Successful Strategies for Managing Acid-Related Disease in Primary Care

1
Successful Strategies forManaging Acid-Related
Disease in Primary Care

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

2
Faculty Disclosure

• Dr Pandolfino consultant/speaker/grant support
  AstraZeneca Medtronic, Inc. Santarus, Inc.

3
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!

4
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.
5
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!

6
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
7
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, PaWB Saunders Co 2002599-622.
8
Traditional Assumptions Concerning GERD Natural
History
Spectrum/Progression
Mild Reflux NERD
Moderate to Severe Reflux Erosive Esophagitis
Severe Reflux Barretts Esophagus
NERD nonerosive reflux disease.Adapted from
Fass R, Ofman JJ. Am J Gastroenterol.
2002971901-1909.
9
Evolving GERD Phenotypic Model
Progression Within the Group
NERD
ErosiveEsophagitis
BarrettsEsophagus
Typical and Atypical Symptoms
StrictureUlcerGI Bleeding
Adenocarcinomaof the Esophagus
Fass R, Ofman JJ. Am J Gastroenterol.
2002971901-1909. Pandolfino JE, Shah N. Dig
Liver Dis. 200638648-651.
10
Association Between GERD Symptom Frequency and
Duration
N 1438 (n 189 with esophageal
adenocarcinoma). Lagergren J, et al. N Engl J
Med. 1999340825-831.
11
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. 2002971901-1909. Lagergren J,
et al. N Engl J Med. 1999340825-831.
12
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.
13
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!

14
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.
15
GERD Symptom Profile on Presentation in Primary
Care
Jones R, et al. Scand J Gastroenterol Suppl.
199521135-38.
16
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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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.
2005100190-200.
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Algorithm for Diagnostic Referral in Patients
Presenting With GERD Symptoms
History and Physical Examination

• Typical Symptoms Only
• Heartburn
• Regurgitation

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

• Early Referral Symptoms
• Dysphagia
• Early satiety
• Frequent vomiting
• GI bleeding
• Weight loss

Empiric Treatment
Diagnostic Testing
Katz PO. Am J Gastroenterol. 199994(11
Suppl)S3-S10.
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Additional GERD Diagnostic Techniques
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 Barretts 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 Barretts Reasonably accurate for severe esophagitis but much less accurate for mild esophagitis

• Additional study needed to determine impact of
  newer techniques of impedance and tubeless pH
  monitoring on GERD management

EAE esophageal acid exposure. DeVault KR, et
al. Am J Gastroenterol. 2005100190-200.
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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!

21
Focus of Medical Management of GERDCompensatory,
Not Curative

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

H2RAs histamine2-receptor antagonists.
22
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.
23
Meta-Analysis of PPIs Versus Ranitidine for
Healing Erosive Esophagitis
Healing Rate Ratio (95 CI) Versus Ranitidine 300
mg
P lt.05 for all PPIs vs ranitidine 300 mg
Lansoprazole 30 mg (N 948)
Rabeprazole 20 mg (N 338)
1.25
1.0
1.75
1.5
2.0
0.75
Favors PPI
Favors H2RA
CI confidence interval.Caro JJ, et al. Clin
Ther. 200123998-1017.
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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.
25
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.
26
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.
27
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.
28
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!

29
What Is a PPI Failure?

• FDA-approved dose?
• 2 ? the FDA-approved dose?
• FDA-approved dose BID?
• 2 ? the FDA-approved dose BID?

I typically continue evaluation after the
patient has failed double-dose treatment
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GERD Esophagitis, NERD, or Functional Heartburn?
Endoscopy
GERDSymptoms?
MII/pH Monitoring Excess Esophageal Acid Exposure
MII/pH Monitoring Symptom Correlation
MII multichannel intraluminal impedance.
31
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.
32
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
33
Nonerosive Reflux Disease
Abnormal Reflux
Nonacid mediated
Acid mediated
34
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
• Osteoporosis
• Clostridium difficile colitis
• Refractory or PPI unresponsive GERD requires
  concern for other etiology
• Nonacid reflux
• Functional heartburn

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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!

NSAIDs nonsteroidal anti-inflammatory drugs.
36
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.
37
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.
38
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.
39
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.
40
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.
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Case Study
43
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

44
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!

46
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!

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Q A
48
PCE Takeaways
49
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

50
PCE Takeaways

• 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 Barretts esophagus

51
PCE Takeaways

• PPIs are very effective for most patients with
  GERD
• PPIs are the mainstay of therapy, with good
  long-term safety
• If GERD is refractory or PPI unresponsive, look
  for other etiology
• Nonacid reflux
• Functional heartburn

52
PCE Takeaways NSAIDS

• 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
• Consider antisecretory cotherapy in patients
• With history of ulcer
• Taking multiple NSAIDs, including aspirin
• Taking high-dose NSAIDs
• Taking an anticoagulant
• Aged gt60 years

53
Key Question

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