Recent management of gerd from consensus to clinical application dr taulin agustinus
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Transcript of Recent management of gerd from consensus to clinical application dr taulin agustinus
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