2018 CONSENSUS UPDATES + RISKS/BENEFITS OF PPI USE/media/Images/Swedish/CME1... · 2019-01-21 · 2018 CONSENSUS UPDATES + RISKS/BENEFITS OF PPI USE . SWEDISH MEDICAL CENTER . JONAH

I N I N F A N T G E R D

2018 CONSENSUS UPDATES + RISKS/BENEFITS OF PPI USE

SWEDISH MEDICAL CENTER JONAH ESSERS, MD, MPH

OBJECTIVES

ØHighlight the 2018 updates to infant GERD recommendations

ØProvide an update on data involving long term risks of PPI therapy

Ø Put PPI therapy in infants in to context with known risks of PPI use

PEDIATRIC GERD DEFINITIONS

ØGastro-esophageal reflux (GER): passage of gastric contents into the esophagus Ø+/- regurgitation

Ø+/- vomiting.

ØGastro-esophageal reflux disease (GERD): GER with troublesome symptoms and/or complications.

ØNew guidelines are mindful of these terms and are specific in recommendations surrounding GERD –vs- GER.

Rosen et al., JPGN. 516-554, 2018

THE TROUBLE WITH INFANT GERD

ØDefining troublesome is….er….troublesome

ØSymptoms vary widely

ØMany symptoms are not specific to GERD

ØNo gold standard tool exists for diagnosing reflux

ØDiagnostics are often invasive

ØFamilies are often quite concerned

2018 CONSENSUS ON INFANT GERD

ØThorough H&P sufficient for GER

Ø If there are warning signs, test/treat as this may be a GERD mimic

Ø If no warning signs: test/treat not warranted

Ø Infants with fussiness, crying, and back arching is challenging: Ø If growth, feeding, and

developmental milestones are normal, no rx not recommended

Ø Families may pressure to “treat”

Rosen et al., JPGN. 516-554, 2018

GERD DIAGNOSTICS?

ØNo role for a 2-4 week “PPI trial” in making an infant GERD diagnosis Ø5 RCT’s show lack of efficacy in improving symptoms

ØNo role for imaging in making an infant GERD diagnosis

ØNo role for pH testing in making an infant GERD diagnosis

ØNo role for EGD in making an infant GERD diagnosis

Weak recommendations

Poor quality data

Rosen et al., JPGN. 516-554, 2018

GERD THERAPY

ØThickened feeds slightly reduce symptoms…supposedly ØRice cereal--?arsenic

ØXantham Gum--NEC concern under 1 year of age ØCarob bean thickeners—after 42 weeks gestation.

ØElimination of cow milk protein (i.e. a subset of GERD is allergy) ØMom dairy free for 2-4 weeks

ØTrial of extensively hydrolyzed formula

ØDon’t limit volumes but avoid overfeeding!

ØDon’t stop breast feeding!

Weak recommendations

Poor quality data

Rosen et al., JPGN. 516-554, 2018

GERD THERAPY

ØNo PPI’s or H2 blockers for crying, distress, or “pain”

ØNo PPI’s or H2 blockers for visible reflux

ØNo Erythromycin, baclofen, or metoclopramide as first line GERD therapy

Strong recommendations

Poor quality Data

Rosen et al., JPGN. 516-554, 2018

POSITION CHANGES

ØLeft lateral position ØReduces reflux events on pH probe testing

ØDue to risk of SIDS, supine positioning still recommended

ØElevation of the head of the bed Ørisk of infant rolling to foot of bed and causing respiratory compromise

ØWedges? Data remains most null on role of wedges in improving outcomes associated with infant GERD

Weak recommendations

Poor quality data

Rosen et al., JPGN. 516-554, 2018

Rosen et al., JPGN. 516-554, 2018

GERD TESTING ARSENAL

Catch reflux “red-handed” • 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

Upper Endoscopy

pH/impedance probe

Upper GI Series

PROTON PUMP INHIBITORS (PPI)

• Lansoprazole • Omeprazole • Esomeprazole • Pantoprazole

• Rabeprazole

Ø Reduce gastric acid by irreversible binding to proton pumps in gastric parietal cells

Ø First approved in 1989

Ø $11 billion in expenditures annually

FDA INDICATIONS FOR PPI USE

ØHealing of erosive esophagitis

ØMaintenance of healed erosive esophagitis

ØTreatment of gastric and duodenal ulcers

ØTreatment and prophylaxis for NSAID induced ulcers

ØTreatment of Helicobacter pylori infection (in combination with Abx)

ØManagement of Zollinger-Ellison Syndrome

Proposed Risks with

PPI Use

Mg Deficienc

y

B12 Deficiency

C. difficile

Kidney Injury

Fractures

SIBO

Dementia

Pneumonia

HYPOMAGNESEMIA

ØFirst reported in 2006 in NEJM

ØPatients presented with carpo-pedal spasm

ØPPI duration was at least one year

ØSerum magnesium normalized upon cessation of PPI

ØMeta-analysis on 9 studies and 109,798 patients: Ø43% increase in risk of hypomagnesemia

ØThis suggests causation

ØFDA released safety warning in 2011: “consider monitoring Mg”

Epstein M, McGrath S, Law F. N Engl J Med. 2006; 355(17):1834-1836. Cheungpasitporn W, et al. Ren Fail. 2015;37(7):1237-1241

Likely Causal

B12 DEFICIENCY

Ø3.2% of adults may have B12 deficiency

ØGastric acid required for release of B12 from dietary proteins

ØCase-control study evaluating risk factors for B12 deficiency Ø25,956 cases and 184,199 controls at Kaiser Permanente

ØPPI treatment for 2+ years: 65% increased risk of B12 deficiency

ØNo official guidelines recommend B12 testing

Evatt ML, et al. Public Health Nutr. 2010;13(1):25-31. Lam JR, et al. JAMA. 2013;310(22):2435-2442.

Likely Causal

CLOSTRIDIUM DIFFICILE

ØMeta-analysis of 42 observational studies Ø Incident CDI OR=1.74; (1.47-2.85)

ØRecurrent CDI OR=2.51; (1.16-5.44)

ØH2 blockers (eg. Ranitidine) had less overall risk of CDI than PPI

ØProposed mechanisms: Ø Survival of C diff in alkaline stomach

ØMicrobiome changes after 4-8 weeks of PPI

Ø Increased SIBO may convert spores into toxin producing bacteria

ØStudies plagued by heterogeneity, non-randomization, and varying PPI dose and duration

Targownik LE, et al; CaMos Research Group. Am J Gastroenterol. 2012;107(9):1361-1369.

Likely causal

SIBO (SMALL INTESTINAL BACTERIAL OVERGROWTH)

ØSuppression of gastric acid may encourage SIBO

ØTwo ways to diagnose SIBO: ØDuodenal/jejunal aspirates (more sensitive/invasive)

ØGlucose hydrogen breath analysis (less sensitive/non-invasive)

ØMeta-analysis of 11 studies: increased risk of SIBO in PPI users ØOR 2.28 (1.24-4.21) for combined methods

Ø7.5 times greater risk of SIBO in studies using aspirates over studies using breath analysis

ØUnclear clinical importance

Lo WK, Chan WW. Clin Gastroenterol Hepatol. 2013;11(5):483-490

Association but unclear if

causal

BONE FRACTURES

ØBaseline risk of osteoporosis Ø 40-50% in women

Ø 13-22% in men

ØObservational studies show increased risk of fracture with PPI

ØFDA released warning in 2010

ØMeta-analysis of 18 observational studies Ø Fracture at any site: RR=1.33 (1.15-1.54)

ØHip fracture: RR=1.26 (1.16-1.36)

Ø Spine fracture: RR=1.58 (1.38-1.82)

ØRisk 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):339-347.

Association but unclear if

causal

? BONE MINERAL DENSITY

ØProposed mechanism for fracture is that PPI’s decrease calcium absorption and thus decrease BMD

ØPlacebo controlled, double blind, cross-over study ØElderly post-menopausal women

ØDecreased absorption of calcium carbonate after 1 week of omeprazole

O’Connell MB, et al. Am J Med. 2005;118(7):778-781.

?OSTEOPOROSIS

ØNo clear evidence that PPI use associated with osteoporosis

ØLongitudinal population-based study of PPI users and BMD at 0,5,10 years Ø8340 enrolleesà4512 had 10 year BMD analysis

ØAt baseline, PPI users had lower hip and femoral head BMD

Ø In continuous PPI users, there was no change in rate of BMD loss at 5 and 10 years compared to baseline

ØShort term and long term PPI use associated with fractures

Ø Suggests PPI-induced fracture not due to osteoporosis

Targownik LE, et al; CaMos Research Group. Am J Gastroenterol. 2012;107(9):1361-1369.

Unlikely to be associated

DEMENTIA

ØTwo prospective studies in 75+ years old, with no baseline dementia Ø3076 patients: 38% increase risk of dementia and 42% increase risk of

Alzheimer’s

Ø37,679 patients: 44% increased risk of dementia

ØContrasts with two large national cohorts ØNHS II with 13,864 middle aged women: no clear association ØFinnish registry with 70,718 patients: no clear association

ØProposed Mechasisms: ØPPI increases b-amyloid synthesis and decreased b-amyloid degradation ØB12 deficiency

Haenisch B, et al. Eur Arch Psychiatry Clin Neurosci. 2015;265(5):419-428. Gomm W, et al. JAMA Neurol. 2016;73(4):410-416. Lochhead P. Gastroenterology. 2017;153(4):971-979.e4. Taipale H, et al. Am J Gastroenterol. https://doi.org/10.1038/ajg.2017.196.

Association but unclear if

causal

KIDNEY DISEASE

ØProspective atherosclerosis study, 10,482 participants ØMedian follow up 13.9 years Ø 50% increased risk of CKD in PPI users –vs- non-users Ø 64% increased risk of AKI

ØResults replicated in a cohort of 248,751 patients Ø 17% increased risk of CKD in PPI users ØHigher rate if PPI was twice daily over once daily ØConfounding by NSAID use

ØVA data: 173,321 new PPI users and 20,270 new H2 blocker users Ø 28% increased risk of CKD in PPI –vs- H2 blocker users ØDoubling of creatinine, lowering of GFR, higher ESRD

Lazarus B, et al. JAMA Intern Med. 2016; 176(2):238-246. Xie Y, et al. J Am Soc Nephrol. 2016;27(10):3153-3163. Antoniou T, et al. CMAJ Open. 2015;3(2):E166-E171.

Association but unclear if

causal

A TO-DO LIST FOR PPI USE

Fracture risk RDA for Ca/Vit D

B12 CBC q2 years B12 q5 years

Mg Check Mg in symptomatic patients

C diff Cautious use of antibiotics

Fracture risk BMD screen per national guideline

No clear concensus

Today…

Old Age

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

My personal

SUMMARY ON INFANT GERD CONSENSUS STATEMENT

ØIn general, testing and treating is discouraged for most straight forward GER

ØAny warning signs should prompt a test/treat strategy

ØWe all struggle with infants with perceived quality of life issues around reflux. Where to place medication remains controversial ØAvoid overfeeding

ØThicken feeds

ØTrial off of cow milk protein

Consider Medication

SUMMARY ON PPI THERAPY

ØMounting evidence is mostly observational and little of it proves causality

ØEnough unknown information to create a reasonable amount of anxiety from providers and parents

ØTake a careful risk-benefit assessment

ØAttempt to taper or discontinue often