRR 95% of time Positive? Negative? Zero? Positive? Negative? Zero? Statistically vs. clinically significant results Statistically vs. clinically significant results

31. What were the results? POWER! POWER! Ability of a study to detect a true difference Ability of a study to detect a true difference Directly related to sample size Directly related to sample size 1-β (β = type II error) 1-β (β = type II error) Study powered to detect a clinically significant difference of 20% (power 80%), 95% CI Study powered to detect a clinically significant difference of 20% (power 80%), 95% CI Need 60/group = 240 subjects Need 60/group = 240 subjects Enrolled 236, Completed 218 Enrolled 236, Completed 218 “POWER : research design :: SENSITIVITY : diagnostic test”

32. Will the results help me take care of my patient? Can the results be applied? YES. Can the results be applied? YES. Could Kali have been enrolled? Could Kali have been enrolled? All clinically important outcomes considered? YES. All clinically important outcomes considered? YES. Substitute endpoints vs. “POEMS” Substitute endpoints vs. “POEMS” Adverse effects on other outcomes Adverse effects on other outcomes Are likely benefits worth potential harms/risks? Are likely benefits worth potential harms/risks? NNT = 1/ARR NNT = 1/ARR Consider baseline risk without intervention Consider baseline risk without intervention

33. Criticisms: Study Population What about <3mo? What about <3mo? Present earlier = Higher-grade reflux? Already abx? Present earlier = Higher-grade reflux? Already abx? Included in study? Included in study? Exclusion of noncompliants? Exclusion of noncompliants? Exclusion of pyelonephritis x2? Exclusion of pyelonephritis x2? Initial presentation with cystitis? Initial presentation with cystitis? Febrile UTI without DMSA changes? Febrile UTI without DMSA changes? How many therefore excluded? How many therefore excluded?

34. Criticisms: Study Design DMSA as inclusion criteria (multicenter)? DMSA as inclusion criteria (multicenter)? Account for 18 lost before study end? Account for 18 lost before study end? Unknown prognostic factors Unknown prognostic factors Recalculate results assuming they did well/poorly Recalculate results assuming they did well/poorly Blinding of patients/personnel? Blinding of patients/personnel? Placebo Placebo Diagnosis Diagnosis Larger sample size? Larger sample size?

35. Criticisms: Data Analysis Reporting of CIs, ARR/RRR? Reporting of CIs, ARR/RRR? Magnitude/precision of treatment effect Magnitude/precision of treatment effect Rule in/out effect different from Ho Rule in/out effect different from Ho Data crunching using Chi-Square? Data crunching using Chi-Square? Different data combinations? Different data combinations? Did not achieve POWER Did not achieve POWER

36. Further Questions… UTI prophylaxis vs. intermittent therapy? UTI prophylaxis vs. intermittent therapy? And risk of renal scarring And risk of renal scarring Over time, given resolution VUR Over time, given resolution VUR Larger sample size Larger sample size VUR in context of abnormal anatomy? VUR in context of abnormal anatomy? Mechanism of scarring in pyelonephritis? Mechanism of scarring in pyelonephritis? What else? What else?

37. Back to our patient… What would you do? What would you do? Call Dr.Cartwright and Dr.Lechner and get those patients enrolled! Call Dr.Cartwright and Dr.Lechner and get those patients enrolled!

38. References 1. Atala A, Keating MA. Vesicoureteral reflux and megaureter. In Campbell’s Urology Vol 2, 7 th ed. Philadelphia: WB Saunders 1988. 2. Behrman Re, Kliegman RB, Jenson HB. Nelson Textbook of Pediatrics, 17 th ed. Philadelphia: Saunders, 2004. 3. Biggi A et.al. Prognostic value of the acute DMSA scan in children with first urinary tract infection. Pediatr Nephrol 2001;16:800-804. 4. Bjorgvinsson E, Majd M, Eggli KD. Diagnosis of acute pyelonephritis in children: comparison of sonography and 99mTc-DMSA scintigraphy. Am J Roentgenol 1991;157(3):539-543. 5. Dawson B, Trapp RG. Basic and clinical biostatistics, 3 rd ed. New York: Lange Medical Books 2001. 6. DeSadeeler C et.al. A multicenter trial on interobserver reproducibility in reporting on 99mTc-DMSA planer scintigraphy: a Belgian survey. J Nucl Med 2000;41(1):23-26. 7. Elder JS 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. 8. Garin EH et.al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006;117:626-632. 9. Garin EH, Campos A, Homsy Y. Primary vesicoureteral reflux: review of current concepts. Pediatr Nephrol 1998;12:249-256.

39. References 10. Gordon I et.al. Primary vesicoureteral reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta- analysis. J Am Soc Nephrol 2003;14:739-744. 11. Guyatt GH et.al. How to use an article about therapy or prevention. A. Are the results of the study valid? JAMA 1993;270:2598-2601. 12. Guyatt GH et.al. How to use an article about therapy or prevention. B. What were the results and will they help me in caring for my patients? JAMA 1994;271:59-63. 13. Lee RS et.al. Antenatal hydronephrosis as a predictor of postnatal outcome: a meta- analysis. Pediatrics 2006;118(2):586-593. 14. Penido Silva JM et.al. Clinical course of prenatally detected primary vesicoureteral reflux. Pediatr Nephrol 2006;21:86-91. 15. Schwab CW et.al. Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol 2002;168:2594-2599. 16. Williams G et.al. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr 2001;138(6):868-874. 17. Yu RN, Roth DR. Treatment of vesicoureteral reflux using endoscopic injection of nonanimal stabilized hyaluronic acid/dextranomer gel: initial experience in pediatric patients by a single surgeon. Pediatrics 2006;118(2):698-703.