Gastroesophageal Reflux Disease

Gastroesophageal Reflux Disease
Sutep Gonlachanvit Gl Motility Research Unit Department of Internal Medicine Chulalongkorn University

GERD – New Definition

GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms
and I or complications
Symptomatic
Syndromes
Typical reflux syndrome
Reflux chest pain syndrome
Syndromes with Esophageal Injury
Reflux esophagitis
Reflux stricture
Barrett’s
esophagus
Adenocarcinoma
Established
Association
Reflux cough
Reflux laryngitis
Reflux asthma
Reflux dental erosions

Proposed
Association
Sinusitis
Pulmonary
fibrosis
Pharyngitis
Recurrent otitis media
Vakil et al. Can ป Gastroenterol 2005

Causes of increased exposure of the esophagus to gastric refluxate
LES
‘dysfunction
Defective
esophageal
clearance
Hiatal hernii
\
Increased intra-abdoทinal pressure
Katzka & DiMarino 1995

Prevalence
4 Gonlachanvit-GERD
Time Trends of GERD symptoms: Review of Cross-sectional population-based studies
Prevalence of at least weekly heartburn and / or acid regurgitation
I
Europe
USA
ASIA
South America
I *
1980 1985 1990 1995 Date of publication
2000 2005 2010
35
30
25
15
10
5
I
EL-Serag HB. Clin Gastroenterol Hepatol. 2007;5:17-26

Gonlachanvit-GERD
The Changing Epidemiology of GERD Complications
A 6-fold increased incidence of adenocarcinoma was found from 1975-2001
The rate of increase of adenocarcinoma is greater than
• Melanoma
• Prostate cancer
• Breast cancer
• Lung cancer
• Colorectal cancer
l!
ริ. 3 ra 2
Esophageal Adenocarcinoma
Melanoma
Prostate Cancer
Breast Cancer
Lung Cancer
Colorectal Cancer

1975 1980 1985 1990 1995 2000
5
5
4
1
0
Pohl, Welch. J Natl Cancer Inst. 2005;97:142-146.

6 Gonlachanvit-GERD
Factors Responsible for the Changing Epidemiology of GERD
■ Increased longevity1
■ Obesity epidemic2
■ Comorbid conditions affecting the esophagus3
■ Use of drugs that affect LES pressure and gastric emptying3
■ Self-treatment / access to OTC Medications?
1. Lee et al. Clin Gastroenterol Hepatol. 2007;5:1392-1398.
2. Watanabe et al. J Gastroenterol. 2007;42:267-274.
3. Bonatti et al. J Gastrointest Surg. 2007; Epub ahead of print.

Multivariate odds ratio for reflux symptoms
7 Gonlachanvit-GERD
Higher Body Mass Index Increases Risk of GERD Symptoms
• Even moderate weight gain among persons of normal weight can cause or worsen reflux symptoms
• Weight loss is associated with a decreased risk of symptoms

Body mass index (kg/m2)
N = 2306 women with at least weekly GERD symptoms and 3904 with no symptoms
Jacobson BC, et al. N Engl J Med. 2006;354:2340-2348.

8 Gonlachanvit-GERD
Obesity in Thailand (2004)
50%
25%
BMI 25-30 >30 Abd Obesity
• Rate of obesity significantly increased from 1997 to 2004
• Persons living in urban areas more likely to be obese than those in rural areas

Aekplakorn etal. Obesity 2007; 15:3113

Diagnosis : Reflux symptoms
■ When patients present predominantly with heartburn and acid regurgitation, there are
59-78% of sensitivity and 60-66 % of
specificity for diagnosis of GERD.
■ Heartburn and acid regurgitation without
dyspeptic symptoms are more specific for
GERD than heartburn and acid regurgitation with other Gl symptoms*.
* Klauser AG et al. Lancet 335:205, 1990.

% Patients with the Symptoms
Heartburn and Acid Regurgitation in GERD: Thai vs
Germany
P0.001 p<0.05

Heartburn Acid Regurgitation Heartburn Acid Regurgitation
Gonlachanvit ร.
Neurogastroenterol Motil 2006
Klauser AG, et al Lancet 1990

GERD symptom score

Placebo
Capsicum
Baseline
Week 1
Week 2
Week 4
Week 6
[mean + SE(* p value < 0.05, ** p value < 0.01)]
Digestive Disease Week 2009

Diagnosis: Endoscopy
■ Endoscopy is the most useful available tests for assessing reflux esophagitis as well as its complications such as stricture and Barrett’S esophagus.
■ Sensitivity = 20-68 %, specificity = 96 %
■ Sensitivity is depended on the prevalence of NERD in the population.
■ Indications for endoscopy are:
• A brief history of symptoms in older patients (>50 yr)
• Weight loss
• Dysphagia or bleeding
• Failure to respond to antireflux medications.
• Long history of reflux symptoms (>5 years)

Endoscopy : Reflux esophagitis
The LA Classification system
– Grade A reflux esophagitis
One (or more) mucosal break no longer than 5 mm that does not extend between the tops of two mucosal folds

LurxJel el al 1999. Pursued wnh permission Irom Professor G Tyi’ja ana Professor J Deft
The LA Classification system
– Grade B reflux esophagitis
One (or more) mucosal break more than 5 mm long, thal does not extend between the lops of two mucosal folds

Lundel «1 al 1999, PuWished wnh เ»™เรรเ0<า Irom Prcfessc< G Tyiijaj art) Professor J Deft
The LA Classification system
– Grade c reflux esophagitis
The LA Classification system
– Grade D reflux esophagitis
One (or more) mucosal break that IS conimuoos between the tops of two or more mucosal folds, but which involves less lhan 75% of Ihe circumference

One (or more) mucosal break which involves at least 75% of the esophageal circumference
. L

LurvJel el al 1999. Pufc*sl>«j Iftflh pemnsstcfi 1rcxn ProfesscrG Tytjat and Professor J Dent
LuftJel el al 1999. FuWisfted Wiih peimission from PrefessofG Tyijal and Professor J Dert

Causes of Dyspepsia in cu Hospital During 2000-2002
(Endoscopic data, N=1,708)
100
0.71
4.5
0.9
2.5
1.05
GU
GU+DU GERD Ca
stomach
90
80
70
60
50
40
30
20
0
อบ
80.7
NUD

15 Gonlachanvit-GERD
Do symptoms predict the presence of EE?
■ 1011 consecutive pts at the Mayo Clinic undergoing EGD for GERD symptoms
■ Completed validated GERQ survey
■ 20% had erosive esophagitis
■ Erosive esophagitis associated:
• With age, gender, heartburn frequency and any regurgitation or dysphagia (P<0.0001)
► Pts with daily heartburn 5x more likely to have EE
• Not with severity or duration
Locke. GE 2003;58:661

16 Gonlachanvit-GERD
Esophageal Manometry
Water
Perfused
Manometry
System
High
Resolution
Manometry
System

” Diagnosis 24 hour esophageal pH monitoring
■ The gold standard for measuring esophageal acid exposure
■ Indications for 24 hr esophageal pH monitoring
• When patients present with atypical symptoms, such as NCCP and ENT symptoms
• When symptoms do not respond to conventional medications
• เท preparation for antireflux surgery
• เท difficult cases, for evaluation the adequacy of antireflux medications
■ pH monitoring parameters:
• Quantitation of the actual time the esophageal mucosa is exposed to gastric juice
• Measurement of the esophageal ability to clear refluxed acid
• Correlation of reflux episodes with symptoms

18 Gonlachanvit-GERD
24 hour esophageal pH monitoring

^ ft Home (j Studies pt Patients |f^ Protocols # Equipment Q Personnel Hi Archives Setup M ‘
047684139 pH – [1 ch esophageal pH monitoring 2003-12-04 08:49]
STUDY DETAILS pH Review Details
CAPTURE
REVIEW
Overview
Details
REPORT
PROTOCOL
0
% 4.93
ff ET 1
:er T GGls
21:00 21:30 22:00

22:30

20 Gonlachanvit-GERD
Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring

21 Gonlachanvit-GERD
Esophageal impedance testing
Bolus Movement
Bolus ErUP^
Bolus En^
Bolus En^
Bolus En^
Bolus Entry : \ _ Bolus En^
I—1 Rnli IC Fntrv I I
[Bolus Entry I ■ Sj
A
Bolus En^
Bolus En^
Bolus Ertw
Bolus En^
Bolus Movement

Gonlachanvit-GERD
Multichannel Intraesophageal Impedance
(MII-pH) Monitoring
An Acid Reflux
-pH

22

Gonlachanvit-GERD
Multichannel Intraesophageal Impedance
(MII-pH) Monitoring
Non Acid Reflux
-pH

23

24 Gonlachanvit-GERD
37 patients with non-diagnostic EGD and previous normal 24 hr. pH study
24 hr. Mil pH testing
6 patients (16%) Positive standard 24 hr pH test
7 patient (18%) Negative symptom index

10 patients (27%) Positive symptom index for acid reflux
14 patients (38%) Positive symptom index for non-acid reflux

Kline et al. Clinical Gastroenterol and Hepatol 2008; 6: 880-885

25 Gonlachanvit-GERD
168 Patients with Persistent Symptoms
on Medication
Impedance-pH Monitoring on Medication
144 Patients Symptomatic During study
Acid Reflux Associated with Symptom
11 % (16 patients)
Reflux Not Associated with Symptom 52 % (75 patients)
Nonacid Reflux Associated with Symptom 37 % (53 patients)
Mainie et at. Gut 2006:55:1398-1402

26 Gonlachanvit-GERD
Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring
■ MII-pH is superior to standard pH monitoring for evaluation of non-acid refluxes.
■ More sensitive than standard pH monitoring for detecting of GER during on PPI therapy.
■ Demonstrate extent of GER.
■ Demonstrate liquid, gas, mix liquid-gas refluxes.

PPI Test in Thai GERD Patients

Symptom scores
Effect of PPI test on GERD and the other symptoms in all
patients
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
1/
*
7C
«5»
V

&
□ Baseline
■ End of treatment
aร”’
* p < 0.05

PPI tests for diagnosis of GERD
Sensitivity 34.3%
Specificity 46.4%
Positive predictive value 44.0%
Negative predictive value 36.0%
Accuracy 60.3%

Non-Cardiac Chest
Pain

Esophageal manometry & Total % time pH < 4 in NCCP
N=45
Total % time pH < 4
< 4.5 % >_4.5 % Total
EM Normal 7 10 17
NSEMD 5 8 13
Hypertensive LES 2 0 2
Scleroderma like
0 2 2
DES 3 2 5
Nutcracker 1 2 3
Missing data 3 0 3
Total 21 24 45
p > 0.05

Extraesophageal GERD (LPR)

% of Patients
% of ENT Symptoms in Patients Referred for pH Monitoring (N=59)
Globus Hoarseness Sore throat Clearing throat Chr cough

Dual Channel 24 hour esophageal pH monitoring

Diagnosis of GERD in ENT Patients (Gold standard = 24 hr pH
Monotoring)
Abnormal upper esophageal pH Abnormal lower esophageal pH
(pH <4 > 1%) (pH<4>4%)

Prevalence
Prevalence of GERD เท Thai Asthma patients using 24 hr pH monitoring (ท=56)
Prevalence 37.50%
15 pts (71.43%) had GERD symptoms
Jaimchariyatam N, Wongtim ร, Udompanich V, Sittipunt c, Kawkitinarong K, Chaiyakul ร et al. J Med Assoc Thai 2011; 94(6):671-678.

Uncontrolled Asthma and GERD
■ The association between GERD and level of asthma control by ACT score at KCMH
• GERD in partly controlled asthma
prevalence = 25.72%
• GERD in uncontrolled asthma
prevalence = 51.17%
• GERD in poorly controlled asthma
prevalence = 80.89%
Wongtim ร., et al 2009

Conclusions
■ GERD is common in Thailand.
■ Around 50% of patients with typical or atypical GERD symptoms have positive pH tests.
■ Heartburn is less prevalence in Thai GERD patients.
■ GERD patients with atypical symptoms are more common than typical GERD at KCMH.
■ PPI tests in Thai patients at tertiary care center provide low sensitivity and specificity for diagnosis of GERD.

Treatment of GERD
Benefit of GERD Treatment
■ Decrease mortality = No evidence support
■ Decrease morbidity = Yes, prevent stricture and bleeding esophageal ulcer
■ Relieve GERD symptoms = Yes
■ Improve quality of life = Yes

Impact of Lifestyle Modification on GERD
■ 16 trials examined effectiveness of lifestyle changes
Lifestyle Change Effect
Tobacco cessation No significant effect
Alcohol cessation No significant effect
Weight loss Improved pH metry results and symptoms
Elevation of head of bed Improved pH metry results and symptoms
Left lateral decubitus position Raised LES pressure, improved pH metry results
Lifestyle changes are logical and may work if used on an individual basis
LES = lower esophageal sphincter
Kaltenbach T, et al. Arch Intern Med. 2006;166(9):965-971.

GERD Management

Non-erosive reflux disease (NERD)
NERD
• Abnormal increase acid exposure (Typical NERD)
• Normal acid exposure but positive symptom index
(esophageal hypersensitivity to acid)
F:M = 1:1
Unlikely to progress to erosive reflux disease
Heartburn severity and effect on QOL is similar to
erosive reflux disease.
May have symptoms of dyspepsia
Aim of treatment = control symptoms

Erosive reflux disease
ERD = reflux symptoms + esophagitis (Gr c or อ on
endoscopy
M>F (2-3:1)
May progress to more severe esophagitis and
stricture!
เท severe esophagitis, after stop antireflux
medications, 80% of patients have symptom
recurrence within 6 months. I £
Aims of treatment Ifej^
• Mild esophagitis = controls symptoms m
• Severe esophagitis = controls symptoms, heals esophagitis, and maintains remission of symptoms and esophagitis.

GERD Management

Non-erosive reflux disease
(NERD)
Reflux esophagitis (RE)
Healing and Maintenance of Esophagitis
Induce symptom remission and prevent symptom recurrence

Speed of Healing of Reflux Esophagitis
Esophagitis cases healed
%
100
Room for
improvement!
83.6
51.9
28.2
PPIs
H2-receptor >p<0.0005 antagonists
Placebo
4 6 8 Time (weeks)
Meta-analysis: ท=7635
Chiba et al. Gastroenterology 1997
80
60
40
20
0
0
2
10
12

Speed of Symptom Resolution in Patients with Reflux Esophagitis
Patients free from heartburn %
80 ๅ Room for improvement!
PPIs
p<0.0001

H2-receptor
antagonists
Meta-analysis ท=2198
1-2 3-4
Weeks of treatment
6-8
60
40
20
0-
0
Chiba et al. Gastroenterology 1997

% patients in symptomatic remission
GERD tends to be ล chronic condition
100
• No mucosal breaks LA grade A A LA grade B T LA grade c
Time after cessation of therapy (months)
80
60
40
20
0
0
1
2
3
4
5
6
Lundell et al. Gut 1999

Pooled relapse rate over 6-12 months (%)
Maintenance Therapies for Healed Erosive Esophagitis
100 80 60 – 40 – 20 – 0 –
Cochrane systematic review of 36 controlled trials

H2RA Prokinetics Half-dose Full-dose
PPI
PPI
80
55
45
32
Donnellan c, et al. Gastroenterology. 2003;124:A108.

GERD Management
Uninvestigated GERD
เวท-erosive reflux disease
(NERD)
Reflux esophagitis (RE)
Induce symptom remission and prevent symptom recurrence

On demand therapy

Response to PPI (%)
Symptom Response with On-demand vs. Continuous PPI Therapy for GERD
100%-
86%

75%

176 pts with END or Grade I/ll esophagitis and >moderate H-burn who improved with rabeprazole 10 mg/d
Continuous
On-demand
Bour et al. Aliment Pharm Ther 2005,21:805

□ท-demand PPI therapy for the maintenance of healed erosive esophagitis
Patients in endoscopic remission
□ท ce-daily es omeprazole 20 mg
□ท-demand esomeprazole 20 mg
ITT = 241
ITT = 229
Patients [%)
100 -I
30 60 90 120 150
Time after randomization (days)
‘p<0.001
Sjostedt et al, Gastroenterology2005; 128: A528

Treatment of Uninvestigated GERD
Uninvestigated GERD with Empiric
no Alarm Symptoms “■^ Therapy


Non-erosive reflux disease
(NERD)
Reflux esophagitis (RE)
Alarm Symptoms
Weight loss
Dysphagia
Odynophagia
Bleeding, anemia
Frequent vomiting
Recent onset in old age
Long duration of symptoms

GERD: Initial Management
step-in with ล PPI for 4 weeks
The fastest, most economical path to:
—► Symptom relief
-► Diagnostic confirmation
After O’Connor et al. Am ป Gastroenterol 2000 Dent, Talley. Aliment Pharmacol Ther 2003 (Suppl 1)
Dent et al. Gut 2004 (Suppl 4)

GERD: Long-term management

step down to the lowest dose that controls symptoms
Continuous daily therapy
Intermittent courses of therapy
On-demand therapy
Dent & Talley. Aliment Pharmacol Ther 2003 ( Suppl 1)
Dent et al. Gut 2004 (Suppl 4)

Patie]its( I
Treatment of Uninvestigated GERD On demand PPI vs Maintenance Therapy PPI and H2
Receptor Antagonist
Hansen AN, etal. Int J Clin Pract2006, 1, 15-22

Algorithm for the management of Typical GERD in
primary care
Typical GERD Symptoms
Alarm features present
Alarm features absent
PPI test
Symptom persist Symptom respond
D1, r_„ [—/-^r\—►NERD: On demand Rx
Refer for EGD Maintain therapy
t Erosive: Maintenance 4 พ®6kร
Frequent relapses, alarm features
On-demand
therapy

Safety of Long-Term PPI Therapy in GERD
■ Enteric Infection
– Increased risk of Clostridium difficile infection in PPI users
– Risk Increased from 0.02% to 0.06%
■ Pneumonia
– Flawed study as they did not control for important confounders
-Adjusted relative risk 1.89 (1.3-2.6)
■ Osteoporosis
– Increased risk of hip fractures
-Adjusted OR 2.65 (1.8-3.9)
■ Rebound Symptoms
■ Drug Interaction
OR = odds ratio.
Dial ร, et al. JAMA. 2005;294(23):2989-2995. Laheij RJ, et al. JAMA. 2004;292(16): 1955-1960. Yang YX, et al. JAMA. 2006;296(24):2947-2953. Giten D, etal. Gastroenterology. 1999;116:239-247.

Effect of Omeprazole on The Antiplatelet Activity of Clopidogrel
The variability in the response to clopidogrel has been linked, at least in part, to its cytochrome P450-dependent metabolism steps including CYP2C19 and CYP3A4.
Gilard M, et al. ป Am Coll Cardiol 2008; 51(3):256-260.

Mean PR I on Days 1 and 7 in the Two Groups
On Day- 1. โทรan platelet reactivity index (PFll) was 83.296 and S3.C|%, respectively, in the placebo and omeprazole groups (nonsignificant). On Day 7. mean PR I was 39.&% and 51.4V respectively, in the placebo and omeprazole groups (p -< O.OOOl). VASP = vasodilator-stimulated p ho sp ho protein.

Effect of PPI on Recurrent Ml
(13,636 cases vs 2,057 controls)
Association Between Acid-Reducing Therapy and Recurrent Ml
End point Odds ratio (95% Cl)
Recurrent Ml within 90 d
Current exposure to PPI (within 30 d) 1.27 (1.03 – 1.57)
Previous exposure to PPI (31 – 90 d) 0.86 (0.63 – 1.19)
Remote exposure to PPI (91 – 180 d) 0.81 (0.57- 1.18)
Juurlink DN, Gomes T, Ko DT, et al. CMAJ. 2009; DOI: 10.1503/cmaj.082001.

61 Gonlachanvit-GERD
Methods
■ Multicenter, international, randomized, double-blind, double-dummy, placebo-controlled, parallel group, phase 3 efficacy and safety study of CGT-2168, a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), compared with clopidogrel.
■ Patients were stratified based on two baseline factors: H. pylori serology (positive or negative) and concomitant use of any NSAID
■ All patients were to receive enteric coated aspirin at a dose of 75 to 325 mg.
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872

62 Gonlachanvit-GERD
Results
^ 362^atient^abov^h^nitiaUarge^^200^^^^^^
■ 393 sites
■ Median follow-up 133 days (maximum 362 days)
■ 136 adjudicated cardiovascular events (preliminary)
■ 105 adjudicated Gl events (preliminary)
• 143 had been planned
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872

Baseline Characteristics
Variable
H. Pylori Positive
Used NSAIDs
Sex – Male
White/Black/Other
History of ACS
History of Ml
History of PAD
History of stroke
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872

Survival Probability
Survival Curves for PPI Treated vs Placebo
Composite Cardiovascular Events
95*a-V.70-1.51
Placebo: 67 events, 1821 at risk Treated: 69 events, 1806 at risk
Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status
Placebo
COGENT — Presented at TCT 2009 http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872

Survival Probability
Survival Curves for PPI Treated vs Placebo Re vase น I a rizat i o ท
Placebo
95% Cl = 0.59; 1.55
Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pvlori Status
30 60 90 120 150 180 210 240 270 300 330 360 390
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872
0

Survival Probability
Survival Curves for PPI Treated vs Placebo
Ml Events
-iTreated
Placebo
HR = 0.96 95% Cl = 0.59; 1.56
Placebo: 37 events, 1851 at risk Treated: 36 events, 1839 at risk
Adjustment through Cox Proportional Hazards Model Adjusted to Positive NSAID Use and Positive H. Pylori Status
I I I I I I I I I I I I
30 60 90 120 150 180 210 240 270 300 330 360
COGENT — Presented at TCT 2009ays
http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872
0
I
390

Survival Curves for PPI Treated vs Placebo
Composite Gl Events
– – ■Treated
95% Cl = 0.36; 0.85
p=0.007
Ipreliminary)
Placebo
Placebo: 67 events, 1895 at risk Treated: 38 events, 1878 at risk
0 30 60 90 120 150 180 210 240 270 300 330 360 390
COGENT — Presented at TCT 2009
Days
http://www.cardiosource.com/clinicaltrials/trial.asp?triallD=1872

68 Gonlachanvit-GERD
Summary
-PPIs’ side effects have been identified reported.
– PPI should be used only in patients who really need It.

Gonlachanvit-GERD 69
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