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

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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!

?