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Successful Strategies for Managing Acid-Related Disease in Primary Care . John E. Pandolfino, MD Assistant Professor of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois. Faculty Disclosure.

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successful strategies for managing acid related disease in primary care

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

faculty disclosure
Faculty Disclosure
  • Dr Pandolfino:consultant/speaker/grant support: AstraZeneca; Medtronic, Inc.; Santarus, Inc.
key question


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!

learning objectives
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 question5


Key Question

Which of the following increases a person’s

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!

g astro e sophageal r eflux d isease




Nonerosive GERD

(EGD negative)





Impairs Quality

of Life

Barrett’s Metaplasia




EGD = esophagogastroduodenoscopy; ENT = ear, nose, and throat.

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

pathophysiologic determinants of esophagitis severity and chronicity



Pathophysiologic Determinants of Esophagitis Severity and Chronicity

Aggressive Factors

Causticity of

gastric juice

N of reflux


  • 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

Defensive Factors





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
Traditional Assumptions Concerning GERD Natural History


Mild Reflux:


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
Evolving GERD “Phenotypic Model”

Progression Within the Group




Typical and Atypical Symptoms

StrictureUlcerGI Bleeding

Adenocarcinomaof the Esophagus

Fass R, Ofman JJ. Am J Gastroenterol. 2002;97:1901-1909.

Pandolfino JE, Shah N. Dig Liver Dis. 2006;38:648-651.

association between gerd symptom frequency and duration
Association Between GERD Symptom Frequency and Duration

N = 1438 (n =189 with esophageal adenocarcinoma).

Lagergren J, et al. N Engl J Med. 1999;340:825-831.

summary of disease progression importance of early treatment
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 progression barrett s esophagus
Summary of Disease ProgressionBarrett’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 question13


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!

gerd endoscopic findings in general practice
GERD: Endoscopic Findings in General Practice

Percent of patients with:

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
GERD Symptom Profile on Presentation in Primary Care

Jones R, et al. Scand J Gastroenterol Suppl. 1995;211:35-38.

when is empiric therapy appropriate
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
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
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. 1999;94(11 Suppl):S3-S10.

additional gerd diagnostic techniques
Additional GERD Diagnostic Techniques
  • 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. 2005;100:190-200.

key question20


Key Question

What overall percentage of patients with erosive

esophagitis experience healing of erosions with

8 weeks of standard-dose PPI therapy?

  • <75%
  • 75%-84%
  • 85%-94%
  • 95%-100%

Use your keypad to vote now!

focus of medical management of gerd compensatory not curative
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 h 2 ras and placebo for healing erosive esophagitis
Meta-Analysis of PPIs, H2RAs, and Placebo for Healing Erosive Esophagitis

(n) = Number of studies













Total Healed (%)

















Therapy (weeks)

Chiba N, et al. Gastroenterology. 1997;112:1798-1810.

meta analysis of ppis versus ranitidine for healing erosive esophagitis

Omeprazole 20 mg (N = 1575)

Pantoprazole 40 mg (N = 249)

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)

Rabeprazole 20 mg (N = 338)







Favors PPI

Favors H2RA

CI = confidence interval.Caro JJ, et al. Clin Ther. 2001;23:998-1017.

PPI Therapy Is Extremely Effective in the Majority of Patients With GERD—Comparison Studies Versus Omeprazole








Patients With Healed

Erosive Esophagitis (%)






N = 8531

N = 2862

N = 2023

N = 13044*

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.

comparison of maintenance therapies for erosive esophagitis
Comparison of Maintenance Therapies for Erosive Esophagitis

PPI Healing Dose

PPI Maintenance Dose


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. 2004;4.

continuous versus on demand ppi therapy maintaining esophagitis healing
Continuous Versus On-Demand PPI Therapy—Maintaining Esophagitis Healing

Esomeprazole 20 mg QD (n = 241)

Harder to maintain healing with more severe esophagitis

Esomeprazole 20 mg on demand (n = 229)














Patients in Endoscopic Remission at 6 Months (%)













All patients

P <.0001

Stratified According to Baseline Los Angeles Grade

Sjostedt S, et al. Aliment Pharmacol Ther. 2005;22:183-191.

on demand therapy for maintenance of symptom control nonerosive gerd

Esomeprazole 20 mg QD

Esomeprazole 40 mg QD

Lansoprazole 15 mg QD


On-Demand Therapy for Maintenance of Symptom Control*—Nonerosive GERD

Rabeprazole 10 mg QD

P <.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. 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 question28


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!

what is a ppi failure
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

gerd esophagitis nerd or functional heartburn




Los Angeles A-D Esophagitis


  • NERD (hypersensitive)
  • Weakly acidic reflux

Functional Heartburn

GERD: Esophagitis, NERD, or Functional Heartburn?



MII/pH Monitoring

Excess Esophageal Acid Exposure

MII/pH Monitoring

Symptom Correlation

MII = multichannel intraluminal impedance.

abnormal ph monitoring in symptomatic patients taking ppis
Abnormal pH Monitoring in Symptomatic Patients Taking PPIs

250 GERD patients

  • pH testing should only be performed after patients have failed double-dose PPI, if testing on medication

Typical (135)

Extra-esophageal (115)

BID PPI (56)

BID PPI (75)

QD PPI (40)

QD PPI (79)

% time pH <4

0.3 (0%-15%)

0.3 (0%-30%)

1.2 (0%-28%)

0 (0%-4.8%)

# abnormal

4 (7%)

12 (30%)

24 (31%)

1 (1%)

Charbel S, et al. Am J Gastroenterol. 2005;100:283-289.

potential etiologies of heartburn not all heartburn is gerd


  • Eosinophilic esophagitis
  • Functional heartburn
  • Alkaline reflux?
  • Distention

Heartburn not caused by acid reflux

Potential Etiologies of Heartburn—Not All Heartburn Is GERD
  • Esophagitis
  • Histopathologic esophagitis
  • Healed esophagitis
  • Acid-sensitive esophagus
  • Weakly acidic reflux?

Heartburn caused by acid reflux

EMD = esophageal motility disorder

n on e rosive r eflux d isease

No Reflux

  • Functional
  • Not uniquely chemosensitive
  • Not uniquely mechanosensitive
Nonerosive Reflux Disease

Abnormal Reflux





reflux treatment in 2007 summary
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
key question35


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.

burden of nsaids
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
Aspirin Alone or With Another NSAID: Risk of Upper GI Complications





Relative Risk of Upper GI Complications






Aspirin75 mgQD

Aspirin150 mgQD

Aspirin300 mgQD


Aspirin + OtherNSAIDs

Weil J, et al. BMJ. 1995;310:827-830.

identify individuals with risk factors for adverse events


Past Complicated Ulcer


Multiple NSAIDs*


High-Dose NSAIDs




Past Uncomplicated Ulcer


Age >60 Years







Identify Individuals With Risk Factors for Adverse Events
  • Use non-NSAID analgesic whenever possible
  • Use the lowest effective NSAID dose

Odds Ratio

*Including aspirin.

Gabriel SE, et al. Ann Intern Med. 1991;115:787-796.

Garcia Rodriguez LA, et al. Lancet. 1994;343:769-772.

a practical guide to nsaid therapy
A Practical Guide to NSAID Therapy

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
Antisecretory Cotherapy

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.

gi advisory committee consensus on nsaids
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 presentation
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
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


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!

decision point46


Decision Point

Does this patient need any diagnostic testing

and if so which test?

  • No testing needed—just treat
  • H pylori testing needed
  • Refer for endoscopy
  • Upper GI is all that is needed initially

Use your keypad to vote now!

pce takeaways49
PCE Takeaways
  • If left untreated, GERD can progress to erosive esophagitis, Barrett’s 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 patient’s history is typical for uncomplicated GERD
pce takeaways50
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 Barrett’s esophagus
pce takeaways51
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
pce takeaways nsaids
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 >60 years
key question53


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!