Successful Strategies for Managing Acid-Related Disease in Primary Care

Col. Roy K.H. Wong, MD Professor of Medicine Uniformed Services University of the Health Sciences Bethesda, Maryland Chief of Gastroenterology Walter Reed Army Medical Center Washington, DC

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%

?

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Faculty Disclosure

 Dr Wong: speakers bureau: AstraZeneca, Janssen Kwoya Co. Ltd, 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.

2.

3.

4.

Long-standing GERD symptoms Frequent GERD symptoms Both of the above No study has connected GERD symptom characteristics and adenocarcinoma risk

?

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G

astro

E

sophageal

R

eflux

D

isease

Nonerosive GERD (EGD negative) Esophagitis Extraesophageal GERD Impairs Quality of Life Stricture Bleeding Barrett’s Metaplasia and Adenocarcinoma ENT Dental Asthma EGD = esophagogastroduodenoscopy; ENT = ear, nose, and throat.

Pathophysiologic Determinants of Esophagitis Severity and Chronicity

GERD Severity ≈ N of reflux events Acid clearance

 

Causticity of gastric juice Tissue resistance Aggressive Factors Defensive Factors

 Chronic condition usually not attributed to excess acid secretion  Treatment approaches are compensatory, rather than curative  Therapeutic focus is on refluxate causticity 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

Spectrum/Progression 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

.

Evolving GERD “Phenotypic Model”

Progression Within the Group NERD Erosive Esophagitis Barrett’s Esophagus Typical and Atypical Symptoms Stricture Ulcer GI Bleeding

Fass R, Ofman JJ.

Am J Gastroenterol

. 2002;97:1901-1909.

Pandolfino JE, Shah N.

Dig Liver Dis

. 2006;38:648-651.

Adenocarcinoma of the Esophagus

Association Between GERD Symptom Frequency and Duration 18 16 2 0 6 4 14 12 10 8 1.0

7.5

5.2

16.4

0 <12 12-20 >20 Symptom Duration (Years)

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

Lagergren J, et al.

N Engl J Med

. 1999;340:825-831.

1.0

5.1

6.3

16.7

0 1 2-3 Symptom Frequency (Times per Week) >3

Summary of Disease Progression Importance 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

 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 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%

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GERD: Endoscopic Findings in General Practice

2 2 Percent of patients with: Normal Mucosa Erythema Nonconfluent Erosions Confluent Erosions Circumferential Erosions Ulcer, Stricture, Barrett's Esophagus 30 12

N = 789 patients with GERD.

Jones R, et al.

Scand J Gastroenterol Suppl.

1995;211:35-38.

22 32

GERD Symptom Profile on Presentation in Primary Care

Retrosternal Burning Epigastric Burning Retrosternal Pain Epigastric Pain Belching Fullness Fluid Retention Flatulence Nausea Pharyngeal Burning 0 20 34 40 45 45 48 63 61 60 58 56 60 %

Jones R, et al.

Scand J Gastroenterol Suppl.

1995;211:35-38.

80 86 100

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.

Algorithm for Diagnostic Referral in Patients Presenting With GERD Symptoms

History and Physical Examination

Typical Symptoms Only

 Heartburn  Regurgitation

Early Referral Symptoms

 Dysphagia   Early satiety Frequent vomiting   GI bleeding Weight loss Empiric Treatment

Atypical Symptoms

 Asthma  Chronic cough   Chronic hoarseness Nausea and vomiting  Unexplained chest pain Diagnostic Testing Katz PO.

Am J Gastroenterol

. 1999;94(11 Suppl):S3-S10.

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 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  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.

Key Question

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

1.

2.

3.

4.

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

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?

Focus of Medical Management of GERD —Compensatory, Not Curative

It’s all about acid!

 PPIs  H2RAs  Antacids H 2 RAs = histamine 2 -receptor antagonists.

Meta-Analysis of PPIs, H

2

RAs, and Placebo for Healing Erosive Esophagitis

100 (n) = Number of studies

(3) (26) (2)

PPIs 80

(27) (4) (22)

H 2 RAs 60

(25) (25)

40

(23) (9) (2)

Placebo

(5) (8)

20

(5)

0 2 4 6 Therapy (weeks)

Chiba N, et al.

Gastroenterology

. 1997;112:1798-1810.

8 12

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) Omeprazole 20 mg (N = 1575) Pantoprazole 40 mg (N = 249) Rabeprazole 20 mg (N = 338) 2.0

0.75

Favors H 2 RA

CI = confidence interval.

Caro JJ, et al.

Clin Ther

. 2001;23:998-1017.

1.0

1.25

1.5

Favors PPI 1.75

PPI Therapy Is Extremely Effective in the Majority of Patients With GERD — Comparison Studies Versus Omeprazole 100 80 60 40 85%-95% Omeprazole Lansoprazole Pantoprazole Rabeprazole Esomeprazole 20 0 N = 853 1 N = 286 2 N = 202 3 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.

N = 1304 4*

Comparison of Maintenance Therapies for Erosive Esophagitis

30 20 10 0 70 60 50 40 PPI Healing Dose PPI Maintenance Dose 38 randomized, controlled trials Follow-up time: 24-52 weeks 58 18 29 NNT = 2.9

23 N = 5964 N = 1583

NNT = number needed to treat.

Donnellan C, et al.

Cochrane Database Syst Rev

. 2004;4.

H 2 RA 66 NNT = 4.7

39 N = 1156

Continuous Versus On-Demand PPI Therapy — Maintaining Esophagitis Healing Esomeprazole 20 mg QD (n = 241) Esomeprazole 20 mg on demand (n = 229) Harder to maintain healing with more severe esophagitis 100 90 80 70 60 50 40 30 81 58 93 78 90 65 90 51 80 44 20 10 0 All Patients P <.0001

A B C D 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 40 36 35 30 25 20 28 20 Lansoprazole 15 mg QD Rabeprazole 10 mg QD Esomeprazole 20 mg QD Esomeprazole 40 mg QD Placebo 16 15 10 5 6 5 9 P <.05 for all PPIs vs placebo in each study 0

*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 Question

What constitutes PPI therapy failure?

1.

2.

3.

4.

Failure of the FDA-approved dose Failure of 2  Failure of 2  the FDA-approved dose the FDA-approved dose BID Failure is not defined

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?

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?

GERD Symptoms?

Endoscopy – + – MII/pH Monitoring Excess Esophageal Acid Exposure + MII/pH Monitoring Symptom Correlation + – Functional Heartburn MII = multichannel intraluminal impedance. Los Angeles A-D Esophagitis NERD • NERD (hypersensitive) • Weakly acidic reflux

Abnormal pH Monitoring in Symptomatic Patients Taking PPIs

250 GERD patients

Typical (135) QD PPI (79) BID PPI (56) Extra-esophageal (115) QD PPI (40) BID PPI (75)

% time pH <4

1.2 (0%-28%) 0.3 (0%-15%) 0.3 (0%-30%) 0 (0%-4.8%)

# abnormal

24 (31%) 4 (7%) 12 (30%) 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

. 2005;100:283-289.

Potential Etiologies of Heartburn — Not All Heartburn Is GERD

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

     EMD Eosinophilic esophagitis Functional heartburn Alkaline reflux?

Distention EMD = esophageal motility disorder

N

on

e

rosive

R

eflux

D

isease

Acid Abnormal Reflux mediated No Reflux Non –acid mediated    Functional Not uniquely chemosensitive Not uniquely mechanosensitive

Reflux Treatment in 2007 Summary

  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 Question

Of the following factors, which places patients at the highest risk for developing GI complications/adverse events?

1.

2.

Use of multiple NSAIDs (including aspirin) Use of high-dose NSAIDs 3.

4.

Use of an anticoagulant Past uncomplicated ulcer

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NSAIDs = nonsteroidal anti-inflammatory drugs.

?

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

8 3 2 1 5 4 7 6 0 Aspirin 75 mg QD Aspirin 150 mg QD Aspirin 300 mg QD NSAIDs Aspirin + Other NSAIDs

Weil J, et al.

BMJ

. 1995;310:827-830.

Identify Individuals With Risk Factors for Adverse Events

13.5

Past Complicated Ulcer Multiple NSAIDs* High-Dose NSAIDs Anticoagulant Past Uncomplicated Ulcer Age >60 Years Steroids 5.5

7 6.4

6.1

9 2.2

0

  *Including aspirin.

Gabriel SE, et al.

Ann Intern Med.

Garcia Rodriguez LA, et al.

1991;115:787-796.

Lancet

. 1994;343:769-772.

5 10 Odds Ratio

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

15

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 CV = cardiovascular.

*Ibuprofen should be used with caution in individuals taking aspirin.

Fendrick AM, et al

. Am J Manag Care.

2004;10:740-741.

Non-NSAID therapy

or

Gastroprotective agent with traditional NSAID

Antisecretory Cotherapy

Therapy

Misoprostol H 2 RAs PPIs

Advantages

  Reduces risk of gastric and duodenal ulcers Reduces ulcer complications  

Alleviate dyspeptic symptoms

Heal active ulcers

only

NSAID discontinued if   Alleviate dyspeptic symptoms

Heal active ulcers even when NSAID is continued Disadvantages

   Poor adherence Adverse effects (diarrhea in 20% of patients) Contraindicated in women of childbearing age  

Ineffective in preventing gastric ulcers

Less effective than PPIs  Cost 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

 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 obesity  Otherwise normal

Case Study: Medical and Treatment History

    Medical history includes knee replacement surgery, hypertension, hypercholesterolemia, and pulmonary embolism Tried over-the-counter antacids and H 2 RAs 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.

2.

3.

4.

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 H 2 RA at bedtime Check for

Helicobacter pylori

infection

?

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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.

3.

4.

H pylori

testing needed Refer for endoscopy Upper GI is all that is needed initially

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Q & A

PCE Takeaways

PCE Takeaways

1.

2.

3.

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 Takeaways

1.

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 Takeaways

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.

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% 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 Question

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!