2018 CONSENSUS UPDATES + RISKS/BENEFITS OF PPI USE

Transcription

1 2018 CONSENSUS UPDATES + RISKS/BENEFITS OF PPI USE IN INFANT GERD SWEDISH MEDICAL CENTER JONAH ESSERS, MD, MPH

2 OBJECTIVES Highlight the 2018 updates to infant GERD recommendations Provide an update on data involving long term risks of PPI therapy Put PPI therapy in infants in to context with known risks of PPI use

3 PEDIATRIC GERD DEFINITIONS Gastro-esophageal reflux (GER): passage of gastric contents into the esophagus +/- regurgitation +/- vomiting. Gastro-esophageal reflux disease (GERD): GER with troublesome symptoms and/or complications. New guidelines are mindful of these terms and are specific in recommendations surrounding GERD vs- GER. Rosen et al., JPGN , 2018

4 THE TROUBLE WITH INFANT GERD Defining troublesome is.er.troublesome Symptoms vary widely Many symptoms are not specific to GERD No gold standard tool exists for diagnosing reflux Diagnostics are often invasive Families are often quite concerned

5 2018 CONSENSUS ON INFANT GERD Thorough H&P sufficient for GER If there are warning signs, test/treat as this may be a GERD mimic If no warning signs: test/treat not warranted Infants with fussiness, crying, and back arching is challenging: If growth, feeding, and developmental milestones are normal, no rx not recommended Families may pressure to treat Rosen et al., JPGN , 2018

6 Weak recommendations GERD DIAGNOSTICS? Poor quality data No role for a 2-4 week PPI trial in making an infant GERD diagnosis 5 RCT s show lack of efficacy in improving symptoms No role for imaging in making an infant GERD diagnosis No role for ph testing in making an infant GERD diagnosis No role for EGD in making an infant GERD diagnosis Rosen et al., JPGN , 2018

7 Weak recommendations GERD THERAPY Poor quality data Thickened feeds slightly reduce symptoms supposedly Rice cereal--?arsenic Xantham Gum--NEC concern under 1 year of age Carob bean thickeners after 42 weeks gestation. Elimination of cow milk protein (i.e. a subset of GERD is allergy) Mom dairy free for 2-4 weeks Trial of extensively hydrolyzed formula Don t limit volumes but avoid overfeeding! Don t stop breast feeding! Rosen et al., JPGN , 2018

8 Strong recommendations GERD THERAPY Poor quality Data No PPI s or H2 blockers for crying, distress, or pain No PPI s or H2 blockers for visible reflux No Erythromycin, baclofen, or metoclopramide as first line GERD therapy Rosen et al., JPGN , 2018

9 Weak recommendations POSITION CHANGES Poor quality data Left lateral position Reduces reflux events on ph probe testing Due to risk of SIDS, supine positioning still recommended Elevation of the head of the bed risk of infant rolling to foot of bed and causing respiratory compromise Wedges? Data remains most null on role of wedges in improving outcomes associated with infant GERD Rosen et al., JPGN , 2018

10 Rosen et al., JPGN , 2018

11 GERD TESTING ARSENAL ph/impedan ce probe Upper GI Series Upper Endoscopy Catch reflux redhanded Assess medication efficacy Correlate a symptom with reflux (like cough or Sandifer) Check anatomy Web Ring/sling Stricture Hiatal hernia Diagnose Inflammation Eosinophilic esophagitis Erosive esophagitis Acid injury

12 PROTON PUMP INHIBITORS (PPI) Lansoprazole Omeprazole Esomeprazole Pantoprazole Rabeprazole Reduce gastric acid by irreversible binding to proton pumps in gastric parietal cells First approved in 1989 $11 billion in expenditures annually

13 FDA INDICATIONS FOR PPI USE Healing of erosive esophagitis Maintenance of healed erosive esophagitis Treatment of gastric and duodenal ulcers Treatment and prophylaxis for NSAID induced ulcers Treatment of Helicobacter pylori infection (in combination with Abx) Management of Zollinger-Ellison Syndrome

14 Pneumonia Mg Deficienc y B12 Deficiency Dementia Proposed Risks with PPI Use C. difficile SIBO Fractures Kidney Injury

15 Likely Causal HYPOMAGNESEMIA First reported in 2006 in NEJM Patients presented with carpo-pedal spasm PPI duration was at least one year Serum magnesium normalized upon cessation of PPI Meta-analysis on 9 studies and 109,798 patients: 43% increase in risk of hypomagnesemia This suggests causation FDA released safety warning in 2011: consider monitoring Mg Epstein M, McGrath S, Law F. N Engl J Med. 2006; 355(17): Cheungpasitporn W, et al. Ren Fail. 2015;37(7):

16 Likely Causal B12 DEFICIENCY 3.2% of adults may have B12 deficiency Gastric acid required for release of B12 from dietary proteins Case-control study evaluating risk factors for B12 deficiency 25,956 cases and 184,199 controls at Kaiser Permanente PPI treatment for 2+ years: 65% increased risk of B12 deficiency No official guidelines recommend B12 testing Evatt ML, et al. Public Health Nutr. 2010;13(1): Lam JR, et al. JAMA. 2013;310(22):

17 Likely causal CLOSTRIDIUM DIFFICILE Meta-analysis of 42 observational studies Incident CDI OR=1.74; ( ) Recurrent CDI OR=2.51; ( ) H2 blockers (eg. Ranitidine) had less overall risk of CDI than PPI Proposed mechanisms: Survival of C diff in alkaline stomach Microbiome changes after 4-8 weeks of PPI Increased SIBO may convert spores into toxin producing bacteria Studies plagued by heterogeneity, non-randomization, and varying PPI dose and duration Targownik LE, et al; CaMos Research Group. Am J Gastroenterol. 2012;107(9):

18 Association but unclear if causal SIBO (SMALL INTESTINAL BACTERIAL OVERGROWTH) Suppression of gastric acid may encourage SIBO Two ways to diagnose SIBO: Duodenal/jejunal aspirates (more sensitive/invasive) Glucose hydrogen breath analysis (less sensitive/non-invasive) Meta-analysis of 11 studies: increased risk of SIBO in PPI users OR 2.28 ( ) for combined methods 7.5 times greater risk of SIBO in studies using aspirates over studies using breath analysis Unclear clinical importance Lo WK, Chan WW. Clin Gastroenterol Hepatol. 2013;11(5):

19 Association but unclear if causal BONE FRACTURES Baseline risk of osteoporosis 40-50% in women 13-22% in men Observational studies show increased risk of fracture with PPI FDA released warning in 2010 Meta-analysis of 18 observational studies Fracture at any site: RR=1.33 ( ) Hip fracture: RR=1.26 ( ) Spine fracture: RR=1.58 ( ) Risk was significant in short term (< 1 year) and in long term use Johnell O, Kanis J. Osteoporos Int. 2005;16(suppl 2):S3-S7. Zhou B, Huang Y, Li H, Sun W, Liu J. Osteoporos Int. 2016;27(1):

20 ? BONE MINERAL DENSITY Proposed mechanism for fracture is that PPI s decrease calcium absorption and thus decrease BMD Placebo controlled, double blind, cross-over study Elderly post-menopausal women Decreased absorption of calcium carbonate after 1 week of omeprazole O Connell MB, et al. Am J Med. 2005;118(7):

21 Unlikely to be associated?osteoporosis No clear evidence that PPI use associated with osteoporosis Longitudinal population-based study of PPI users and BMD at 0,5,10 years 8340 enrollees 4512 had 10 year BMD analysis At baseline, PPI users had lower hip and femoral head BMD In continuous PPI users, there was no change in rate of BMD loss at 5 and 10 years compared to baseline Short term and long term PPI use associated with fractures Suggests PPI-induced fracture not due to osteoporosis Targownik LE, et al; CaMos Research Group. Am J Gastroenterol. 2012;107(9):

22 Association but unclear if causal DEMENTIA Two prospective studies in 75+ years old, with no baseline dementia 3076 patients: 38% increase risk of dementia and 42% increase risk of Alzheimer s 37,679 patients: 44% increased risk of dementia Contrasts with two large national cohorts NHS II with 13,864 middle aged women: no clear association Finnish registry with 70,718 patients: no clear association Proposed Mechasisms: PPI increases b-amyloid synthesis and decreased b-amyloid degradation B12 deficiency Haenisch B, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(5): Gomm W, et al. JAMA Neurol. 2016;73(4): Lochhead P. Gastroenterology. 2017;153(4): e4. Taipale H, et al. Am J Gastroenterol.

23 Association but unclear if causal KIDNEY DISEASE Prospective atherosclerosis study, 10,482 participants Median follow up 13.9 years 50% increased risk of CKD in PPI users vs- non-users 64% increased risk of AKI Results replicated in a cohort of 248,751 patients 17% increased risk of CKD in PPI users Higher rate if PPI was twice daily over once daily Confounding by NSAID use VA data: 173,321 new PPI users and 20,270 new H2 blocker users 28% increased risk of CKD in PPI vs- H2 blocker users Doubling of creatinine, lowering of GFR, higher ESRD Lazarus B, et al. JAMA Intern Med. 2016; 176(2): Xie Y, et al. J Am Soc Nephrol. 2016;27(10): Antoniou T, et al. CMAJ Open. 2015;3(2):E166-E171.

24 No clear concensus A TO-DO LIST FOR PPI USE Old Age Fracture risk B12 CBC q2 years B12 q5 years Mg Check Mg in symptomatic patients C diff Cautious use of antibiotics BMD screen per national guideline Fracture risk RDA for Ca/Vit D Today

25 My personal HIERARCHY OF PPI THOUGHTS Keep reading We are stewards of our future elderly For peds, no major action items Periodic check of basic labs What we don t yet know is scary! (e.g. microbiome changes) Risk/benefit analysis often falls in favor of PPI use

26 SUMMARY ON INFANT GERD CONSENSUS STATEMENT In general, testing and treating is discouraged for most straight forward GER Any warning signs should prompt a test/treat strategy We all struggle with infants with perceived quality of life issues around reflux. Where to place medication remains controversial Avoid overfeeding Thicken feeds Trial off of cow milk protein Consider Medication

27 SUMMARY ON PPI THERAPY Mounting evidence is mostly observational and little of it proves causality Enough unknown information to create a reasonable amount of anxiety from providers and parents Take a careful risk-benefit assessment Attempt to taper or discontinue often