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Successful Strategies forManaging Acid-Related Disease
in Primary Care
Byron Cryer, MD
Associate Professor of Medicine
University of Texas Southwestern Medical School
Dallas, Texas
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!
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Faculty Disclosure
Dr Cryer: consultant: AstraZeneca Pharmaceuticals, Merck & Co., Inc., Pfizer Inc, TAP Pharmaceutical Products Inc.
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!
Lagergren J, et al. N Engl J Med. 1999;340:825-831.
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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
Esophagitis
Barrett’s Metaplasiaand
Adenocarcinoma
BleedingStricture
Nonerosive GERD(EGD negative)
Impairs Qualityof Life
ExtraesophagealGERD
Dental
Asthma
ENT
EGD = esophagogastroduodenoscopy; ENT = ear, nose, and throat.
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.
Pathophysiologic Determinants of Esophagitis Severity and Chronicity
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
GERDSeverity
≈Tissue
resistanceAcid
clearance
Causticity ofgastric juice
N of refluxevents
Aggressive Factors
Defensive Factors
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.
Traditional Assumptions Concerning GERD Natural History
Spectrum/Progression
NERD ErosiveEsophagitis
StrictureUlcer
GI Bleeding
Barrett’sEsophagus
Typical and Atypical Symptoms
Adenocarcinomaof the Esophagus
Evolving GERD “Phenotypic Model”
Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.Pandolfino JE, Shah N. Dig Liver Dis. 2006;38:648-651.
Progression Within the Group
Association Between GERD Symptom Frequency and Duration
7.5
5.2
16.4
1.0
0
2
4
6
8
10
12
14
16
18
0 <12 12-20 >20
Symptom Duration (Years)
Es
op
ha
ge
al
Ad
en
oc
arc
ino
ma
O
dd
s R
ati
o
5.16.3
16.7
1.0
0 1 2-3 >3Symptom Frequency
(Times per Week)N = 1438 (n =189 with esophageal adenocarcinoma).Lagergren J, et al. N Engl J Med. 1999;340:825-831.
Summary of Disease ProgressionImportance 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 ProgressionBarrett’s Esophagus
Barrett’s esophagus can develop after years of reflux diseaseHowever, usually diagnosed on initial endoscopyOnce developed, typically remains despite
antireflux therapy Barrett’s may progress to esophageal
adenocarcinomaHowever, 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%
Use your keypad to vote now!Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.
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GERD Symptom Profile on Presentation in Primary Care
34
45
45
48
56
58
60
61
63
86
0 20 40 60 80 100
Pharyngeal Burning
Nausea
Flatulence
Fluid Retention
Fullness
Belching
Epigastric Pain
Retrosternal Pain
Epigastric Burning
Retrosternal Burning
%
Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.
GERD: Endoscopic Findings in General Practice
22
32
30
12
2 2
Normal Mucosa
Erythema
Nonconfluent Erosions
Confluent Erosions
Circumferential Erosions
Ulcer, Stricture, Barrett'sEsophagus
Percent of patients with:
N = 789 patients with GERD.Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.
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.
Additional GERD Diagnostic Techniques
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.
Endoscopy Allows for direct visualization of
the esophagus Should be considered at
presentation if patients have symptoms of complicated GERD or are at risk for Barrett’s
“Technique of choice” to diagnose these conditions
Ambulatory pH Monitoring Identifies patients with excess EAE and those with
symptoms that correlate with esophageal acid Helps to confirm acid reflux in patients with
persistent symptoms without evidence of esophageal mucosal damage, especially when a trial of acid suppression has failed
Monitors control of reflux in patients on therapy but with continued symptoms
Esophageal Manometry Used to guide placement of pH
monitoring probes May be helpful prior to antireflux
surgery
Barium Esophagram Not recommended for routine GERD diagnosis Not accurate for diagnosing Barrett’s Reasonably accurate for severe esophagitis but
much less accurate for mild esophagitis
Algorithm for Diagnostic Referral in Patients Presenting With GERD Symptoms
Typical Symptoms Only Heartburn Regurgitation
History and Physical Examination
Early Referral Symptoms Dysphagia Early satiety Frequent vomiting GI bleeding Weight loss
Atypical Symptoms Asthma Chronic cough Chronic hoarseness Nausea and vomiting Unexplained chest pain
Empiric Treatment Diagnostic
Testing
Katz PO. Am J Gastroenterol. 1999;94(11 Suppl):S3-S10.
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%
Use your keypad to vote now!
Castell DO, et al. Am J Gastroenterol. 1996;91:1749-1757.Mössner J, et al. Aliment Pharmacol Ther. 1995;9:321-326.Dekkers C, et al. Aliment Pharmacol Ther. 1999;13:49-57.Kahrilas P, et al. Aliment Pharmacol Ther. 2000;14:1249-1258.
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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.
Chiba N, et al. Gastroenterology. 1997;112:1798-1810.
Meta-Analysis of PPIs, H2RAs, and Placebo for Healing Erosive Esophagitis
0
20
40
60
80
100
2
To
tal
Hea
led
(%
)
4 6 8 12
Therapy (weeks)
(5) (8)(5)
(9) Placebo(2)(23) (25)
(25)(22) H2RAs
PPIs
(4)(27)
(3)(26)
(2)(n) = Number of studies
CI = confidence interval.Caro JJ, et al. Clin Ther. 2001;23:998-1017.
Meta-Analysis of PPIs Versus Ranitidine for Healing Erosive Esophagitis
Healing Rate Ratio (95% CI) Versus Ranitidine 300 mg
Rabeprazole 20 mg (N = 338)
Favors PPI
1.251.0 1.751.5 2.0
Favors H2RA
0.75
P <.05 for all PPIs vs ranitidine 300 mg
Pantoprazole 40 mg (N = 249)
Omeprazole 20 mg (N = 1575)
Lansoprazole 30 mg (N = 948)
PPI Therapy Is Extremely Effective in the Majority of Patients With GERD—Comparison Studies Versus Omeprazole
*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.
85%-95%
Rabeprazole
Esomeprazole
Pantoprazole
Lansoprazole
Omeprazole
0
20
40
60
80
100
N = 8531 N = 2862 N = 2023 N = 13044*
8 Weeks
Pat
ien
ts W
ith
Hea
led
E
rosi
ve E
sop
hag
itis
(%
)
Comparison of Maintenance Therapies for Erosive Esophagitis
1823
39
29
58
66
0
10
20
30
40
50
60
70
N = 5964 N = 1583 N = 1156
Eso
ph
agit
is R
elap
se (
%)
NNT = number needed to treat.Donnellan C, et al. Cochrane Database Syst Rev. 2004;4.
PPI Maintenance Dose H2RAPPI Healing Dose
NNT = 2.9
NNT = 4.7
38 randomized, controlled trialsFollow-up time: 24-52 weeks
Continuous Versus On-Demand PPI Therapy—Maintaining Esophagitis Healing
Sjostedt S, et al. Aliment Pharmacol Ther. 2005;22:183-191.
Stratified According to Baseline Los Angeles Grade
Pat
ien
ts in
En
do
sco
pic
R
emis
sio
n a
t 6
Mo
nth
s (%
)
A B C DAll patientsP <.0001
93 90 90
8078
65
5144
81
58
0
10
20
30
40
50
60
70
80
90
100
Esomeprazole 20 mg QD (n = 241)Esomeprazole 20 mg on demand (n = 229)
Harder to maintain healing with more severe esophagitis
16
28
6
20
5
9
36
0
5
10
15
20
25
30
35
40
Dis
co
nti
nu
ed
Du
e t
o
Ina
de
qu
ate
He
art
bu
rn C
on
tro
l (%
)On-Demand Therapy for Maintenance of Symptom Control*—Nonerosive GERD
*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.
Lansoprazole 15 mg QD
Rabeprazole 10 mg QD
Placebo
Esomeprazole 20 mg QD
Esomeprazole 40 mg QD
P <.05 for all PPIs vs placebo in each study
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
Use your keypad to vote now!
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I typically continue evaluation after the patient has failed double-dose treatment
What Is a PPI Failure?
FDA-approved dose? 2 the FDA-approved dose? FDA-approved dose BID? 2 the FDA-approved dose BID?
EndoscopyGERDSymptoms?
MII/pH MonitoringExcess Esophageal
Acid Exposure
MII/pH MonitoringSymptom Correlation
GERD: Esophagitis, NERD, or Functional Heartburn?
–
–
Functional Heartburn
–
Los Angeles A-D Esophagitis+
NERD+
• NERD (hypersensitive)
• Weakly acidic reflux+
MII = multichannel intraluminal impedance.
BID PPI (56)
250 GERD patients
Typical (135)
QD PPI (79)
Abnormal pH Monitoring in Symptomatic Patients Taking PPIs
pH testing should only be performed after patients have failed double-dose PPI, if testing on medication
Extra-esophageal (115)
BID PPI (75)QD PPI (40)
1.2 (0%-28%) 0.3 (0%-15%) 0 (0%-4.8%)0.3 (0%-30%)% time pH <4
24 (31%) 4 (7%) 1 (1%)12 (30%)# abnormal
Charbel S, et al. Am J Gastroenterol. 2005;100:283-289.
Heartburn caused by acid reflux
Heartburn not caused
by acid reflux
EMD Eosinophilic
esophagitis Functional
heartburn Alkaline reflux? Distention
Esophagitis Histopathologic
esophagitis Healed esophagitis Acid-sensitive
esophagus Weakly acidic
reflux?
Potential Etiologies of Heartburn—Not All Heartburn Is GERD
EMD = esophageal motility disorder
Abnormal Reflux
Acid mediated
Non–acid mediated
No Reflux
Functional Not uniquely
chemosensitive Not uniquely
mechanosensitive
Nonerosive Reflux Disease
Reflux Treatment in 2007Summary
Focus has shifted from esophagitis to symptom control PPIs are the mainstay of therapy
Long-term safety is good Minor concerns
OsteoporosisClostridium 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.Gabriel SE, et al. Ann Intern Med. 1991;115:787-796.Garcia Rodriguez LA, et al. Lancet. 1994;343:769-772.
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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 weekly60% of these patients take aspirin34% take NSAIDs daily
COX-2 = cyclooxygenase-2.IMS NPA Plus, 2004 (January 2004-December 2004).Talley NJ, et al. Dig Dis Sci. 1995;40:1345-1350.
Over 100,000 hospitalizations per year due to NSAID-related complications
Weil J, et al. BMJ. 1995;310:827-830.
Rel
ativ
e R
isk
of
Up
per
GI
Co
mp
lica
tio
ns
Aspirin75 mg
QD
Aspirin150 mg
QD
Aspirin300 mg
QD
NSAIDs Aspirin + OtherNSAIDs
0
1
2
3
4
5
6
7
8
Aspirin Alone or With Another NSAID: Risk of Upper GI Complications
Identify Individuals With Risk Factors for Adverse Events
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.
2.2
5.5
6.1
6.4
7
9
13.5
0 5 10 15
Steroids
Age >60 Years
Past Uncomplicated Ulcer
Anticoagulant
High-Dose NSAIDs
Multiple NSAIDs*
Past Complicated Ulcer
Odds Ratio
No/Low NSAID GI Risk NSAID GI Risk
No CV Risk (No
Aspirin)Traditional NSAID
Non-NSAID therapyor
COX-2 inhibitoror
Gastroprotective agentwith traditional NSAID
CV Risk (Consider
Aspirin)
Non-NSAID therapyor
Traditional NSAID* + gastroprotective agent if GI risk
warrants gastroprotection
Non-NSAID therapyor
Gastroprotective agentwith 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.
A Practical Guide to NSAID Therapy
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.
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
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 obesityOtherwise 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 daily 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!
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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
Use your keypad to vote now!
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PCE Takeaways
PCE Takeaways: GERD
1. Acid-related disorders are common in primary care practice, and GERD prevalence is increasing
2. If left untreated, GERD can progress to erosive esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma
3. Focus of medical management of GERD is compensatory, not curative
PCE Takeaways: Empiric Therapy
1. 2005 ACG Practice Guidelines recommend initial trial of empiric PPI therapy if the patient’s history is typical for uncomplicated GERD
2. Further diagnostic testing should be considered if: The patient has alarm symptoms or
atypical symptoms There is no response to empiric therapy The patient has sufficient duration of symptoms
to be at risk for Barrett’s esophagus
PCE Takeaways: PPI Therapy
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. NSAIDs can damage the gastric mucosa through local irritation of the epithelium and systemic inhibition of prostaglandin synthesis
2. 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%
PCE Takeaways: Identify Individuals With Risk Factors for Adverse Events
1. Consider antisecretory cotherapy in patients With history of ulcer Taking multiple NSAIDs, including aspirin Taking high-dose NSAIDs Taking an anticoagulant Aged >60 years Taking oral steroids
Key Question
In what percentage of your patients with chronicGERD 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!
?