astroesophageal reflux disease -...
TRANSCRIPT
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Gastroesophageal Reflux Disease
Sutep Gonlachanvit
GI Motility Research Unit
Department of Internal Medicine
Chulalongkorn University
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GERD - New Definition
GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms
and / or complications
Symptomatic Syndromes
Typical reflux syndrome
Reflux chest pain syndrome
Syndromes with Esophageal Injury
Reflux esophagitis
Reflux stricture
Barrett's esophagus
Adenocarcinoma
Esophageal Syndromes
Established Association
Reflux cough
Reflux laryngitis
Reflux asthma
Reflux dental erosions
Proposed Association
Sinusitis
Pulmonary fibrosis
Pharyngitis
Recurrent otitis media
Extra-esophageal Syndromes
Vakil et al. Can J Gastroenterol 2005
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Causes of increased exposure of the esophagus to gastric refluxate
Defective
esophageal
clearance
LES
‘dysfunction
’ Hiatal hernia
Delayed gastric
emptying Increased intra-abdominal
pressure
Katzka & DiMarino 1995
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Gonlachanvit-GERD 4
Time Trends of GERD symptoms: Review of Cross-sectional population-based studies
Europe
USA
ASIA
South America
1980 1985 1990 1995 2000 2005 2010
35
30
25
20
15
10
5
0
Pre
vale
nce
(%)
Date of publication
EL-Serag HB. Clin Gastroenterol Hepatol. 2007;5:17-26
Prevalence of at least weekly heartburn and / or acid regurgitation
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Gonlachanvit-GERD 5
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
Pohl, Welch. J Natl Cancer Inst. 2005;97:142-146.
Esophageal Adenocarcinoma
Melanoma
Prostate Cancer
Breast Cancer
Lung Cancer
Colorectal Cancer
1975 1980 1985 1990 1995 2000
7
6
5
4
3
2
1
0
Rate
Rati
o (
Rela
tive t
o 1
97
5)
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Gonlachanvit-GERD 6
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.
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Gonlachanvit-GERD 7
Higher Body Mass Index Increases Risk of GERD Symptoms
0
0.5
1
1.5
2
2.5
3
3.5
4
< 20 20 - 22.4 22.5 - 24.9 25 - 27.4 27.5 - 29.9 30 - 34.9 ≥ 35
• 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
Mu
ltiv
ari
ate
od
ds r
ati
o
for
refl
ux s
ym
pto
ms
Body mass index (kg/m2)
Jacobson BC, et al. N Engl J Med. 2006;354:2340-2348.
P < .001 for trend
N = 2306 women with at least weekly GERD symptoms and 3904 with no symptoms
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Gonlachanvit-GERD 8
Obesity in Thailand (2004)
18%16% 16%
37%
9%
26%
0%
25%
50%
25-30 >30 Abd Obesity
Women
Men
Aekplakorn et al. Obesity 2007; 15: 3113
BMI
• Rate of obesity significantly increased from 1997 to 2004
• Persons living in urban areas more likely to be obese than those in rural areas
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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 GI symptoms*.
Diagnosis : Reflux symptoms
* Klauser AG et al. Lancet 335:205, 1990.
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Heartburn and Acid Regurgitation in GERD: Thai vs Germany
35
48
37
62
0
10
20
30
40
50
60
70
% P
atients
with the S
ym
pto
ms Non GERD
GERD
NS
P<0.05
48 48
68
60
0
10
20
30
40
50
60
70
% of
Pati
ents
with
reflu
x sym
ptom
s
Non GERD (pH-)
GERD (pH+)
Gonlachanvit S.
Neurogastroenterol Motil 2006
Klauser AG, et al
Lancet 1990
P<0.001 P<0.05
Heartburn Acid Regurgitation Heartburn Acid Regurgitation
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GERD symptom score
[mean + SE(* p value ≤ 0.05, ** p value ≤ 0.01)]
Placebo Capsicum
** **
**
Digestive Disease Week 2009
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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)
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Endoscopy : Reflux esophagitis
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Causes of Dyspepsia in CU Hospital During 2000-2002 (Endoscopic data, N=1,708)
10.714.5
0.9 2.5 1.05
80.7
0
10
20
30
40
50
60
70
80
90
100
GU DU GU+DU GERD Ca
stomach
NUD
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Gonlachanvit-GERD 15
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
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Gonlachanvit-GERD 16
Esophageal Manometry
Water
Perfused
Manometry System
High
Resolution
Manometry System
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Gonlachanvit-GERD 17
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 In preparation for antireflux surgery In 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
Diagnosis 24 hour esophageal pH monitoring
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Gonlachanvit-GERD 18
24 hour esophageal pH monitoring
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Gonlachanvit-GERD 19
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Gonlachanvit-GERD 20
Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring
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Gonlachanvit-GERD 21
Esophageal impedance testing
Swallow Reflux
Bolus Entry
Bolus Movement
Bolus Movement
Bolus Entry
Bolus Entry
Bolus Entry
Bolus Entry
Bolus Entry Bolus Entry
Bolus Entry
Bolus Entry
Bolus Entry
Bolus Entry
Bolus Entry
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Gonlachanvit-GERD 22
Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring
An Acid Reflux
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Gonlachanvit-GERD 23
Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring
Non Acid Reflux
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Gonlachanvit-GERD 24
37 patients with non-diagnostic EGD
and previous normal 24 hr. pH study
24 hr. MII pH testing
6 patients (16%)
Positive standard
24 hr pH test
10 patients (27%)
Positive symptom index
for acid reflux
14 patients (38%)
Positive symptom index
for non-acid reflux
7 patient (18%)
Negative symptom index
Kline et al. Clinical Gastroenterol and Hepatol 2008; 6: 880–885
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Gonlachanvit-GERD 25
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)
Nonacid Reflux
Associated with Symptom
37 % (53 patients)
Reflux Not
Associated with Symptom
52 % (75 patients)
Mainie et al. Gut 2006;55;1398-1402
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Gonlachanvit-GERD 26
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.
Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring
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PPI Test in Thai GERD Patients
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Effect of PPI test on GERD and the other symptoms in all patients
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Sym
pto
m s
core
s
Baseline
End of treatment
* P ≤ 0.05
* *
*
* *
*
*
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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%
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Non-Cardiac Chest Pain
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Total % time pH < 4
Total < 4.5 %
> 4.5 % EM Total
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
21
24
45
Esophageal manometry & Total % time pH < 4 in NCCP N=45
P > 0.05
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Extraesophageal GERD (LPR)
Nov 05
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% of ENT Symptoms in Patients Referred for pH Monitoring (N=59)
0
10
20
30
40
50
60
70
% o
f P
atien
ts
Globus Hoarseness Sore throat Clearing throat Chr cough
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Dual Channel 24 hour esophageal pH monitoring
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Diagnosis of GERD in ENT Patients (Gold Standard = 24 hr pH Monotoring)
47%
53%
Non GERD
GERD
Abnormal lower esophageal pH (pH<4 > 4%)
52%
48%
Non GERD
GERD
Abnormal upper esophageal pH (pH<4 > 1%)
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Prevalence
Prevalence of GERD in Thai Asthma patients
using 24 hr pH monitoring (n=56)
Prevalence 37.50%
15 pts (71.43%) had GERD symptoms
Jaimchariyatam N, Wongtim S, Udompanich V, Sittipunt C, Kawkitinarong K, Chaiyakul S et
al. J Med Assoc Thai 2011; 94(6):671-678.
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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 S., et al 2009
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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.
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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
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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.
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Uninvestigated GERD
Non-erosive reflux disease (NERD)
Reflux esophagitis (RE)
GERD Management
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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
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Erosive reflux disease
ERD = reflux symptoms + esophagitis (Gr C or D on endoscopy
M>F (2-3:1) May progress to more severe esophagitis and
stricture. In severe esophagitis, after stop antireflux
medications, 80 % of patients have symptom recurrence within 6 months.
Aims of treatment Mild esophagitis = controls symptoms Severe esophagitis = controls symptoms,
heals esophagitis, and maintains remission
of symptoms and esophagitis.
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Uninvestigated GERD
Non-erosive reflux disease (NERD)
Reflux esophagitis (RE)
GERD Management
Healing and
Maintenance of
Esophagitis
Induce symptom
remission and
prevent symptom recurrence
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p<0.0005
0
20
40
60
80
Esophagitis cases healed %
0 2 4 6 8 10 12
Time (weeks)
PPIs
H2-receptor
antagonists
Placebo
100
Meta-analysis: n=7635
83.6
51.9
28.2
Room for improvement !
Speed of Healing of Reflux Esophagitis
Chiba et al. Gastroenterology 1997
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0
20
40
60
Patients free from heartburn %
0 1–2 3–4 6–8 Weeks of treatment
Meta-analysis n=2198
80 Room for improvement !
Speed of Symptom Resolution in Patients with Reflux Esophagitis
Chiba et al. Gastroenterology 1997
H2-receptor
antagonists
PPIs
p<0.0001
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Lundell et al. Gut 1999
% p
atie
nts
in
sym
pto
ma
tic r
em
issio
n
100
80
60
40
20
0 0 1 2 3 4 5 6
Time after cessation of therapy (months)
No mucosal breaks
LA grade A
LA grade B
LA grade C
GERD tends to be a chronic condition
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Maintenance Therapies for Healed Erosive Esophagitis
Donnellan C, et al. Gastroenterology. 2003;124:A108.
Cochrane systematic review of 36 controlled trials
80
55
45
32
19
0
20
40
60
80
100
Placebo H2RA Prokinetics Half-dose PPI
Full-dose PPI
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Uninvestigated GERD
Non-erosive reflux disease (NERD)
Reflux esophagitis (RE)
GERD Management
Induce symptom
remission and
prevent symptom recurrence
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On demand therapy
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Symptom Response with On-demand vs. Continuous PPI Therapy for GERD
86%75%
0%
25%
50%
75%
100%
Continuous On-demand
Bour et al. Aliment Pharm Ther 2005;21:805
Resp
on
se t
o P
PI
(%)
176 pts with END or
Grade I/II esophagitis
and >moderate H-burn
who improved with
rabeprazole 10mg/d
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Uninvestigated GERD with no Alarm Symptoms
Non-erosive reflux disease (NERD)
Reflux esophagitis (RE)
Treatment of Uninvestigated GERD
Empiric Therapy
Alarm Symptoms
Weight loss
Dysphagia
Odynophagia
Bleeding, anemia
Frequent vomiting
Recent onset in old
age
Long duration of symptoms
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Step-in with a PPI
for 4 weeks
Symptom relief
Diagnostic
confirmation
GERD: Initial Management
The fastest, most economical path to:
Empirical therapy
After O'Connor et al. Am J Gastroenterol 2000 Dent, Talley. Aliment Pharmacol Ther 2003 (Suppl 1)
Dent et al. Gut 2004 (Suppl 4)
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Empirical
therapy
successful
Step down
to the lowest
dose that
controls
symptoms
GERD: Long-term management
Dent & Talley. Aliment Pharmacol Ther 2003 ( Suppl 1) Dent et al. Gut 2004 (Suppl 4)
Continuous daily
therapy
Intermittent
courses of therapy
On-demand therapy
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Hansen AN, et al. Int J Clin Pract 2006, 1, 15-22
Treatment of Uninvestigated GERD
On demand PPI vs Maintenance Therapy PPI and H2
Receptor Antagonist
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Algorithm for the management of Typical GERD in primary care
Typical GERD Symptoms
Alarm features present Alarm features absent
Refer for EGD
PPI test
Symptom persist Symptom respond
Maintain therapy for 4 weeks
On-demand therapy
Frequent relapses, alarm features
NERD: On demand Rx
Erosive: Maintenance
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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 S, 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, et al. Gastroenterology. 1999;116:239-247.
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Effect of Omeprazole on The Antiplatelet Activity of Clopidogrel
Gilard M, et al. J Am Coll
Cardiol 2008; 51(3):256-260.
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.
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Effect of PPI on Recurrent MI (13,636 cases vs 2,057 controls)
Juurlink DN, Gomes T, Ko DT, et al. CMAJ. 2009; DOI: 10.1503/cmaj.082001.
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Gonlachanvit-GERD 61
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?trialID=1872
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Gonlachanvit-GERD 62
Results
3627 patients (above the initial target of 3200)
393 sites
Median follow-up 133 days (maximum 362 days)
136 adjudicated cardiovascular events (preliminary)
105 adjudicated GI events (preliminary)
143 had been planned
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1872
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Baseline Characteristics
Variable Treated
n (%)
Placebo
n (%)
p-value for
difference
H. Pylori Positive 923 (49.2) 926 (49.0) 0.938
Used NSAIDs 116 (6.2) 105 (5.6) 0.456
Sex – Male 1251 (66.7) 1313 (69.6) 0.061
White/Black/Other 1756/68/51 1769/63/56 0.808
History of ACS 669 (36.1) 699 (37.5) 0.382
History of MI 484 (26.1) 466 (25.0) 0.468
History of PAD 172 (9.3) 158 (8.5) 0.426
History of Stroke 208 (5.8) 114 (6.1) 0.757
Mean (SD)
Median
Mean (SD)
Median
Age 67.2 years (10.8)
68.7 years
67.2 years (11.1)
68.6 years
0.984
BMI 29.2 kg/m2 (5.6)
28.4
29.2 kg/m2 (5.3)
28.3
0.655
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1872
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Days
Su
rviv
al P
rob
ab
ility
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0.9
0
0.9
2
0.9
4
0.9
6
0.9
8
1.0
0
Placebo
Treated
Survival Curves for PPI Treated vs Placebo
Composite Cardiovascular Events
Adjustment through Cox Proportional Hazards Model
Adjusted to Positive NSAID Use and Positive H. Pylori Status
HR = 1.02
95% CI = 0.70; 1.51
Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
COGENT — Presented at TCT 2009 http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1872
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Days
Su
rviv
al P
rob
ab
ility
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0.9
00
.92
0.9
40
.96
0.9
81
.00
Placebo
Treated
Survival Curves for PPI Treated vs Placebo
Revascularization
Adjustment through Cox Proportional Hazards Model
Adjusted to Positive NSAID Use and Positive H. Pylori Status
HR = 0.95
95% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk
Treated: 69 events, 1806 at risk
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1872
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Days
Su
rviv
al P
rob
ab
ility
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0.9
00
.92
0.9
40
.96
0.9
81
.00
Placebo
Treated
Survival Curves for PPI Treated vs Placebo
MI Events
Adjustment through Cox Proportional Hazards Model
Adjusted to Positive NSAID Use and Positive H. Pylori Status
HR = 0.96
95% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk
Treated: 36 events, 1839 at risk
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1872
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Days
Su
rviv
al P
rob
ab
ility
0 30 60 90 120 150 180 210 240 270 300 330 360 390
0.9
00
.92
0.9
40
.96
0.9
81
.00
Placebo
Treated
Survival Curves for PPI Treated vs Placebo
Composite GI Events
HR = 0.55
95% CI = 0.36; 0.85
p=0.007
(preliminary)
Placebo: 67 events, 1895 at risk
Treated: 38 events, 1878 at risk
COGENT — Presented at TCT 2009
http://www.cardiosource.com/clinicaltrials/trial.asp?trialID=1872
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Gonlachanvit-GERD 68
Summary
-PPIs’ side effects have been
identified reported.
- PPI should be used only in patients who really need it.
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Gonlachanvit-GERD 69
Thank you