Recent management of gerd from consensus to clinical application dr. Taolin Agustinus, SpPD, FINASUM PIT VII IDI Kota Bogor, 1-2 November 2014

1. RECENT MANAGEMENT OF GERD: From Consensus To Clinical Application
Dr.Agus Taolin, SpPD

2. “GERD is a condition which develops when the refluxof stomach content causes troublesome symptoms and / or complications”
Esophageal
Syndromes
Extra-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

3. USA
•20%adultssuffersfromsymptomsofrefluxonceaweek
•>40%suffersfromsuchsymptomsonceinamonth
•Prevalenceofesophagitis:7% ASIA-AFRICAprevalenceofesophagitisislowerthaninUSA
•China1,5%
•Korea1,7%

4. 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.2003TypicalAtypical
NCCP -14.5%
Chronic cough -13%
Laryngeal disorder-10%
Asthma-4.8%

5. Social and medical impact of GERD in TaiwanLiu et al. Aliment Pharmacol Ther 2005Heartburn 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.

6. INDONESIA
•DivisionofGastroenterologyDepartmentofInternalMedicine,MedicalFacultyUniversityofIndonesia:22,8%casesofesophagitisamongallpatientswhounderwentendoscopicexaminationduetodyspepsia(SyafruddinL.1998)

7. 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.

8. 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

9. 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

10. Medical Conditions Associated withGastroesophageal 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

11. 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

12. CLINICAL MANIFESTATIONSpectrum 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

13. 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

14. Esophagitis
Grade B
Grade A
Grade D
Grade C

15. Barrett’s esophagus

16. 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 :

17. 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)

18. 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

20. Acid Suppression/PPI test
•ThisPPItestisnowwidelyusedtodiagnoseGERDpatientsespeciallyinprimarycaresetting eventhoughsomereports(Kahrilasetal. 2005andametaanalysisstudybyNumansetal.2004.)confirmedthatPPItesthasahighsensitivitybutlowspecificity.
•The test is positive when 50% -75% symptoms improvement is observed after 1-2 weeks treatment

21. 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

22. BEsevereERD*NERD + mild ERD+
New concept based on ProGERD 2005No complicationsNegligible 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 2006Evolving concepts of the progression of GERD: implications for clinical management

23. MANAGEMENT
•Eventhoughthisconditionisrarelyfatal becauseoflong-termcomplication(ulceration, esophagealstricture,Barrett’sesophagus) GERDrequiresadequatemanagement
•Management of GERD:
–Lifestyle modification
–Drugs
–Surgical therapy
–Endoscopic therapy

24. 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

25. Reduce weight
Stop smoking
Avoid reflux-promoting agents (e.g. alcohol, coffee, some foods) (not evidence based)
Elevate head
of 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

26. Drugs
•GERD motility disorder
•The Fact acid suppression therapy more effective than prokinetic drugs
•PPIis the drug of choice

27. Initial
management
Long-term
managementGERD: clinical management

28. Initial treatment (6-8 weeks)
recovery rate >80%
Maintenance therapy/
On demand therapy

29. Symptom-based
diagnosis
Risk
assessment
Empirical
therapy
up to 95% in primary care
NERD
RE
~35%
CRD
~5%
~60% Endoscopy
Alarm
symptoms
Reflux
esophagitis
Complicated reflux disease
Labenz & Malfertheiner 2005GERD: initial management

30. 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 agentDomperidoneCisapride

31. 4. Proton pump inhibitor
•Drug of choicein 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

32. 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

33. 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 therapy
Frequent relapses

34. 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 Therapy
On demand therapy
PPI test (1-2 weeks)
Sensitivity: 68-80%
Symptoms recurrent or persist
Moderate & Severe Esophagitis
Recurrent Symptom
Alarm Symptoms
Age > 40 years

35. Wong et al. J Gastroenterol Hepatol 2004For mild GERD symptom
•Treat before testFor 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

36. Pharmacokinetic and acid
inhibition profiles
Efficacy
Indications and formulations
Potential for drug interactions
Tolerability/safety
Choosing a PPI to manage GERD:
factors to consider

37. 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

38. 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 Percent (%) Time
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

39. 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
% of Time
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 volunteers
RAB - rabeprazole
PAN - pantoprazole
95% confidence intervals are represented by vertical lines

40. ? 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 be
abandoned
Current
guidelinesMainstream options for therapy of GERD
after Dent et al 2002

41. 0
20
40
60
Patients free from heartburn%
0
1–2
3–4
6–8
Weeks of treatment
H2-receptorantagonistsMeta-analysis n=2198
PPIs
P<0.0001
80Speed of symptom resolution in patients with reflux esophagitis
Chiba et al 1997

42. P<0.0005
0
20
40
60
80
Esophagitis cases healed, %
0
2
4
6
8
10
12
Time (weeks)
PPIs
H2-receptorantagonists
Placebo
100
Meta-analysis: n=7635
83.6
51.9
28.2
Chiba et al 1997Speed of healing of reflux esophagitis

43. 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)
Patients achieving symptom relief (%)
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

44. 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

45. 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)
Relief 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

46. 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
Complete Relief With Rabeprazole (%)
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

47. 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

48. 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

49. PPIs –Drug Interactions
Rabeprazole
Pantoprazole
Lansoprazole
Omeprazole
Esomeprazole
Non-pH dependent interaction with
None
None
Sucralfate
Theophylline
Phenytoin Diazepam Warfarin Disulfram Cyclosporin
Benzodiazepines
Diazepam
pH-dependent interaction with
Ketoconazole Digoxin
US FDA Approved Package Insert

50. 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

51. Management of Complication
•Long term complication:
-Stricture
-Barrett’s esophagus
carcinoma
•Stricture of the esophagus
-Diameter <13 mm dilatation
Failed
surgery

52. 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
Total Barrett's Esophagus Patients
(%)
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

53. •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

54. Endoscopic treatment
•Relatively new/experimental
•Four basic types of endoscopic therapy:
–Endoscopic suturing
–Radiofrequency ablation
–Injection therapy
–Bulking procedures

56. 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

57. •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

58. Thank You