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Successful Strategies for
Managing Acid-Related Disease
in Primary Care
David C. Metz, MD
Professor of Medicine
Division of Gastroenterology
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Key Question
In what percentage of your patients with chronic
GERD do you consider long-term management
strategies?
1. 0%-25%
2. 26%-50%
3. 51%-75%
4. 76%-100%
Use your keypad to vote now!
?
Faculty Disclosure
 Dr Metz: consultant: Altana Pharma U.S.,
Eisai Inc.; consultant, grants/research support:
TAP Pharmaceutical Products Inc.; consultant,
honorarium: AstraZeneca; consultant,
grants/research support, honorarium:
Wyeth Pharmaceuticals.
Learning Objectives
 Identify patients at risk for GI complications of
acid-related disorders
 Describe effective strategies for managing GERD
 Discuss options for minimizing GI risk in patients
requiring NSAID therapy
GERD = gastroesophageal reflux disorder; GI = gastrointestinal; NSAID = nonsteroidal
inflammatory drug.
Key Question
Which of the following increases a person’s
risk of developing esophageal adenocarcinoma?
1. Long-standing GERD symptoms
2. Frequent GERD symptoms
3. Both of the above
4. No study has connected GERD symptom
characteristics and adenocarcinoma risk
Use your keypad to vote now!
?
GastroEsophageal Reflux Disease
All individuals exposed to the physical complications from
gastroesophageal reflux or who experience clinically
Extraesophageal
significant
impairment
of health-related well
being
Esophagitis
Nonerosive
GERD
(quality
of life) due to reflux-related symptoms GERD
(EGD
negative)
Genval Working Group 1997
Stricture
Impairs Quality
of Life
Bleeding
Barrett’s Metaplasia
and
Adenocarcinoma
EGD = esophagogastroduodenoscopy; ENT = ear, nose, and throat.
ENT
Asthma
Dental
Pathophysiologic Determinants
of Esophagitis Severity and Chronicity
GERD
Severity
≈
N of reflux
events

Causticity of
gastric juice
Acid
clearance

Tissue
resistance
Aggressive
Factors
Defensive
Factors
 Chronic condition usually not attributed to excess acid secretion

Number of acid reflux events and caustic nature of refluxate are primary
determinants of GERD severity
 Tissue resistance and acid clearance also contribute
 Treatment approaches are compensatory, rather than curative
 Therapeutic focus is on refluxate causticity
 Few existing medical therapies affect the number of reflux events
 No noninvasive therapies to correct GERD-associated anatomical
and motor abnormalities
Barlow WJ, Orlando RC. Gastroenterology. 2005;128:771-778.
Dent J, et al. Gut. 2005;54:710-717.
DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.
Kahrilas PJ, et al. In: Gastrointestinal and Liver Disease: Pathophysiology/
Diagnosis/Management. 7th ed. Philadelphia, Pa:WB Saunders Co; 2002:599-622.
Traditional Assumptions Concerning
GERD Natural History
Spectrum/Progression
Mild Reflux:
NERD
Moderate to Severe Reflux:
Erosive Esophagitis
Severe Reflux:
Barrett’s Esophagus
NERD = nonerosive reflux disease.
Adapted from Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.
Evolving GERD “Phenotypic Model”
Progression Within the Group
NERD
Typical and
Atypical Symptoms
Erosive
Esophagitis
Stricture
Ulcer
GI Bleeding
Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.
Pandolfino JE, Shah N. Dig Liver Dis. 2006;38:648-651.
Barrett’s
Esophagus
Adenocarcinoma
of the Esophagus
Association Between GERD Symptom
Frequency and Duration
Esophageal Adenocarcinoma
Odds Ratio
18
16.4
16.7
16
14
12
10
7.5
8
6.3
5.2
6
5.1
4
2
1.0
1.0
0
0
<12
12-20
>20
Symptom Duration (Years)
N = 1438 (n =189 with esophageal adenocarcinoma).
Lagergren J, et al. N Engl J Med. 1999;340:825-831.
0
1
2-3
Symptom Frequency
(Times per Week)
>3
Summary of Disease Progression
Importance of Early Treatment
 NERD patients may develop esophagitis on follow-up
 However,
usually mild esophagitis
 Esophagitis may heal in patients who continue to have
symptoms on PPI therapy
 Left untreated, esophagitis may progress to worse
complications, including esophageal ulcer and stricture
 Long-standing and frequent GERD symptoms have
been shown to increase the risk of esophageal
adenocarcinoma
PPI = proton pump inhibitor.
Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.
Lagergren J, et al. N Engl J Med. 1999;340:825-831.
Summary of Disease Progression
Barrett’s Esophagus
 Barrett’s esophagus can develop after years of
reflux disease
 However, usually diagnosed on initial endoscopy
 Once developed, typically remains despite
antireflux therapy
 Barrett’s may progress to esophageal
adenocarcinoma
 However, sizeable proportion of adenocarcinoma
diagnoses are made without evidence of Barrett’s
Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.
Key Question
Approximately what percentage of patients
presenting to general practices with GERD
symptoms have normal mucosa or erythema
only on endoscopy?
1. 75%
2. 55%
3. 35%
4. 15%
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GERD: Endoscopic Findings
in General Practice
2 2
Percent of patients with:
12
22
Normal Mucosa
Erythema
Nonconfluent Erosions
Confluent Erosions
Circumferential Erosions
30
Ulcer, Stricture, Barrett's
Esophagus
32
N = 789 patients with GERD.
Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.
GERD Symptom Profile on
Presentation in Primary Care
Retrosternal Burning
86
Epigastric Burning
63
Retrosternal Pain
61
Epigastric Pain
60
Belching
58
Fullness
56
Fluid Retention
48
Flatulence
45
Nausea
45
Pharyngeal Burning
34
0
20
40
60
%
Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.
80
100
When Is Empiric Therapy Appropriate?
 2005 ACG Practice Guidelines: “If the patient’s history is typical for
uncomplicated GERD, an initial trial of empirical therapy…is appropriate.”
 Rationale:
 Classic reflux symptoms (ie, heartburn, regurgitation) have a positive
predictive value of >80% for GERD
 Regardless of endoscopic findings (erosive vs nonerosive),
most patients with typical symptoms are treated with PPIs
 Further diagnostic testing should be considered if:
 The patient has alarm symptoms
 There is no response to empiric therapy
 The patient has symptoms of sufficient duration to put him/her
at risk for Barrett’s esophagus
Age >50 – Controversial
Longstanding heartburn – How long?
DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.
Warning Signs/Alarm Symptoms
 Dysphagia
 Odynophagia
 Persistent vomiting
 Anorexia
 Unintentional weight loss
 Anemia
 Fever
 Gastrointestinal bleeding (occult or overt)
The presence of any of these symptoms
indicates the need for further testing
DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.
Algorithm for Diagnostic Referral in Patients
Presenting With GERD Symptoms
History and Physical Examination
Typical Symptoms Only
 Heartburn
 Regurgitation
Early Referral Symptoms
 Dysphagia
 Early satiety
 Frequent vomiting
 GI bleeding
 Weight loss
Empiric
Treatment
Katz PO. Am J Gastroenterol. 1999;94(11 Suppl):S3-S10.
Atypical Symptoms
 Asthma
 Chronic cough
 Chronic hoarseness
 Nausea and vomiting
 Unexplained chest pain
Diagnostic
Testing
Additional GERD Diagnostic
Techniques
Endoscopy
 Allows for direct visualization of
Ambulatory pH Monitoring
 Identifies patients with excess EAE and those with
symptoms that correlate with esophageal acid
the esophagus
 Helps to confirm acid reflux in patients with
 Should be considered at
persistent symptoms without evidence of
presentation if patients have
esophageal mucosal damage, especially when a
symptoms of complicated
trial of acid suppression has failed
GERD or are at risk for Barrett’s
 Monitors control of reflux in patients on therapy
“Technique of choice” to
but with continued symptoms
diagnose these conditions
Esophageal Manometry
Barium Esophagram
 Used to guide placement of pH
 Not recommended for routine GERD diagnosis
monitoring probes
 Not accurate for diagnosing Barrett’s
 May be helpful prior to antireflux  Reasonably accurate for severe esophagitis but
surgery
much less accurate for mild esophagitis
 Additional study needed to determine impact of newer techniques
of impedence and tubeless pH monitoring on GERD management
EAE = esophageal acid exposure.
DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.
Key Question
What overall percentage of patients with erosive
esophagitis experience healing of erosions with
8 weeks of standard-dose PPI therapy?
1. <75%
2. 75%-84%
3. 85%-94%
4. 95%-100%
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Focus of Medical Management of
GERD—Compensatory, Not Curative
It’s all about acid!
 PPIs
 H2RAs
 Antacids
H2RAs = histamine2-receptor antagonists.
Meta-Analysis of PPIs, H2RAs, and
Placebo for Healing Erosive Esophagitis
Total Healed (%)
100
(n) = Number of studies
80
(4)
(3)
(25)
(2)
0
(23)
(5)
20
2
PPIs
(27)
60
40
(26)
(2)
4
(25)
(8)
6
Therapy (weeks)
Chiba N, et al. Gastroenterology. 1997;112:1798-1810.
(22)
(9)
(5)
8
12
H2RAs
Placebo
Meta-Analysis of PPIs Versus Ranitidine
for Healing Erosive Esophagitis
Healing Rate Ratio (95% CI) Versus Ranitidine 300 mg
P <.05 for all PPIs
vs ranitidine 300 mg
Lansoprazole 30 mg (N = 948)
Omeprazole 20 mg (N = 1575)
Pantoprazole 40 mg (N = 249)
Rabeprazole 20 mg (N = 338)
0.75
Favors H2RA
CI = confidence interval.
Caro JJ, et al. Clin Ther. 2001;23:998-1017.
1.0
1.25
1.5
1.75
Favors PPI
2.0
PPI Therapy Is Extremely Effective
in the Majority of Patients With GERD—
Comparison Studies Versus Omeprazole
Patients With Healed
Erosive Esophagitis (%)
100
85%-95%
80
Omeprazole
Lansoprazole
60
Pantoprazole
40
Rabeprazole
Esomeprazole
20
0
N = 8531
N = 2862
N = 2023
8 Weeks
*P <.05 versus omeprazole.
1. Castell DO, et al. Am J Gastroenterol. 1996;91:1749-1757.
2. Mössner J, et al. Aliment Pharmacol Ther. 1995;9:321-326.
3. Dekkers C, et al. Aliment Pharmacol Ther. 1999;13:49-57.
4. Kahrilas P, et al. Aliment Pharmacol Ther. 2000;14:1249-1258.
N = 13044*
Comparison of Maintenance Therapies
for Erosive Esophagitis
PPI Healing Dose
Esophagitis Relapse (%)
70
60
PPI Maintenance Dose
38 randomized, controlled trials
Follow-up time: 24-52 weeks
58
50
NNT = 4.7
39
40
29
30
20
H2RA
66
NNT = 2.9
23
18
10
0
N = 5964
N = 1583
NNT = number needed to treat.
Donnellan C, et al. Cochrane Database Syst Rev. 2004;4.
N = 1156
Continuous Versus On-Demand PPI Therapy—
Maintaining Esophagitis Healing
Patients in Endoscopic
Remission at 6 Months (%)
Esomeprazole 20 mg QD (n = 241)
Esomeprazole 20 mg on demand (n = 229)
100
90
80
93
81
90
90
80
78
70
60
Harder to maintain healing
with more severe esophagitis
65
58
51
50
44
40
30
20
10
0
All Patients
P <.0001
A
B
C
D
Stratified According to Baseline Los Angeles Grade
Sjostedt S, et al. Aliment Pharmacol Ther. 2005;22:183-191.
Discontinued Due to
Inadequate Heartburn Control (%)
On-Demand Therapy for Maintenance
of Symptom Control*—Nonerosive GERD
40
36
35
Lansoprazole 15 mg QD
Rabeprazole 10 mg QD
28
30
Esomeprazole 20 mg QD
25
Esomeprazole 40 mg QD
20
20
Placebo
16
15
10
9
6
5
P <.05 for all PPIs
vs placebo in each study
5
0
*After an initial acute treatment period with continuous PPI to control symptoms, asymptomatic patients
were enrolled in the on-demand period.
Bigard MA, Genestin E. Aliment Pharmacol Ther. 2005;22:635-643.
Bytzer P, et al. Aliment Pharmacol Ther. 2004;20:181-188.
Talley NJ, et al. Eur J Gastroenterol Hepatol. 2002;14:857-863.
Key Question
What constitutes PPI therapy failure?
1. Failure of the FDA-approved dose
2. Failure of 2  the FDA-approved dose
3. Failure of 2  the FDA-approved dose BID
4. Failure is not defined
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?
GERD: Esophagitis, NERD,
or Functional Heartburn?
GERD
Symptoms?
+
Los Angeles A-D
Esophagitis
+
NERD
+
• NERD
(hypersensitive)
• Weakly acidic reflux
Endoscopy
–
MII/pH Monitoring
Excess Esophageal
Acid Exposure
–
MII/pH Monitoring
Symptom Correlation
–
Functional Heartburn
MII = multichannel intraluminal impedance.
Abnormal pH Monitoring in
Symptomatic Patients Taking PPIs
250 GERD patients
Typical (135)
QD PPI (79)
% time pH <4
# abnormal
1.2 (0%-28%)
24 (31%)
Extra-esophageal (115)
BID PPI (56)
QD PPI (40)
0.3 (0%-15%)
4 (7%)
BID PPI (75)
0.3 (0%-30%)
0 (0%-4.8%)
12 (30%)
1 (1%)
 pH testing should only be performed after patients have failed
double-dose PPI, if testing on medication
Charbel S, et al. Am J Gastroenterol. 2005;100:283-289.
Potential Etiologies of Heartburn—
Not All Heartburn Is GERD
 Esophagitis
 Histopathologic
esophagitis
 Healed esophagitis
 Acid-sensitive
esophagus
 Weakly acidic
reflux?
EMD = esophageal motility disorder
 EMD
 Eosinophilic
esophagitis
 Functional
heartburn
 Alkaline reflux?
 Distention
Nonerosive Reflux Disease
Abnormal Reflux
Acid
mediated
Non–acid
mediated
No Reflux
 Functional
 Not uniquely
chemosensitive
 Not uniquely
mechanosensitive
Reflux Treatment in 2007
Summary
 Focus has shifted from esophagitis to symptom control
 PPIs are the mainstay of therapy
 Long-term
safety is good
 Minor concerns
Osteoporosis
Clostridium difficile colitis
 Refractory or PPI unresponsive GERD requires concern
for other etiology
 Nonacid reflux
 Functional heartburn
Key Question
Of the following factors, which places patients
at the highest risk for developing GI
complications/adverse events?
1. Use of multiple NSAIDs (including aspirin)
2. Use of high-dose NSAIDs
3. Use of an anticoagulant
4. Past uncomplicated ulcer
Use your keypad to vote now!
NSAIDs = nonsteroidal anti-inflammatory drugs.
?
Burden of NSAIDs
 More than 111 million NSAID/COX-2 inhibitor
prescriptions written in 2004
 70% of persons aged ≥65 years take NSAIDs
at least weekly
 60% of these patients take aspirin
 34% take NSAIDs daily
Over 100,000 hospitalizations per year
due to NSAID-related complications
COX-2 = cyclooxygenase-2.
IMS NPA Plus, 2004 (January 2004-December 2004).
Talley NJ, et al. Dig Dis Sci. 1995;40:1345-1350.
Aspirin Alone or With Another NSAID:
Risk of Upper GI Complications
Relative Risk of Upper GI
Complications
8
7
6
5
4
3
2
1
0
Aspirin
75 mg
QD
Aspirin
150 mg
QD
Weil J, et al. BMJ. 1995;310:827-830.
Aspirin
300 mg
QD
NSAIDs
Aspirin
+ Other
NSAIDs
Identify Individuals With Risk Factors
for Adverse Events
13.5
Past Complicated Ulcer
9
Multiple NSAIDs*
High-Dose NSAIDs
7
Anticoagulant
6.4
6.1
Past Uncomplicated Ulcer
5.5
Age >60 Years
2.2
Steroids
0
5
10
Odds Ratio
 Use non-NSAID analgesic whenever possible
 Use the lowest effective NSAID dose
*Including aspirin.
Gabriel SE, et al. Ann Intern Med. 1991;115:787-796.
Garcia Rodriguez LA, et al. Lancet. 1994;343:769-772.
15
A Practical Guide to NSAID Therapy
No/Low
NSAID GI Risk
NSAID GI Risk
No CV Risk
(No Aspirin)
Traditional NSAID
Non-NSAID therapy
or
COX-2 inhibitor
or
Gastroprotective agent
with traditional NSAID
CV Risk
(Consider
Aspirin)
Non-NSAID therapy
or
Traditional NSAID* +
gastroprotective agent if GI risk
warrants gastroprotection
Non-NSAID therapy
or
Gastroprotective agent
with traditional NSAID
CV = cardiovascular.
*Ibuprofen should be used with caution in individuals taking aspirin.
Fendrick AM, et al. Am J Manag Care. 2004;10:740-741.
Antisecretory Cotherapy
Therapy
Advantages
Misoprostol  Reduces risk of gastric and
duodenal ulcers
 Reduces ulcer complications
H2RAs
PPIs
 Alleviate dyspeptic
symptoms
 Heal active ulcers only if
NSAID discontinued
 Alleviate dyspeptic symptoms
 Heal active ulcers even
when NSAID is continued
Lazzaroni M, et al. Dig Liver Dis. 2001;33:S44-S58.
Graham DY, et al. Arch Intern Med. 2002;162:169-175.
Peura DA. Am J Med. 2004;117:63S-71S.
Disadvantages
 Poor adherence
 Adverse effects (diarrhea
in 20% of patients)
 Contraindicated in women
of childbearing age
 Ineffective in preventing
gastric ulcers
 Less effective than PPIs
 Cost
GI Advisory Committee Consensus
on NSAIDs
 Recognized the CV effects of 3 COX-2 inhibitors:
celecoxib, valdecoxib, and rofecoxib
 Endorsed NSAID with a PPI over COX-2 inhibitors
 Naproxen was the NSAID identified as most favorable
 Be careful with ibuprofen + aspirin
 Advised against combination therapy with aspirin and
COX-2–selective agents
 Endorsed using a gastroprotective agent in patients
requiring aspirin plus an NSAID
US FDA Arthritis Advisory Committee, Drug Safety and Risk Management Advisory Committee,
February 16-18, 2005.
Case Study
Case Study: Presentation
 Caucasian male aged 50 years with a history
of heartburn 3 times per week
 Occasional nocturnal symptoms with regurgitation
and mild dysphagia
 Trouble sleeping and chronic cough
 Vital signs stable
 Mild obesity
 Otherwise normal
Case Study: Medical
and Treatment History
 Medical history includes knee replacement surgery,
hypertension, hypercholesterolemia, and pulmonary embolism
 Tried over-the-counter antacids and H2RAs for
4 weeks
 Mild improvement but still had significant breakthrough
symptoms
 Other medications
 Ibuprofen for knee pain 600 mg TID PRN
 Hydrochlorothiazide
 Potassium chloride
 Atorvastatin
 No known drug allergies
Decision Point
?
How would you manage this patient?
1. 4 weeks of empiric therapy with standard-dose PPI
2. 4 weeks of empiric therapy with PPI BID
3. Switch patient to standard-dose PPI therapy and
add OTC H2RA at bedtime
4. Check for Helicobacter pylori infection
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Decision Point
Does this patient need any diagnostic testing
and if so which test?
1. No testing needed—just treat
2. H pylori testing needed
3. Refer for endoscopy
4. Upper GI is all that is needed initially
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?
Q&A
PCE Takeaways
PCE Takeaways
1. If left untreated, GERD can progress to erosive
esophagitis, Barrett’s esophagus, and esophageal
adenocarcinoma
2. Focus of medical management of GERD is
compensatory, not curative
3. 2005 ACG Practice Guidelines recommend initial
trial of empiric PPI therapy if the patient’s history
is typical for uncomplicated GERD
PCE Takeaways
1. Know when to consider further testing:



Alarm symptoms or atypical symptoms
No response to empiric therapy
The patient has sufficient duration of symptoms
to be at risk for Barrett’s esophagus
PCE Takeaways
1. PPIs are very effective for most patients
with GERD
2. PPIs are the mainstay of therapy, with good
long-term safety
3. If GERD is refractory or PPI unresponsive,
look for other etiology
 Nonacid reflux
 Functional heartburn
PCE Takeaways: NSAIDS
1. 15% to 30% of regular NSAID users develop
ulcers, and potentially fatal complications such
as GI bleeding, perforation, or obstruction occur
in 1% to 2%
2. Consider antisecretory cotherapy in patients
 With history of ulcer
 Taking multiple NSAIDs, including aspirin
 Taking high-dose NSAIDs
 Taking an anticoagulant
 Aged >60 years
Key Question
In what percentage of your patients with chronic
GERD will you likely initiate long-term
management protocols?
1. 0%-25%
2. 26%-50%
3. 51%-75%
4. 76%-100%
Use your keypad to vote now!
?