RECENT MANAGEMENT OF GERD:

From Consensus To Clinical

Application

Dr.Agus Taolin, SpPD

“GERD is a condition which develops when the reflux

of stomach content causes troublesome symptoms

and / or complications”

Esophageal

SyndromesExtra-esophageal

Syndromes

Symptomatic

Syndromes

Typical Reflux

Syndrome

Reflux Chest

Pain Syndrome

Syndromes

with Esophageal

Injury

Reflux Esophagitis

Reflux Stricture

Barrett’s Esophagus

Adenocarcinoma

Established

Associations

Reflux Cough

Reflux Laryngitis

Reflux Asthma

Reflux Dental Eros.

Proposed

Associations

Pharyngitis

Sinusitis

Idiopathic

Pulmonary Fibrosis

Recurrent Otitis

Media

Vakil N et al. Am J Gastroenterol 2006; in press

The Montréal definition of GERD

INTRODUCTION

USA

• 20% adults suffers from symptoms of

reflux once a week

• >40% suffers from such symptoms once in

a month

• Prevalence of esophagitis : 7%

ASIA-AFRICA prevalence of esophagitis

is lower than in USA

• China 1,5%

• Korea 1,7%

Most common GERD symptom in Asia

Acid regurgitation - 87%

Feeling of acidity in the stomach - 45%

Angina-like chest pain - 35%

Heartburn - 30%

Dyspepsia - 29%

Dysphagia - 6.5%

Wong BCY et al. Aliment Pharmacol Ther. 2003

Typical

Atypical

NCCP - 14.5%

Chronic cough - 13%

Laryngeal disorder - 10%

Asthma - 4.8%

Social and medical impact of GERD in

Taiwan

Liu et al. Aliment Pharmacol Ther 2005

Heartburn sufferers in Taiwan

• Have more atypical GERD symptoms.

• More medical consultation.

• Increased frequency of absenteeism.

• More sleep disturbance.

Heartburn consulters in Taiwan

• Co-existing globus.

• Higher costs for antacid, PPI, sedatives, tranquilizers,

and antidepressants.

INDONESIA

• Division of Gastroenterology Department

of Internal Medicine, Medical Faculty

University of Indonesia: 22,8% cases of

esophagitis among all patients who

underwent endoscopic examination due to

dyspepsia (Syafruddin L. 1998)

Figure 1. Prevalence of Reflux esophagitis 1997 VS 2002

5.7

25

.81

0 5 10 15 20 25 30 35

% of case

1997 2002

Ari F. Syam et al. 2005.

Impaired mucosal defence

de Caestecker, BMJ 2001; 323:736–9.

Johanson, Am J Med 2000; 108(Suppl 4A): S99–103.

peristaltic

Hiatus hernia

Impaired LES

–transient LES relaxations (TLESR)

– hypotensive LES

H+

Pepsin

Bile and

pancreatic

enzymes

esophageal

clearance of acid

(lying flat, alcohol,

coffee)

acid output

(smoking, coffee)

H. pylori

intragastric pressure

(obesity, lying flat)

bile reflux

gastric emptying (fat)

Pathophysiology of GERD

salivary HCO3

Environmental Risk Factors for

Gastroesophageal Reflux Disease

Risk Factor Mechanism of Risk

Smoking Weakened LES? (small risk)

Alcohol Mucosal damage ? (small risk)

Medications Weakening of LES, mucosal damage

Meals and specific foods Gastric distension, weakening of LES, irritation of

esophageal mucosa

Helicobacter pylori Beneficial influence as corpus gastritis reduces acid

output

Naso-gastric tubes Conduit for acid reflux in supine patients

Abdominal trauma Disruption of diaphragm?

LES = lower esophageal sphincter

Fass, 2004

Medical Conditions Associated with

Gastroesophageal Reflux Disease

Associated Condition Mechanism of Risk

Obesity Increased intra-abdominal pressure

Diabetes mellitus Delayed gastric emptying

Zollinger-Ellison syndrome Increased acid output

Pregnancy Increased intra-abdominal pressure, weakened LES

Myotomy in achalasia Destroyed LES

CRST syndrome Impaired peristalsis

Sicca syndrome Impaired esophageal clearance

Psychiatric disease Impaired esophageal motility

Mental retardation of childhood Impaired esophageal motility

LES = lower esophageal sphincter

Fass, 2004

The role of H. pylori infection in

the pathogenesis of GERD:

• There is little evidence that H. pylori

infection has pathogenic role in GERD.

• Virulent strain (Cag A positive) inverse

relationship.

• Depends on anatomical distribution of

gastritis (antral predominant gastritis or

corpus predominant gastritis) and pre-

existing GERD

CLINICAL MANIFESTATION

Spectrum of Gastroesophageal Reflux Disease

Organ Types of Disease Manifestation

General Symptoms Belching, heartburn, regurgitation, chest pain,

dysphagia, pharyngeal soreness, hoarseness, coughing

Esophagus Erosion, ulcer, stricture, Barrett’s metaplasia,

adenocarcinoma

Throat Pharyngitis, laryngitis, sinusitis, aphonia, laryngeal

stenosis, cancer

Mouth Tooth decay, gingivitis

Lung Asthma, chronic obstructive pulmonary disease,

pneumonia

Fass, 2004

DIAGNOSIS

1. Upper GI endoscopy

– Upper GI endoscopy is the gold standard of

the diagnosis of GERD mucosal break

– To assess macroscopic changes in the

esophageal mucosa. Biopsy sample is taken

in patient with suspected malignancy/Barret’s

esophagus

– Some patient with characteristic symptom of

GERD may exist without any mucosal break

NERD

Esophagitis Grade BGrade A

Grade DGrade C

Barrett’s esophagus

Alarm symptoms (e.g. dysphagia, weight

loss, bleeding, abdominal mass, age >40

years)

Diagnostic problems (e.g. atypical

symptoms)

No response to empirical treatment in

patient with characteristic symptoms

By patient request, or referred from other

clinician

Endoscopy are considered

to be performed in patients with :

2. Esophageal radiography with barium

swallow

• Only performed in patient with

esophageal stenosis secondary to peptic

esophagitis resulting in dysphagia

3. 24 hours pH monitoring

To monitor episodes of esophageal acidification by placement of a pH microelectrode in the distal esophagus

(The newest technique : BRAVO)

4. Esophageal Manometry

This test may sometimes useful when a

barium swallow and endoscopy have

been normal

5. Acid Suppression Test / PPI Test

As the empirical treatment to evaluate

the symptoms of GERD after taking

high dose of PPI

Acid Suppression/PPI test

• This PPI test is now widely used to diagnose

GERD patients especially in primary care setting

eventhough some reports (Kahrilas et al.

2005 and a meta analysis study by Numans et

al. 2004.) confirmed that PPI test has a high

sensitivity but low specificity.

• The test is positive when 50% - 75% symptoms

improvement is observed after 1-2 weeks

treatment

Rabeprazole 20 mg twice daily as a

diagnostic test for GERD

PPI Dose Days Sen (%) Spe (%)

Rabeprazole 20 mg twice daily 7 83 45

Esomeprazole 40 mg once daily &

20 mg twice daily

14 79 - 86 24 - 65

Omeprazole 20 mg twice daily 7 71 - 81 55

Lansoprazole 60 mg daily 7 85 73

Johnsson F et al. Scand J Gastroenterol 1998

Johnsson F et al. Scand J Gastroenterol 2003

Juul-Hansen P et al. Scand J Gastroenterol 2001

Stanislas Bruley des Varannes et al. World J Gastroenterol 2006

BEsevere

ERD*NERD + mild ERD+

New concept based on ProGERD 2005

No complications

Negligible progression

>85%

Potentially serious

complications

<15%

Focus of treatment: Symptoms Symptoms & lesions

+Grade A and B according to the LA classification

*Grade C and D according to the LA classification

Labenz & Morgner-Miehlke 2006

Evolving concepts of the progression of

GERD: implications for clinical management

MANAGEMENT

• Even though this condition is rarely fatal

because of long-term complication (ulceration,

esophageal stricture, Barrett’s esophagus)

GERD requires adequate management

• Management of GERD:

– Lifestyle modification

– Drugs

– Surgical therapy

– Endoscopic therapy

Goals in the management of

GERD• Provide complete (sufficient) relief from

heartburn and other symptoms

• Heal underlying esophagitis

• Maintain symptomatic and endoscopic

remission

• Treat or, ideally, prevent complications

Dent et al 1999

Reduce weight

Stop smoking

Avoid reflux-promoting agents (e.g. alcohol, coffee, some foods) (not evidence based)

Elevate headof bed

Consider alternatives to

reflux-promoting drugs (e.g. theophylline, anticholinergics)

Modifications

Eat small meals,no late meals,

reduce fat

Lifestyle modifications for the

management of GERD

Drugs

• GERD motility disorder

• The Fact acid suppression therapy

more effective than

prokinetic drugs

• PPI is the drug of choice

Initial

management

Long-term

management

GERD: clinical management

Initial treatment (6-8 weeks)

recovery rate >80%

Maintenance therapy/

On demand therapy

Symptom-baseddiagnosis

Riskassessment

Empiricaltherapy

up to 95% in primary care

NERD

RE~35%

CRD~5%

~60%

Endoscopy

Alarmsymptoms

Reflux esophagitis

Complicated reflux disease

Labenz & Malfertheiner 2005

GERD: initial management

1. Antacid

• The mainstay for rapid, save, effective relief of

symptoms without significant healing effect

• Dose: 15 mL qid

2. H2-Receptor Antagonist

( Ranitidine, Famotidine, Nizatidine)

• As an acid suppressor (and increase the chance for

lesions to heal) should be used in double dose than

those used for treatment of duodenal ulcer

Only effective in mild GERD

3. Prokinetic agentDomperidone

Cisapride

4. Proton pump inhibitor

• Drug of choice in the treatment of GERD

• Very effective (clinically and endoscopically) in symptoms relief and healing of severe grade esophagitis and GERD refractory to H2RA:

• Dose for GERD:

- Omeprazole : 2 x 20 mg

- Lanzoprazole : 2 x 30 mg

- Pantoprazole : 2 x 40 mg

- Rabeprazole : 2 x 10 mg

- Esomeprazole : 2 x 40 mg

6-8 weeks maintenance/on demand therapy

• Combination with prokinetic drugs enhance effectivity

Dose for NERD:

- Omeprazole : 1 x 20 mg

- Lanzoprazole : 1 x 30 mg

- Pantoprazole : 1 x 40 mg

- Rabeprazole : 1 x 10 mg

- Esomeprazole: 1 x 40 mg

• >4 weeks on demand therapy

Algorithm of the management of GERD in primary care

(National Consensus in the Management of GERD in

Indonesia, Indonesian Society of Gastroenterology,2004)

Typical GERD Symptoms

*Heartburn

*Regurgitation

Alarm symptom present

Age >40 years

Alarm symptoms absent

Symptoms persist

Maintain therapy 4 weeks

Empirical treatment/PPI test

Endoscopy

Symptoms respond

On-demand therapyFrequent relapses

Algorithm of the management of GERD (National

Consensus in the Management of GERD in Indonesia,

Indonesian Society of Gastroenterology2004)

Typical GERD Symptoms

*Heartburn

*Regurgitation

Uninvestigated Investigated

Mild esophagitis

NERD

Empirical Treatment

/ PPI Test

Initial Treatment

Maintenance TherapyOn demand therapy

PPI test (1-2 weeks)

Sensitivity: 68-80%

Symptoms recurrent

or persist

Moderate & Severe

Esophagitis

Recurrent Symptom

Alarm Symptoms

Age > 40 years

Wong et al. J Gastroenterol Hepatol 2004

For mild GERD symptom

• Treat before test

For severe GERD symptom

• Gastroenterologist - test before treat

• Primary care physician - treat before test

• ENT doctor - treat before test

Most doctors heard of PPI testing but only 33-52% of them

had used it before.

Clinical practice pattern in Asia

Pharmacokinetic and acid

inhibition profiles

Efficacy

Indications and formulations

Potential for drug interactions

Tolerability/safety

Choosing a PPI to manage GERD:

factors to consider

In vitro chemical activation rates of PPIs

vary with pH

Kromer W et al. Differences in pH – Dependent Activation Rates of Subtituted Benzimidazoles and Biological in vitro Correlates.

Pharmacology 1998; 56 : 57 - 70

During night-time, mean percent time pH > 3 & pH > 4 was significantly higher on a single dose of rabeprazole 20 mg than esomeprazole 40 mg

0

5

10

15

20

25

30

35

40

45

50

Intragastric pH > 3 Intragastric pH > 4

Mean

Perc

en

t (%

) T

ime

Rabeprazole 20 mg

Esomeprazole 40 mg

Warrington S et al. Eur J Clin Pharmacol 2006; 62: 685 - 691

N = 24 Helicobacter pylori – negative healthy volunteers

P = NS:

• Mean AUC0-24 h

• Mean % time pH > 3

• Mean % time pH > 4

*P < 0.05 *P < 0.05

51

37.7

24.9

11.2

35.7

23.9

14.2

5.8

0

10

20

30

40

50

60

70

80

90

100

pH > 3 pH > 4 pH > 5 pH > 6

pH Threshold

% o

f T

ime

Oral RAB 20

IV PAN 40

D Armstrong et al. Aliment Pharmacol Ther 2007; 25 (2): 185 - 196

Day 1 - Oral Pariet 20 mg is significantly more effective than IV pantoprazole 40 mg in % time pH > 3, 4, 5 & 6 over 24 hours

Complete 24-Hour Recording (0 - 24 hours)

P < 0.05 for All

N = 33 Helicobacter pylori - negative volunteersRAB - rabeprazole

PAN - pantoprazole

95% confidence intervals are represented by vertical lines

? x2 daily PPI + H2RA

x2 daily PPI

x1 daily PPI

x1 daily ½ PPI

Prokinetic + H2RA

Prokinetic*

Antacids + lifestyle

Antacids

Lifestyle

H2RA*OR

*no clear dose-response established

Highest efficacy

Lowest efficacy

Recommended

Should beabandoned

Current

guidelines

Mainstream options for therapy of

GERD

after Dent et al 2002

0

20

40

60

Patients free from heartburn%

0 1–2 3–4 6–8Weeks of treatment

H2-receptor

antagonists

Meta-analysis n=2198

PPIs

P<0.0001

80

Speed of symptom resolution in

patients with reflux esophagitis

Chiba et al 1997

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

Chiba et al 1997

Speed of healing of reflux

esophagitis

More patients had satisfactory relief of day – time

heartburn & regurgitation with Pariet 10mg

than with esomeprazole 20mg

79.4%

71.4%

75.7%

60.5%

71.1%

85.7% 86.0%

92.5%

55%

65%

75%

85%

95%

1 2 3 4 (wk)

Pa

tie

nts

ac

hie

vin

g s

ym

pto

m r

elie

f (%

)

Esomeprazole 20mg/d n=52 Rabeprazole 10mg/d n=52

p = 0.045

Fock KM, Rabeprazole vs Esomeprazole in non erosive gastro – oesophageal reflux disease: A Randomized, double blind study

In Urban Asia. World Journal of Gastroenterology, 2005 ; 11 (20): 3011 - 3170

Superior reduction in severe heartburn with

Pariet 20mg than high dose Omeprazole 40mg,

within 3 days

4.7%

10.3%

0%

2%

4%

6%

8%

10%

12%

Rabeprazole 20mg Omeprazole 40mg

Patients

n = 230 patients

Report of severe daytime heartburn during the first 3 days

( post hoc analysis )

Holtman G. et al. A Randomized, double – blind, comparative study of standard-dose and high dose omeprazole in

gastro – oesophageal reflux disease. Aliment Pharmacol Ther 2002; 16 : 479 - 485

Rabeprazole 10 mg was statistically superior to omeprazole 20 mg in partial pain relief rate on Day 1 & acid regurgitation relief rate on Day 7

0

20

40

60

80

100

120

D1 (Partial Pain) D7 (Acid Regurgitation)

Reli

ef

Rate

(%

)

Rabeprazole 10 mg (N = 108)

Omeprazole 20 mg (N = 103)

P = NS:

Abdominal Bloatness Relief Rate

Belching Relief Rate

Active Duodenal Ulcer

*P < 0.05

*P < 0.05

Lin S et al. Zhonghua Nei Ke Za Zhi 2002; 41 (9): 589-91

Rabeprazole provided effective relief of daytime & nighttime heartburn

& regurgitation in a majority of patients suffering from erosive GERD

who reported ineffective relief with prior OME or LAN therapy

65.6

82.2

75.5

81

77.8

82.3

76.8

84.4

63.5

77.2

66.2

74.8

66.4 66 66.7

72.3

0

10

20

30

40

50

60

70

80

90

100

At Day 7 At Week 4 At Day 7 At Week 4

Co

mp

lete

Re

lie

f W

ith

Ra

be

pra

zo

le (

%)

Daytime Heartburn

Nighttime Heartburn

24-Hour Heartburn

Regurgitation

N = 290 previously on omeprazole OME

N = 210 previously on lansoprazole LAN Fitzgerald S et al. Gastroenterology 2001; 120 (5) Suppl 1: A441

Prior Omeprazole Prior Lansoprazole

A high percentage achieve heartburn relief * –Future of Acid Suppression Therapy (FAST) Study

M. Robinson et al. Aliment Pharmacol Ther 2002; 16: 445-454

* Patients with moderate or severe symptoms at baseline who achieve mild or no symptoms

PPIs – Meals & Time of Dosing

Rabeprazole Pantoprazole Lansoprazole Omeprazole Esomeprazole

Meal No effect on bioavailability

↓ absorption up to 2 hours or

longer

Cmax & AUC

↓ 50 - 70% if given 30

minutes after food compared

to fasting conditions

Cmax ↓ 25% when 20 mg

when administered

with applesauce, unlike 40 mg

AUC ↓ 43-53% after food

intake compared to

fasting conditions

Time of Dosing

No effect on bioavailability

No effect on bioavailability

Before meals Before meals 1 hour before meals

US FDA Approved Package Insert

PPIs – Drug Interactions

Rabeprazole Pantoprazole Lansoprazole Omeprazole Esomeprazole

Non-pH dependent interaction

with

None None SucralfateTheophylline

Phenytoin Diazepam Warfarin Disulfram

CyclosporinBenzodiazepines

Diazepam

pH-dependent interaction

withKetoconazole Digoxin

US FDA Approved Package Insert

Use of PPIs in Pregnancy

B - Animal studies showed no fetal risk but no controlled clinical study; or

animals studies showed no adverse effects but not seen in clinical study. If there

is a clinical need for a Category B drug, it is considered safe

C - Animal studies showed teratogenic or embryocidal effects but no clinical study;

or no animal study available. Drugs in this category should be given only when

the potential benefit justifies the potential risks to the fetus

Drug FDA Pregnancy Category

Rabeprazole B

Pantoprazole B

Lansoprazole B

Esomeprazole B

Omeprazole C

US FDA Approved Package Insert

Management of Complication

• Long term complication:

- Stricture

- Barrett’s esophagus

carcinoma

• Stricture of the esophagus

- Diameter <13 mm dilatation

Failed

surgery

Wani S et al. Aliment Pharmacol Ther 2005; 22 (7): 627 - 633

The majority of Barrett’s oesophagus patients (73.9%)

can achieve normalization of oesophageal acid exposure on rabeprazole 20 mg twice daily therapy (median total % time pH < 4 = 0.2%)

73.9

26.1

0

10

20

30

40

50

60

70

80

90

100

To

tal

Barr

ett

's E

so

ph

ag

us P

ati

en

ts

(%) Normal pH*

Abnormal pH*

N = 46

*Patients with intra-oesophageal pH < 4 for longer than 4.2% of the

total monitoring period were considered to have an ABNORMAL result

• fundoplication

• The best candidates for fundoflication are those with . .

– Esophagitis documented by endoscopy,

– Need for continuous PPI therapy

– Abnormal pH monitoring studies,

– Normal esophageal motility studies,

– Responders to PPI therapy with persistent volume regurgitation

Surgical treatment

Endoscopic treatment

• Relatively new/experimental

• Four basic types of endoscopic therapy:

– Endoscopic suturing

– Radiofrequency ablation

– Injection therapy

– Bulking procedures

SUMMARY

• GERD is common in western population

low prevalence in Asia –Africa

countries. In Indonesia seems to be

increased

• Characteristic symptoms of GERD is

heartburn Disphagia, nausea,

regurgitation

• Early endoscopy is recommended in all

patients presenting with reflux symptoms

• PPI test is widely used as the empirical

treatment of GERD, especially in primary care

setting

• PPIs are the drug of choice for the initial

management and long term care of all patients

with GERD. Treatment should always be started

with a highly effective PPI

• Anti reflux surgery should be reserved for (a few)

carefully selected patients

• Endoscopic treatment are currently experimental

SUMMARY

Thank You