failure of ppi therapy -...

Joel E. Richter, MD, MACG

Intractable GERD: How to

ACG/FGS Annual Spring Symposium

Intractable GERD: How to Diagnose and Manage in 2014

Joel E Richter, MD, FACP, MACGHugh Culverhouse Chair and Director

Division of Digestive Diseases and NutritionDivision of Digestive Diseases and NutritionJoy McCann Culverhouse Center for Swallowing

DisordersUniversity of South Florida

Tampa, Florida

Failure of PPI Therapy• 10 - 40% of GERD patients fail to respond symptomatically

to standard once daily dose of PPIsFass R. Aliment Pharmacol Ther 2005

• Over 7 years (1997-2004), Manitoba province had 50%increase in use of BID PPIs (9.7% to 15.2%)Targownik LE. Am J Gastroenterol 2007Targownik LE. Am J Gastroenterol 2007

• Only 58% of GERD patients receiving PPIs report a highlevel of satisfaction with their therapyBytzer P. Clinical Gastroenterol and Hepatol 2009

ACG/FGS Spring Symposium - Bonita Springs, FL Copyright 2014 American College of Gastroenterology

1


Is There a Clinical or pH Profile for PPI Non-Responders?

• 100 patient: 43 responders 57 non-responders100 patient: 43 responders, 57 non responders• Clinical predictors:

BMI<25 kg/m2 Normal endoscopyIBS or functional dyspepsia

• No 24 hr pH-impedance parameters off PPIs• No 24 hr pH-impedance parameters off PPIswere predictive of response to PPIs

Zerbid F et al. Gut 2012

Failure to Respond to Once a Day PPI

• What to do next??• What to do next??Check complianceDose appropriatelySwitch PPIIncrease to BID PPI (up to 25% improve)Increase to BID PPI (up to 25% improve)


2


Sub-Optimal Proton Pump Inhibitor Dosing

100 ptsReferred by

PCPs46% dosedoptimally

Gunaratnam NT, et al. Alimentary Pharmacol Ther 2006

Failure to Respond to Once a Day PPI

• What to do next??• What to do next??Check complianceDose appropriatelySwitch PPIIncrease to BID PPI (up to 25% improve)Increase to BID PPI (up to 25% improve)


3


Failure to Respond to Once Daily PPIs:Switch PPI or Double Dose?

• Multicenter randomized double blind, double dummy trial• 328 pts with persistent heartburn on lansoprazole 30 mg• Randomly assigned to esomeprazole 40 mg

lansoprazole 30 mg BID• Both equally effective for:

- heartburn free days: 55% eso vs 58% lansoprazole- symptom score improvement for heartburn acidsymptom score improvement for heartburn, acid

regurgitation and epigastric pain-rescue antacid use

Fass R et al Clin Gastroenterol and Hepatology 2006

Persistent Heartburn Symptoms

Switch or Double Dose PPIs?None Mild Moderate Severe

100

Patie

nts (

%) 70

605040302010

8090

Lansoprazole30 mg twice daily

(n=44)

Esomeprazole40 mg once daily

(n=138)

Lansoprazole30 mg twice daily

(n=144)

Esomeprazole40 mg once daily

(n=138)

Week 4P=.25

Week 8P=.35

100

Fass R, et al. Clin Gastroenterol Hepatol. 2006;4:50-56.


4


GERD SymptomsPresence of esophagitis is unknown

Initial Treatment and Diagnostic Approach

Single dose PPI

Failure to improve

• Dose appropriately• Switch to newer PPI• BID PPI

Failure to improve –Refractory GERD or

Refractory Symptoms?

UGI Findings in Refractory GERD

PPI failures No TreatmentN=105 N=91

N l 54% 41%• Normal 54% p=.04 41%• Esophagitis 7% p<.001 31%

LA A/B 7% 29%LA C/D 0% 2%

• Barretts 4% 3%• Eosinophilic E 1% 0%• Ulcer Disease 1% 4%• Cancer 0% 1%

Poh CH et al GIE 2010


5


Failure to improve –Refractory GERD


Upper Endoscopy

Esophagitis—10% Non-esophagitis—90%

1. Pill esophagitis

2. Skin disease with esophagitisp g

3. Hypersecretor – ZE syndrome

4. CYP2C19 Genotype differences

5. Eosinophilic esophagitis

Fosamax Pill Esophagitis


6


PILL INDUCED ESOPHAGEAL INJURY

• 92 patients in 5 years—6% EGDs59 women, mean age 59, 25-87

• Common symptoms:odynophagia 75% chest pain 60% heartburn 55%vomiting 58% dysphagia 33% hematemesis 15%

• Causative pills:NSAIDs/ASA 41% tetracyclines 22%KCL tablets 10% alendronates 9%Other 16%--ascorbic acid, quinidine, antibiotics

S Abid et al Endscopy 2005

Lichen planus


7


Eosinophilic EsophagitisDemographics and Presenting Symptoms

• Presenting symptoms:• Presenting symptoms:Dysphagia: >90% Food impaction: 50%Heartburn: 33% Chest pain/ vomiting: 20%Most carry a diagnosis of GERD

Potter JW GIE 2004, Desai TK GIE 2005, Remedios M GIE 2005


8


Prevalence of Eosinophilic Esophagitis in Patients with Dysphagia

A Prospective Study

• 376 patients with dysphagia undergoing endoscopy

• Findings:Total # Biopsied #EoE(%)

Normal 180 102 10(10%)Reflux esophagitis 84 48 7(14%)Schatzki ring 28 18 1( 5%)Stricture 17 8 4(50%)Suggestive EoE 21 21 8(38%)Other* 46 30 3(10%)

*achalasia, Barretts, ulcer, cancer

Prasad G Am J Gastro 2007

Overall rate: 14.5%


Upper Endoscopy



pp py


1. Pill esophagitis

2. Skin disease with esophagitis

3. Hypersecretor – ZE syndrome

•Persistent acid reflux•Weak or non-acid GER•Sensitive esophagus•Missed GERyp y

4. Genotype differences


•Wrong diagnosis•Achalasia•Gastroparesis•“Functional” heartburn


9


PPI Resistant Patients—What is the Clinical Question??

• Insufficent PPIs to control acid reflux??• Insufficent PPIs to control acid reflux??

4

30

ROLE OF PH MONITORING IN SYMPTOMATIC PATIENTS ON THERAPY

Dis

tal T

otal

Tim

e pH

<

10

15

20

25

Upper limit of normal

%

0

5

QDATYPICAL GERD

(n = 145) )

BIDQD BIDTYPICAL GERD

(n = 175) )

Samer and Vaezi, A m J Gastroenterol 2005


10


Symptom Analysis

SI>50%

SSI>10%

Calculation of the SAP

Reflux event+

Sym

ptom

-+

+ -

S-R+

S+R+ S+R-

S-R-

Fisher’s exact testtwo-tailed

Weusten BLAM et al. Gastroenterology 1994

= [1 – p value] X 100%SAP


11


Concordance Concordance of Symptom of Symptom Assessments with Omeprazole TestAssessments with Omeprazole Test

Taghavi SA et al. Gut 2005

Hypersensitive Esophagus (SI+/SI-)Response to Omeprazole 20 mg BID for 4 Weeks

All had normal % total time pH<4

Watson, et al. Gut 1997

Reflux symptom score Days per week of reflux symptoms


12


Citalopram (Celexa) 20 mg for 6 months in Treatment of Hypersensitive Esophagus

Viazis N et al. Am J Gastroenterology 2012


• Insufficent PPIs to control acid reflux??• Insufficent PPIs to control acid reflux??• Uncontrolled Weak or Non-Acid Reflux??


13


Impedance pH Monitoring

• Resistance to the flow of alternating currentof alternating current

AirEsophageal LiningSalivaan

ce

SalivaFoodRefluxate

Impe

d


14


Number of Reflux Episodes Off and On PPIs

Hemmink GJM, et al Am J Gastro 2008

Symptom Episodes Off and On PPIs

Hemmink GJM, et al Am J Gastro 2008


15


Etiology of Refractory GERDPersistent Acid Reflux 1% - 15%

Refractory “GERD”

Symptoms onPPIs

Non-Acid GERD Not GERD

50% 60%GERD

30% - 40%

50% - 60%

GER Controlled on PPIs

Another DiagnosisMainie et al Gut 2006Zerbid et al Am J Gastro 2006

Effects of Baclofen 40 mg on Esophageal Function

Transient LES relaxations % Time pH < 4

Zhang Q, et al. Gut 2002


16


Impedance Not Predictor of Response

100%

Predictors of Surgical Outcome: moderate to large hiatal hernia (>4cm);% time ph < 4 greater than 10% and HB/regurg at baseline

30%

40%

50%

60%

70%

80%

90%

Pro

bab

ility

nse

to F

undo

plic

atio

n

Francis and Vaezi, Laryngoscope 2011

+ HeartburnAcid Reflux > 12%

- HeartburnAcid Reflux > 12%

- HeartburnAcid Reflux Š 12%

+ HeartburnAcid Reflux Š 12%

0%

10%

20%

30%

Res

pon

-HB/Regurg +HB/Regurg -HB/Regurg +HB/Regurg-pH -pH +pH +pH


• Insufficent PPIs to control acid reflux??U t ll d N A id R fl ??• Uncontrolled Non-Acid Reflux??

• Patient does not have acid reflux??Look for other diagnosesRefer patients with extraesophageal complaintsRefer patients with extraesophageal complaints

back to ENT, lung, and cardiac specialistsStop unnecessary and expensive PPIs


17


Catheter-Free pH Monitoring

• Capsule device with pH sensor• Attachment to distal esophageal mucosa• Radiotransmission of pH data


Transoral during endoscopyTransoral without endoscopyTransnasal after manometry

Placement methods



18



Transoral during endoscopyTransoral without endoscopyTransnasal after manometry

Placement methods


Extended Recording Time Identifies More Extended Recording Time Identifies More Abnormal GERAbnormal GER

Prakash C et al Clin Gastro Hepatology 2005


19


Normal Bravo pH Test

It’s Like a Baseball Game

• Strike 1atypical symptoms normal endoscopyatypical symptoms, normal endoscopy

• Strike 2no response to BID-QID PPIs for months/yrs

St ik 3• Strike 3normal 24-48 hrs ph test off PPIs for 2 weeks

YOU’RE OUT—NO GERD


20


PPIs and Esophageal pH Testing

High Probability GERD• Classic Symptoms• Suggestive EGD

Low Probability GERD• Atypical Symptoms• Extraesophageal Sx Suggest e G

• Hx of Previous PPI Response

PPBID PPIs

Improved No or Partial Response

•R/O Non-acid Reflux•Diagnosis Made

p g• Normal endoscopy• Previous Failure on PPI

Off PPI

pH TestingBravo Capsule•T l H

Impedance pH on BID PPIsPPIs

↑Non-Acid ↑Acid Normal•Baclofen•? Surgery

•Switch PPIs•? Surgery

•GER or no GER??

•Transnasal pH•Impedance pH

Normal Abnormal pH

•Stop PPIs

•BID PPI Trial

PPI Use after Negative Reflux Tests• Chart review and telephone survey• 90 patients with negative Bravo/impedance• 90 patients with negative Bravo/impedance

pH off PPIs

• 38 (42%) still using PPIs 2 yrs later17 patients recalled being told to stop PPIs15 patient’s chart documented instruction15 patient s chart documented instruction13 on BID PPIs

• No predictors of continued PPI useGawron AJ et al. Clinical GI and Hepatology 2012


21


Rebound Dyspepsia SymptomsPantoprazole vs Placebo

Niklasson, et al. Am J Gastroenterol 2010

Pantoprazole Placebo

WRONG DIAGNOSIS

• Achalasiaesophagus minimally dilateddiagnosis made by manometry

• Delayed gastric emptyingusually postprandial pain and regurgitation are major symptoms-not heartburn

• RuminationRumination

• Aerophagia

• “Functional “ heartburn—up to 58%


22


Increased Prandial Air Swallowing—Potential Cause of Refractory GERD

Bravi I et al. Clin Gastro and Hepatology 2013


Upper Endoscopy



pp py


1. Pill esophagitis

2. Skin disease with esophagitis

3. Hypersecretor – ZE syndrome •Persistent acid reflux

Bravo 48 hr pHLow probability

Impedance pHHigh probability

yp y

4. Genotype differences


•Weak or non-acid GER•Sensitive esophagus•Missed GER•Wrong diagnosis

•Achalasia•Gastroparesis•“Functional” heartburn


23

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