2 refractory gerd - american college of...
TRANSCRIPT
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
Mean intensity ‘Regurgitation-
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
Mean intensity ‘Regurgitation-
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
Therapeutic gain with PPI (%)
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
Placebo response (%)
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
Therapeutic gain with PPI (%)
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
Placebo response (%)
Esomeprazole 40 mg twice daily
mg twice daily
Kahrilas PJ et al. DDW 2012EER #25 v7/10/12 PJK
Global average (range)
ACG Regional Course- IndianapolisCopyright ACG 2012
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
No significant difference in PEF
Day -7 to +112
No significant difference in PEF
No significant difference in PEF
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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)
ACG Regional Course- IndianapolisCopyright ACG 2012
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
Montreal Definition of GERD: reflux of gastric contents causes “troublesome” symptoms
SymptomTriggers
≈ Refluxevents
X
Tissuesensitivity
Acidity ofgastric juice
XAcidclearance
Symptommodulators ≈
RM #21c v4/4/11 PJK
sensitivityclearancemodulators
Prolonged on basis of hiatal hernia or weak peristalsis
ACG Regional Course- IndianapolisCopyright ACG 2012
August 2012 15
Montreal Definition of GERD: reflux of gastric contents causes “troublesome” symptoms
SymptomTriggers
≈ Refluxevents
X
Tissuesensitivity
Acidity ofgastric juice
XAcidclearance
Symptommodulators ≈
RM #21d v4/4/11 PJK
sensitivityclearancemodulators
Hypersensitivity - central and/or peripheral
Montreal Definition of GERD: reflux of gastric contents causes “troublesome” symptoms
Not a primary abnormality of GERD
SymptomTriggers
≈ Refluxevents
X
Tissuesensitivity
Acidity ofgastric juice
XAcidclearance
Symptommodulators ≈
RM #21e v4/4/11 PJK
sensitivityclearancemodulators
ACG Regional Course- IndianapolisCopyright ACG 2012
August 2012 16
PPI therapy of GERD is compensatory, not curative
Targets of PPI therapy
SymptomTriggers
≈ Refluxevents
X
Tissuesensitivity
Acidity ofgastric juice
XAcidclearance
Symptommodulators ≈
RM #21f v4/4/11 PJK
sensitivityclearancemodulators
Causes of persistent “troublesome” symptomsPPI Failures
Abnormal in number, composition, or volume
fl dSymptomTriggers
≈ Refluxevents
Tissuesensitivity
X Acidity ofgastric juice
XAcidclearance
Symptommodulators ≈
refluxed
RM #21f v4/4/11 PJK
sensitivityclearancemodulators
Hypersensitivity - central and/or peripheral
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
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
ACG Regional Course- IndianapolisCopyright ACG 2012
August 2012 19