St

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Fall 2007Symposia Series

• St

• Sheraton Buckhead Hotel AtlantaAtlanta,
  GeorgiaNovember 10, 2007

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Not All Heartburn Is GERD Successful Strategies
forManaging Acid-Related Disease

• John E. Pandolfino, MD
• Associate Professor of Medicine
• Feinberg School of Medicine
• Northwestern University
• Chicago, Illinois

3
Faculty Disclosure

• Dr Pandolfino consultant/speaker/grant support
  AstraZeneca, Medtronic, Inc. speaker Santarus,
  Inc. advisory board Crospon Ltd.

4
Learning Objectives

• Describe effective strategies for managing GERD
• Identify patients at risk for GI complications of
  acid-related disorders
• Discuss options for minimizing GI risk in
  patients requiring NSAID therapy

GERD gastroesophageal reflux disease GI
gastrointestinal NSAID nonsteroidal
anti-inflammatory drug.
5
Key Question

• In what percentage of your patients with chronic
  GERD do you consider long-term management
  strategies?
• 0-25
• 26-50
• 51-75
• 76-100
• Use your keypad to vote now!

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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!
7
Key Question

• What overall percentage of patients with erosive
• esophagitis experience healing of erosions with
• 8 weeks of standard-dose PPI therapy?
• lt75
• 75-84
• 85-94
• 95-100
• Use your keypad to vote now!

PPI proton pump inhibitor.
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What overall percentage of patients with erosive
esophagitis experience healing of erosions with 8
weeks of standard-dose PPI therapy?

1. lt75
2. 75-84
3. 85-94
4. 95-100

Use your keypad to vote now!
9
GastroEsophageal Reflux Disease
All individuals exposed to the physical
complications from gastroesophageal reflux or who
experience clinically significant impairment of
health-related well being (quality of life) due
to reflux-related symptoms Genval Working
Group 1997
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Pathophysiologic Determinants of Esophagitis
Severity and Chronicity
Aggressive Factors
Causticity of gastric juice
N of reflux events
?
Defensive Factors
Tissue resistance
Acid clearance
?

• 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.
2005128771-778. Dent J, et al. Gut.
200554710-717. DeVault KR, et al. Am J
Gastroenterol. 2005100190-200. Kahrilas PJ, et
al. In Gastrointestinal and Liver Disease
Pathophysiology/Diagnosis/Management. 7th ed.
Philadelphia, Pa WB Saunders Co 2002599-622.
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Focus of Medical Management of GERDCompensatory,
Not Curative

• Its all about acid!
• PPIs
• H2RAs
• Antacids

H2RAs histamine2-receptor antagonists.
12
Meta-Analysis of PPIs, H2RAs, and Placebo for
Healing Erosive Esophagitis
(n) Number of studies
100
(2)
(3)
PPIs
(26)
80
(27)
(4)
(22)
H2RAs
60
(25)
Total Healed ()
(25)
(23)
40
(9)
(2)
Placebo
(5)
(8)
(5)
20
0
2
4
6
8
12
Therapy (weeks)
Chiba N, et al. Gastroenterology.
19971121798-1810.
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PPI Therapy Is Extremely Effective in the
Majority of Patients With GERDComparison
Studies Versus Omeprazole
100
85-95
80
Omeprazole
Lansoprazole
60
Pantoprazole
Patients With Healed
Erosive Esophagitis ()
40
Rabeprazole
Esomeprazole
20
0
N 8531
N 2862
N 2023
N 13044
8 Weeks
P lt.05 versus omeprazole. 1. Castell DO, et al.
Am J Gastroenterol. 1996911749-1757. 2. Mössner
J, et al. Aliment Pharmacol Ther.
19959321-326. 3. Dekkers C, et al. Aliment
Pharmacol Ther. 19991349-57. 4. Kahrilas P, et
al. Aliment Pharmacol Ther. 2000141249-1258.
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Comparison of Maintenance Therapies for Erosive
Esophagitis
PPI healing dose
PPI maintenance dose
H2RA
38 randomized, controlled trials Follow-up time
24-52 weeks
NNT 4.7
NNT 2.9
NNT number needed to treat.Donnellan C, et al.
Cochrane Database Syst Rev. 20044.
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Continuous Versus On-Demand PPI
TherapyMaintaining Esophagitis Healing
Esomeprazole 20 mg QD (n 241)
Harder to maintain healing with more severe
esophagitis
Esomeprazole 20 mg on demand (n 229)
100
93
90
90
90
81
80
78
80
70
65
58
60
Patients in Endoscopic Remission at 6 Months ()
51
50
44
40
30
20
10
0
A
B
C
D
All patients P lt.0001
Stratified According to Baseline Los Angeles Grade
Sjostedt S, et al. Aliment Pharmacol Ther.
200522183-191.
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On-Demand Therapy for Maintenance of Symptom
ControlNonerosive GERD
Rabeprazole 10 mg QD
P lt.05 for all PPIs vs placebo in each study
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. 200522635-643. Bytzer P, et al. Aliment
Pharmacol Ther. 200420181-188. Talley NJ, et
al. Eur J Gastroenterol Hepatol. 200214857-863.
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Summary of GERD Treatment

• PPIs are the mainstay of therapy
• Chronic PPI therapy indicated for
• Esophagitis
• Symptoms greater than 3/week
• PPI on-demand therapy may be reasonable for
• Mild NERD
• Mild esophagitis

Kahrilas PJ, et al. In Gastrointestinal and
Liver Disease Pathophysiology/Diagnosis/Manageme
nt. 7th ed. Philadelphia, Pa WB Saunders Co
2002599-622.
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PPIs Have a Good Long-term Safety Profile

• Minor Concerns
• Osteoporosis
• Increased risk of hip fractures
• Adjusted OR 2.65 (1.8-3.9)
• Enteric infection
• Increased risk of Clostridium difficile infection
  in PPI users
• Risk increased from 0.02 to 0.06
• Pneumonia
• Flawed study, with no control for important
  confounders
• Vitamin B12 deficiency
• Data conflicting

Dial S, et al. JAMA. 20052942989-2995. Laheij
RJ, et al. JAMA. 20042921955-1960. Yang YX, et
al. JAMA. 20062962947-2953.
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Key Question

• Approximately what percentage of patients
  presenting to general practices with GERD
  symptoms have normal mucosa or erythema only on
  endoscopy?
• 75
• 55
• 35
• 15
• Use your keypad to vote now!

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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

Use your keypad to vote now!
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When Is Empiric Therapy Appropriate?

• 2005 ACG Practice Guidelines If the patients
  history is typical for uncomplicated GERD, an
  initial trial of empirical therapyis
  appropriate.
• Rationale
• Classic reflux symptoms (ie, heartburn,
  regurgitation) have a positive predictive value
  of gt80 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 Barretts esophagus
• Age gt50 Controversial
• Longstanding heartburn How long?

DeVault KR, et al. Am J Gastroenterol.
2005100190-200.
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Algorithm for Diagnostic Referral in Patients
Presenting With GERD Symptoms
History and Physical Examination

• Early Referral Symptoms
• Dysphagia/odynophagia
• Early satiety
• Persistent vomiting
• GI bleeding
• Weight loss
• Fever

• Typical Symptoms Only
• Heartburn
• Regurgitation

• Atypical Symptoms
• Asthma
• Chronic cough
• Chronic hoarseness
• Nausea and vomiting
• Unexplained chest pain

Empiric Treatment
Diagnostic Testing
Katz PO. Am J Gastroenterol. 199994(11
Suppl)S3-S10.
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Endoscopy

• Indications
• Dysphagia/odynophagia
• Persistent vomiting
• Anorexia
• Unintentional weight loss
• Anemia
• Fever
• Gastrointestinal bleeding (occult or overt)

These symptoms indicate a high risk for
complications or an alternative diagnosis
DeVault KR, et al. Am J Gastroenterol.
2005100190-200.
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GERD Endoscopic Findings in General Practice
Percent of patients with
N 789 patients with GERD. Jones R, et al. Scand
J Gastroenterol Suppl. 199521135-38.
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Endoscopy
26
Endoscopy
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Eosinophilic Esophagitis Can Mimic GERD

• Allergic esophagus infiltrative eosinophilia
• Increasing incidence vs underrecognized
• Signs/symptoms
• Dysphagia, food impaction, abdominal/chest pain,
  vomiting, regurgitation
• Clinical characteristics
• Male predominance (70-80 of cases)
• Family or personal history of allergy/atopy
• Asthma, rhinitis, eczema, food allergy

Eos
GERD
Arora AS, et al. Clin Gastroenterol Hepatol.
20042523-530. Liacouras CA, et al. Clin
Gastroenterol Hepatol. 200531198-1206.
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Differentiating GERD From Eosinophilic
Esophagitis
GERD Eosinophilic Esophagitis
Pathogenesis Abnormal acid exposure Possibly allergic
Symptoms Heartburn, epigastric pain, vomiting/regurgitation Dysphagia, food impaction, reflux-like symptoms
Endoscopy Erosions, ulceration, rings, stricture, normal Rings, furrows, whitish plaques, normal
Histology Basal zone hyperplasia, papillary lengthening, mild eosinophilia Marked eosinophil infiltration (gt20 per high-power field)
Treatment PPI Steroids, dietary elimination, dilation
Arora AS, et al. Clin Gastroenterol Hepatol.
20042523-530. Liacouras CA, et al. Clin
Gastroenterol Hepatol. 200531198-1206.
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Management of Eosinophilic Esophagitis

• Medical therapy can lead to resolution
  ofsymptoms and stricture
• Treatment
• PPI
• Steroids (fluticasone, prednisone)
• Diet (wheat, soy, milk, peanuts, and/or seafood)
• Allergy evaluation?

Dilation therapy
Attwood SE, et al. Dig Dis Sci.
199338109-116. Liacouras CA, et al. Clin
Gastroenterol Hepatol. 200531198-1206.
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Pill Esophagitis Can Mimic GERD
N 92
Other antibiotics
40
8
NSAIDs (including aspirin)
Tetracyclines
22
7
Quinidine
4
10
9
Ascorbic acid
Potassium chloride
Alendronate
NSAIDs nonsteroidal anti-inflammatory drugs.
Abid S, et al. Endoscopy. 200537740-744.
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Key Question

• What constitutes PPI therapy failure?
• Failure of the FDA-approved dose
• Failure of 2 ? the FDA-approved dose
• Failure of 2 ? the FDA-approved dose BID
• Failure is not defined
• Use your keypad to vote now!

32
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

Use your keypad to vote now!
33
Abnormal pH Monitoring in Symptomatic Patients
Taking PPIs
250 GERD patients
Typical (135)
Extra-esophageal (115)
BID PPI (56)
BID PPI (75)
QD PPI (40)
QD PPI (79)
time pH lt4
1.2 (0-28)
0.3 (0-15)
0.3 (0-30)
0 (0-4.8)
abnormal
4 (7)
12 (30)
24 (31)
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.
2005100283-289.
34
Potential Etiologies of HeartburnNot All
Heartburn Is GERD

• Esophagitis
• Histopathologic esophagitis
• Healed esophagitis
• Acid-sensitive esophagus
• Weakly acidic reflux?

Heartburn caused by acid reflux
EMD esophageal motility disorder.
35
GERD Esophagitis, NERD, or Functional Heartburn?
Endoscopy
GERDSymptoms?
MII/pH Monitoring Excess Esophageal Acid Exposure
MII/pH Monitoring Symptom Correlation
MII multichannel intraluminal impedance.
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Catheter-Based Impedance andpH Monitoring

• Best test for reflux detection
• Uncomfortable
• Cumbersome
• Inconvenient

Fass R, et al. Dig Dis Sci. 1999442263-2269.
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Acid Reflux Impedance
Impedance
pH
Time
2 sec
Vela MF, et al. Gastroenterology.
20011201599-1606.
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Nonacid Reflux Impedance
Vela MF, et al. Gastroenterology.
20011201599-1606.
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Improved Patient Tolerance Getting Rid of the
Catheter
Attachment device positioned
Attachment pin fired
Attachment device removed
Recording begins
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48-Hour Telemetry Probe pH Tracing in GERD
Patient
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Refractory GERD Symptoms (Endoscopy Negative)
No Reflux
Abnormal Reflux
Acid mediated
Non-acid mediated

• Functional
• Not uniquely chemosensitive
• Not uniquely mechanosensitive

42
Summary Management of PPI-Refractory GERD
Symptoms

• Refractory acid reflux on double-dose PPI is rare
  
• 7 for typical symptoms
• 1 for atypical symptoms
• Failure of double-dose PPI should lead to a
  search for an alternative diagnosis
• Non-acid reflux
• Functional heartburn
• Eosinophilic esophagitis
• Esophageal motor disorder

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Key Question

• Which of the following increases a persons
• risk of developing esophageal adenocarcinoma?
• Long-standing GERD symptoms
• Frequent GERD symptoms
• Both of the above
• No study has connected GERD symptom
  characteristics and adenocarcinoma risk
• Use your keypad to vote now!

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Which of the following increases a personsrisk
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!
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Association Between GERD Symptom Frequency and
Duration
N 1438 (n 189 with esophageal
adenocarcinoma). Lagergren J, et al. N Engl J
Med. 1999340825-831.
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Summary of Disease ProgressionBarretts Esophagus

• Barretts esophagus can develop after years of
  reflux disease
• However, usually diagnosed on initial endoscopy
• Once developed, typically remains despite
  antireflux therapy
• Barretts may progress to esophageal
  adenocarcinoma
• However, sizeable proportion of adenocarcinoma
  diagnoses are made without evidence of Barretts

Fass R, Ofman JJ. Am J Gastroenterol.
2002971901-1909. Lagergren J, et al. N Engl J
Med. 1999340825-831.
47
ACG Guidelines for Barretts Esophagus
Graded Dysplasia and Proposed Surveillance Graded Dysplasia and Proposed Surveillance Graded Dysplasia and Proposed Surveillance
Grade Documentation Follow-up
None 2 normal EGDs 3 years
Low grade Highest grade on repeat 1 year
High grade Repeat EGD r/o cancer Expert pathologist Focal - every 3 months Multifocal - intervention
Sampliner RE, et al. Am J Gastroenterol.
2002971888-1895.
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Key Question

• Of the following factors, which places patients
• at the highest risk for developing GI
• complications/adverse events?
• Use of multiple NSAIDs (including aspirin)
• Use of high-dose NSAIDs
• Use of an anticoagulant
• Past uncomplicated ulcer
• Use your keypad to vote now!

49
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!
50
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. 1995401345-1350.
51
Aspirin Alone or With Another NSAID Risk of
Upper GI Complications
8
7
6
5
Relative Risk of Upper GI Complications
4
3
2
1
0
Aspirin75 mgQD
Aspirin150 mgQD
Aspirin300 mgQD
NSAIDs
Aspirin OtherNSAIDs
Weil J, et al. BMJ. 1995310827-830.
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Identify Individuals With Risk Factors for
Adverse Events
Odds Ratio

• Use non-NSAID analgesic whenever possible
• Use the lowest effective NSAID dose

Including aspirin. Gabriel SE, et al. Ann Intern
Med. 1991115787-796. Garcia Rodriguez LA, et
al. Lancet. 1994343769-772.
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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.
200410740-741.
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Antisecretory Cotherapy
Therapy Advantages Disadvantages
Misoprostol Reduces risk of gastric and duodenal ulcers Reduces ulcer complications Poor adherence Adverse effects (diarrhea in 20 of patients) Contraindicated in women of childbearing age
H2RAs Alleviate dyspeptic symptoms Heal active ulcers only if NSAID discontinued Ineffective in preventing gastric ulcers Less effective than PPIs
PPIs Alleviate dyspeptic symptoms Heal active ulcers even when NSAID is continued Cost
Lazzaroni M, et al. Dig Liver Dis.
200133S44-S58. Graham DY, et al. Arch Intern
Med. 2002162169-175. Peura DA. Am J Med.
200411763S-71S.
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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-2selective 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.
56
Case Study
57
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

58
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

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Decision Point

• How would you manage this patient?
• 4 weeks of empiric therapy with standard-dose PPI
• 4 weeks of empiric therapy with PPI BID
• Switch patient to standard-dose PPI therapy and
  add OTC H2RA at bedtime
• Check for Helicobacter pylori infection
• Use your keypad to vote now!

60
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

Use your keypad to vote now!
61
Decision Point

• Does this patient need any diagnostic testing
• and if so which test?
• No testing neededjust treat
• H pylori testing needed
• Refer for endoscopy
• Upper GI is all that is needed initially
• Use your keypad to vote now!

62
Does this patient need any diagnostic testing
and if so which test?

1. No testing neededjust treat
2. H pylori testing needed
3. Refer for endoscopy
4. Upper GI is all that is needed initially

Use your keypad to vote now!
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Q A
64
PCE Takeaways
65
PCE Takeaways

• If left untreated, GERD can progress to erosive
  esophagitis, Barretts esophagus, and esophageal
  adenocarcinoma
• Focus of medical management of GERD is
  compensatory, not curative
• 2005 ACG Practice Guidelines recommend initial
  trial of empiric PPI therapy if the patients
  history is typical for uncomplicated GERD

66
PCE Takeaways (contd)

• Consider further testing when patient has alarm
  symptoms or atypical symptoms, or does not
  respond to empiric therapy
• Be on the lookout for eosinophilic esophagitis
• For patients on NSAIDs, consider antisecretory
  cotherapy in patients
• With history of ulcer
• Taking multiple NSAIDs, including aspirin
• Taking high-dose NSAIDs
• Taking an anticoagulant
• Aged gt60 years

67
Key Question

• In what percentage of your patients with chronic
  GERD will you likely initiate long-term
  management protocols?
• 0-25
• 26-50
• 51-75
• 76-100
• Use your keypad to vote now!

68
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!
69
Fall 2007Symposia Series

• St

• Sheraton Buckhead Hotel AtlantaAtlanta,
  GeorgiaNovember 10, 2007