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$: 2 Refractory GERD - American College of Gastroenterologygi.org/.../uploads/2012/08/12ACG_Midwest_Kahrilas_Refractory_GERD.pdf · Refractory GERD Peter J. Kahrilas,,, M.D. Northwestern$
ACG Regional Course- IndianapolisCopyright ACG 2012

August 2012 1

Refractory GERD

Peter J. Kahrilas, M.D.Peter J. Kahrilas, M.D.,,Northwestern Northwestern UniversityUniversityChicago, USAChicago, USA

Observations about PPI use 1990-2012A huge and expensive trend

• GERD Indications have broadened– In 2008 113 4 million PPI prescriptions filledIn 2008, 113.4 million PPI prescriptions filled– 2008 sales totaled $13.9 billion

• Dosing has escalated– Prilosec to Nexium to Dexilant– 35% of US prescriptions are for (unapproved) bid dosage

• Unrealistic expectations of drug efficacy have led to the widespread use of term ‘PPI failure’

• Along with this massive population exposure, increasing recognition of potential safety issues

PPI 2 v7/11/12 PJK


August 2012 2

GERD is a condition which develops whenthe reflux of stomach content causes troublesome

symptoms and / or complications

Esophageal Extra-esophageal p gSyndromes

p gSyndromes

Syndromes with Esophageal Injury

• Refluxesophagitis

SymptomaticSyndromes

• Typical refluxd

EstablishedAssociation

• Reflux cough• Reflux

ProposedAssociation

• Sinusitis• Pulmonary

Vakil N et al. Am J Gastroenterol 2006;101:1900

p g• Reflux stricture

• Barrett'sesophagus

• Adenocarcinoma

syndrome• Reflux chest

pain syndrome

Refluxlaryngitis

• Reflux asthma• Reflux dental

erosions

yfibrosis

• Pharyngitis• Recurrentotitis media

RM #1b v4/20/10 PJK

GERD is a condition which develops whenthe reflux of stomach content causes troublesome

symptoms and / or complications

Esophageal Extra-esophageal p gSyndromes

p gSyndromes

EstablishedAssociation

• Reflux cough• Reflux

SymptomaticSyndromes

• Typical refluxd

Syndromes with Esophageal Injury

• Refluxesophagitis

ProposedAssociation

• Sinusitis• Pulmonary

Vakil N et al. Am J Gastroenterol 2006;101:1900

Refluxlaryngitis

• Reflux asthma• Reflux dental

erosions

syndrome• Reflux chest

pain syndrome

p g• Reflux stricture

• Barrett'sesophagus

• Adenocarcinoma

yfibrosis

• Pharyngitis• Recurrentotitis media

RM #1d v2/21/10 PJK


August 2012 3

Assessing PPI effectiveness using the Reflux Disease Questionnaire (RDQ)

• Six item self-administered questionnaire that evaluates the frequency and intensity of:frequency and intensity of:

• Heartburn:– ‘burning feeling behind the breastbone’– ‘pain behind the breastbone’

• Regurgitation: – ‘acid taste in the mouth’

‘unpleasant movement of material upwards from the stomach’– unpleasant movement of material upwards from the stomach

• Dyspeptic symptoms:– ‘burning feeling in the center of the upper stomach’ – ‘pain in the center of the upper stomach’

RR#9 v1/13/12 PJK

Equivalence of heartburn resolution among drugs and AZD0865 doses

Non-Erosive Reflux Disease Reflux Esophagitis

100AZD0865 25 mgAZD0865 50 mg100

AZD0865 25 mgAZD0865 50 mg

0

20

40

60

80

100

1 2 4

AZD0865 50 mgAZD0865 75 mgEsomeprazole 40 mg

0

20

40

60

80

1 2 4

Patients free from

‘burning feeling

behind the breastbone

(%)

AZD0865 50 mgAZD0865 75 mgEsomeprazole 20 mg

Data from all treatment arms in each study were pooled to gauge the therapeutic impact of potent acid suppression on the RDQ regurgitation items compared with the heartburn item ‘burning feeling behind the breastbone’

1 2 41 2 4Treatment weeks Treatment weeks

RR#13 v5/5/11 PJK


August 2012 4

Relative response of high severity RDQ heartburn and regurgitation items to potent acid inhibition

‘Substernal burning’

Complete resolution at 4 weeks (95% CI)

0 20% 40% 60% 80% 100%

‘Substernal pain’

‘R it ti t’

Substernal burning(entry criterion)

‘Regurgitation-taste’

‘Regurgitation-movement’

NERD (n=1415)NERD (n=1415)High severity symptoms (≥4 days/wk of at least moderate intensity)

RE (n=1460)RE (n=1460)

RR#14b v1/13/12 PJK Kahrilas PJ et al. Clin Gastroenterol Hep 2012; In Press

Regurgitation during 4th week Rx: NERDCircle diameter proportional to # pts

2.5

3.01.14

Mean intensity ‘Regurgitation-

movement’1.0

1.5

2.0

1.14

Low

High

N=83

Mean intensity ‘Regurgitation-taste’

0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0

Low High

RR#18 v1/13/12 PJK Kahrilas PJ et al. Clin Gastroenterol Hep 2012; In Press

N=132


August 2012 5

Regurgitation during 4th week Rx: NERDCircle diameter proportional to # pts

2.5

3.01.14

N=59N=59N=83N=83

N=617


movement’1.0

1.5

2.0

1.14

Low

High

N=83N=83N=39N=39N=304N=304N=132N=132

Mean intensity ‘Regurgitation-taste’

0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0

Low High

RR#18 v1/13/12 PJK Kahrilas PJ et al. Clin Gastroenterol Hep 2012; In Press

Regurgitation during 4th week Rx: RECircle diameter proportional to # pts

2.5

3.0

N=31N=31N=52N=52

1.14N=449

1.0

1.5

2.0

N=30N=30N=195N=195N=141N=141

1.14


movement’

Low

High

0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0

RR#17 v1/13/12 PJK

Mean intensity ‘Regurgitation-taste’Low High

Kahrilas PJ et al. Clin Gastroenterol Hep 2012; In Press


August 2012 6

Therapeutic gain of heartburn vs regurgitation Systematic review: 4 weeks of PPI vs placebo treatment

80

90

100

Upper limit of potential

Esomeprazole 20 mg twice daily

Esomeprazole 40 mg

HB Regurgitation

10

20

30

40

50

60

70

80

Therapeutic gain with PPI (%)

Omeprazole 10 mg

Omeprazole 20 mg

Omeprazole 40 mg

Pantoprazole 10 mg

Pantoprazole 20 mg

Pantoprazole 40 mg

therapeutic gain

RR#4 v5/4/11 PJK Kahrilas PJ, et al. Am J Gastroenterol 2011;106:1419

0

10

0 10 20 30 40 50 60 70 80 90 100

Placebo response (%)

Rabeprazole 20 mg

Global average (error bars represent range)

GERD SymptomsAttributable to GE reflux of gastric content

GERD SymptomsAttributable to GE reflux of gastric content

EsophagealHeartburnRegurgitation

Chest PainDysphagia

ENR 33c v4/4/11 PJK


August 2012 7

Effect of concomitant symptoms on heartburn relief Symptom profile at entry: RDQ heartburn items

Mild Moderate Severe

‘Substernal burning’100

‘Substernal pain’100

Proportion of patients

(%)

10

20

30

40

50

100

60NERD, n=1415, 100% of study populationRE, n=1460, 100% of study population

Proportion of patients

(%)

10

20

30

40

50

100

60NERD, n=1314, 70.2% of study populationRE, n=1375, 71.4% of study population

ESP 44 1/29/12 PJK Kahrilas PJ et al. Am J Gastroenterol 2012;In Press

Symptom frequency (days/wk)

0

1-3 4-6 7NERD RE NERD RE NERD RE

Symptom frequency (days/wk)

0

1-3 4-6 7NERD RE NERD RE NERD RE

N=23N=23NN=60=60

Heartburn RDQ items during 4th week Rx: NERDCircle diameter proportional to # pts

2.5

3.01.14

N=574

N=13N=13N=288N=288N=190N=190

1.0

1.5

2.0

1.14

Mean intensity ‘Substernal pain’

Low

High

0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0

ESP 49 1/29/12 PJK

Mean intensity ‘Substernal burning’Low High

Kahrilas PJ et al. Am J Gastroenterol 2012; In Press


August 2012 8

Heartburn RDQ items during 4th week Rx: RECircle diameter proportional to # pts

2.5

3.01.14

N=10N=10NN=26=26

N=285

1.0

1.5

2.0

1.14

Mean intensity ‘Substernal pain’

Low

High

N=4N=4N=149N=149N=96N=96

0 0.5 1.0 1.5 2.0 2.5 3.0

0.5

0

ESP 50 1/29/12 PJK

Mean intensity ‘Substernal burning’Low High

Kahrilas PJ et al. Am J Gastroenterol 2012;In Press

Chest pain response using PPIs in RCTsSystematic review of trials that included GERD testing

• 7 PPI trials used pH monitoring to define GERD (+) or (-)• 6 of these 7 used bid PPIs• 5 trials used ≥50% improvement to define positive

chest pain response; two used ≥20% improvement• The proportion of patients reporting heartburn varied

widely from zero (exclusion criterion) to essentially the entire GERD (+) population

Kahrilas PJ et al. Gut 2011;60:1473EER #10 v11/21/11 PJK


August 2012 9

Relief of undiagnosed chest pain (≥ 50%) with PPIsGERD (+) vs GERD (-) defined by pH monitoring

80

90

100

L l 30Upper limit of potential GERD (+) GERD (-)

10

20

30

40

50

60

70

80


Lansoprazole 30 mg dailyLansoprazole 60 mg AM and 30 mg PMOmeprazole 40 mg AM and 20 mg PM

pp ptherapeutic gain

Omeprazole 40 mg twice dailyRabeprazole 20 mg

i d il0

10

0 10 20 30 40 50 60 70 80 90 100


Global average (range)

twice daily

Kahrilas PJ et al. Gut 2011;60:1473EER #11 v11/21/11 PJK

Effect of concomitant symptoms on heartburn relief Treatment benefit: with vs without additional RDQ items

• Same Esomeprazole vs AZD 0865 trial data as for regurgitation• RDQ symptoms recorded in an e-diary twice daily• On average, patients responded positively to 4 of the 6 RDQ items• In both NERD and RE study, analyzed the effect of other symptoms

on response of ‘burning feeling behind the breastbone’

Dent J et al. Am J Gastroenterol 2008;103:20–6Kahrilas PJ et al. Clin Gastroenterol Hepatol 2007;5:1385–91RM #47 v5/2/11 PJK


August 2012 10

Concomitant RDQ items affect heartburn treatment response Treatment benefit: with vs without concomitant symptom

Pain behind the breastbone

Concomitant (+) RDQ item

High intensityHigh intensityNERDNERD

Pain in the center of the

High intensityHigh intensity

fupper stomach

Burning feeling in the center of the upper stomach

Unpleasant movement of material upwards from the

stomach

EsophagitisEsophagitis

Acid taste in the mouth

Kahrilas PJ et al. Am J Gastroenterol 2012;In PressRM #48b v1/13/12 PJK

0.1 0.2 1.0 2.00.5 5.0

Odds ratio (95% CI) for less frequent‘burning feeling behind the breastbone’ after 4 weeks Rx

when symptom present vs symptom not present

GERD SymptomsAttributable to GE reflux of gastric content?

GERD SymptomsAttributable to GE reflux of gastric content?

EsophagealHeartburn

Extra-esophagealHoarseness

RegurgitationChest PainDysphagia

CoughThroat clearingThroat painHalitosisWheezingWater brashPalpitations/arrhythmiasEtc.

ENR 33c v4/4/11 PJK


August 2012 11

StudyPlacebo

n/NOdds Ratio

(95% CI) WeightOdds Ratio

(95% CI)PPIn/N

Meta-analysis: efficacy of PPIs in coughPrimary outcome: still coughing at the end of trial

Medical Medical TrialsTrialsKilijanderKilijander 20002000 12/1212/127/97/9 8.2%8.2% 0.12 ( 0.12 ( 0.010.01--2.85 2.85 ))Ours 1999Ours 1999 9/99/97/87/8 7.4%7.4% 0.26 ( 0.26 ( 0.010.01--7.43 7.43 ))

SubtotalSubtotal 15.6%15.6% 0.17 ( 0.17 ( 0.020.02--1.731.73))21211717

Eherer 2003Eherer 2003 4/64/62/52/5 13.5%13.5% 0.33 ( 0.33 ( 0.030.03--3.93 3.93 ))ENT ENT TrialsTrials

VaeziVaezi 20062006 43/4843/4879/9479/94 70.9%70.9% 0.61 ( 0.61 ( 0.210.21--1.80 1.80 ))

SubtotalSubtotal 84 4%84 4% 0 56 (0 56 ( 0 210 21--1 491 49))54549999

0.005 1 10

Favors PPI Favors PlaceboOdds Ratio

0.1

Chang AB et al. Cochrane Database, 2011Chang AB et al. Cochrane Database, 2011

200

TOTALTOTAL 100%100% 0.46 ( 0.46 ( 0.190.19--1.15 1.15 ))7575116116

SubtotalSubtotal 84.4%84.4% 0.56 ( 0.56 ( 0.210.21 1.491.49))54549999

EER #23 v4-14-11 PJK

Improvement of chronic cough with acid suppressionGERD (+) vs GERD (-) defined by pH monitoring

80

90

100

O l 40Upper limit of potential GERD (-)GERD (+)

10

20

30

40

50

60

70

80


Omeprazole 40 mg twice dailyOmeprazole 40 mg twice dailyOmeprazole 40 mg twice daily

pp ptherapeutic gain

Ranitidine 150 mg dailyEsomeprazole 40

i d il0

10

0 10 20 30 40 50 60 70 80 90 100


Esomeprazole 40 mg twice daily

mg twice daily

Kahrilas PJ et al. DDW 2012EER #25 v7/10/12 PJK

Global average (range)


August 2012 12

GER-Asthma Syndrome, 770 PatientsEsomeprazole 40 mg bid (12 weeks)

Three apriori patient groupsNocturnal Resp Sx: yesNocturnal GERD Sx: no

Nocturnal Resp Sx: noNocturnal GERD Sx: yes

Nocturnal Resp Sx: yesNocturnal GERD Sx: yesNocturnal GERD Sx: no Nocturnal GERD Sx: yes Nocturnal GERD Sx: yes

Morning PEF

EsomeprazolePlacebo

Morning PEF

EsomeprazolePlacebo

Morning PEF

EsomeprazolePlacebo

Day -7 to +112

No significant difference in PEF


Day -7 to +112



P<0.058.7 L/min AMImprovement

P<0.058.7 L/min AMImprovement

Day -7 to +112

EER #6 v2-21-10 PJK Kiljander TO, et al. Am J Respir Crit Care Med 2006;173;1091

ALACRC et al. NEJM 2009;360:1487EER #27 v7/11/12 PJK


August 2012 13

ALACRC et al. JAMA 2012;307:373EER #26 v7/11/12 PJK

PPI efficacy for potential manifestations of GERDEstimates based on available RCT data

Esophagitis healingMild

SevereHeartburn relief

PlaceboPlacebo Therapeutic gainTherapeutic gain

EsophagitisNERD

Regurgitation relief

Chest pain (50% relief)GERD (+pH)GERD (-pH)

Chronic cough (improved)GERD (+pH)

PJ Kahrilas 2012RM #46 v7/10/12 PJK

0% 100%25% 50% 75%

Hoarseness (improved)GERD (-)

GERD (+pH)GERD (-pH)


August 2012 14

Abnormal in number, composition, or volume refluxed

Montreal Definition of GERD: reflux of gastric contents causes “troublesome” symptoms

SymptomTriggers

≈ Refluxevents

X

Tissuesensitivity

Acidity ofgastric juice

XAcidclearance

Symptommodulators ≈

RM #21b v4/4/11 PJK

sensitivityclearancemodulators


SymptomTriggers

≈ Refluxevents

X

Tissuesensitivity


XAcidclearance


RM #21c v4/4/11 PJK


Prolonged on basis of hiatal hernia or weak peristalsis


August 2012 15


SymptomTriggers

≈ Refluxevents

X

Tissuesensitivity


XAcidclearance


RM #21d v4/4/11 PJK


Hypersensitivity - central and/or peripheral


Not a primary abnormality of GERD

SymptomTriggers

≈ Refluxevents

X

Tissuesensitivity


XAcidclearance


RM #21e v4/4/11 PJK



August 2012 16

PPI therapy of GERD is compensatory, not curative

Targets of PPI therapy

SymptomTriggers

≈ Refluxevents

X

Tissuesensitivity


XAcidclearance


RM #21f v4/4/11 PJK


Causes of persistent “troublesome” symptomsPPI Failures

Abnormal in number, composition, or volume

fl dSymptomTriggers

≈ Refluxevents

Tissuesensitivity

X Acidity ofgastric juice

XAcidclearance


refluxed

RM #21f v4/4/11 PJK


Hypersensitivity - central and/or peripheral


August 2012 17

Conceptual model of esophageal sensitivity

Increased by Increased by inflammation, inflammation, PainHypersensitivity f ,f ,permeability, permeability, sensitizationsensitization

Sensitivity

Decreased Decreased

‘Normal’ PhysiologicalPhysiological PathologicalPathological

NERD Heartburn

Increasing Stimulus Intensity(chemo and/or mechanoreceptors)

ESP 38 5/4/12 PJK PJ Kahrilas 2012

by scarring, by scarring, metaplasiametaplasia

Barrett’s, stricture No perceptionNo perception HBHB

Pharmacological profile of TCAs

RM #56 v6/13/12 PJK Sperber AD, et al. Aliment Pharmacol Ther 2011;33:514


August 2012 18

Dosing TCAs for functional GI disease

• Low doseI iti t t t t ith 10 25 t b dti• Initiate treatment with 10-25 mg at bedtime

• Increase in 10-25 mg increments at 4 week interval• Watch for side effects

– Reduce dosage– Find alternative drug

• May combine with SSRIs

RM #57 v6/13/12 PJK

• Persistent reflux (‘volume’ or ‘non-acid’ reflux)– Partial response to PPIs, heartburn usually resolves– Refractory chest pain and/or regurgitation– Potentially amenable to anti-reflux surgery

‘Refractory GERD’ & ‘PPI Failures’ are Heterogeneous

• Hypersensitivity– Post-inflammatory? – Potentially amenable to TCAs, SSRIs

• Concomitant, non-reflux symptoms– Dyspepsia– Esophageal motor disorders

IBS– IBS

• Questionable causality– ENT syndromes: laryngitis, cough, etc– Functional heartburn– Sleep apnea, sleep disturbance– Asthma

RM #59 v7/11/12 PJK PJ Kahrilas 2012


August 2012 19

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