Astroesophageal Reflux Disease -...

Gastroesophageal Reflux Disease

Sutep Gonlachanvit

GI 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 / 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

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

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

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)

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.

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

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

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.

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

GERD symptom score

[mean + SE(* p value ≤ 0.05, ** p value ≤ 0.01)]

Placebo Capsicum

** **

**

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

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

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


Esophageal Manometry

Water

Perfused

Manometry System

High

Resolution

Manometry System


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


24 hour esophageal pH monitoring


Multichannel Intraesophageal Impedance – pH (MII-pH) Monitoring


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



An Acid Reflux



Non Acid Reflux


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


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


37 % (53 patients)

Reflux Not


52 % (75 patients)

Mainie et al. Gut 2006;55;1398-1402


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

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

* *

*

* *

*

*

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

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

Extraesophageal GERD (LPR)

Nov 05

% 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

Dual Channel 24 hour esophageal pH monitoring

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%)

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.

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

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.

Uninvestigated GERD

Non-erosive reflux disease (NERD)

Reflux esophagitis (RE)

GERD Management


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 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.

Uninvestigated GERD



GERD Management

Healing and

Maintenance of

Esophagitis

Induce symptom

remission and

prevent symptom recurrence

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

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

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

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

Uninvestigated GERD



GERD Management

Induce symptom

remission and

prevent symptom recurrence

On demand therapy

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

Uninvestigated GERD with no Alarm Symptoms



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

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)

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

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

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

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.

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.

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.


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


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



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



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

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


Revascularization



HR = 0.95

95% CI = 0.59; 1.55 Placebo: 67 events, 1821 at risk




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


MI Events



HR = 0.96

95% CI = 0.59; 1.56 Placebo: 37 events, 1851 at risk




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


Composite GI Events

HR = 0.55

95% CI = 0.36; 0.85

p=0.007

(preliminary)

Placebo: 67 events, 1895 at risk





Summary

-PPIs’ side effects have been

identified reported.

- PPI should be used only in patients who really need it.


Thank you

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