Session 6

Session 6: Navigating Toward Relief: A Case-Based Approach to Treating GERD and Peptic Ulcer Disease Learning Objectives

• List risk factors and current strategies for treating patients with gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD).

• Identify proton pump inhibitor (PPI) administration options and the rationale(s) for their use in patients with acid-related disorders.

Faculty Randolph V. Fugit, PharmD, BCPS Internal Medicine Clinical Specialist Denver Veterans Affairs Medical Center

Adjoint Assistant Professor, Pharmacy Practice University of Colorado Health Sciences Center Denver, Colorado Dr Randolph V. Fugit is an internal medicine clinical specialist at the Denver Veterans Affairs Medical Center as well as an adjoint assistant professor in the Department of Pharmacy Practice at the University of Colorado Health Sciences Center in Denver. Dr Fugit received his doctor of pharmacy degree from the University of New Mexico, Albuquerque. Upon graduation, he completed a clinical pharmacy practice residency at the Albuquerque Veterans Affairs Medical Center, with a focus on internal medicine and ambulatory care. He is a board-certified pharmacotherapy specialist and maintains an active clinical practice in the Department of Internal Medicine at the Denver VA Medical Center. Dr Fugit focuses on pharmacoeconomics and outcomes research, including clinical pathway development; is involved in the management of both acute and chronic disease states in gastroenterology, cardiology, and infectious diseases; and has authored and coauthored numerous publications on these areas. He is currently coauthoring the upper gastrointestinal disorders chapter in Applied Therapeutics: The Clinical Use of Drugs. Dr Fugit also lectures extensively as a national speaker on these topics. Faculty Financial Disclosure Statement The presenting faculty report the following: Dr Fugit has nothing to report. Education Partner Financial Disclosure Statement The content collaborators at The Customer Link, Inc., report the following: Jason Jenkins, medical writer; Pete Sloan, medical editor; and Karin Yao, account supervisor, have nothing to disclose. Drug List Generic Trade alendronate Fosamax amoxicillin Amoxil aspirin various bismuth subcitrate, tetracycline, Pylera metronidazole (combination) celecoxib Celebrex clarithromycin Biaxin clopidogrel Plavix diclofenac Arthrotec, Cataflam,

Solaraze, Voltaren esomeprazole Nexium etodolac Lodine famotidine Pepcid

Generic Trade fenoprofen Nalfon flurbiprofen Ansaid, Ocufen hydrochlorothiazide various ibuprofen various indomethacin Indocin ketoprofen Actron, Orudis,

Oruvail ketorolac Toradol lansoprazole Prevacid levofloxacin Iquix, Levaquin Levothyroxine Synthroid, Levoxyl,

Levothroid, Unithroid

Session 6

Generic Trade lisinopril Prinivil meloxicam Mobic metronidazole various misoprostol Cytotec nabumetone Relafen naproxen various omeprazole Prilosec, Zegerid pantoprazole Protonix piroxicam Feldene potassium chloride various

Generic Trade quinidine Quinaglute rabeprazole Aciphex rifabutin Mycobutin rofecoxib Vioxx tetracycline various theophylline Theo-Dur tinidazole Tindamax, Fasigyn tolmetin Tolectin valdecoxib Bextra

Suggested Reading List Abid S, Mumtaz K, Jafri W, et al. Pill-induced esophageal injury: endoscopic features and clinical outcomes. Endoscopy. 2005;37:740-744. Chen C-L, Robert JJT, Orr WC. Sleep symptoms and gastroesophageal reflux. J Clin Gastroenterol. 2008;42:13-17. Chey WD, Wong BCY. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-1825. El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol. 2007;5:17-26. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther. 2006;23(suppl 2):2-8. Shapiro M, Green C, Faybush EM, et al. The extent of oesophageal acid exposure overlap among the different gastro-oesophageal reflux disease groups. Aliment Pharmacol Ther. 2006;23:321-329. Sostek MB, Chen Y, Andersson T. Effect of timing of dosing in relation to food intake on the pharmacokinetics of esomeprazole. Br J Clin Pharmacol. 2007;64:386-390. Yang Y-X, Hennessy S, Propert K, et al. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology. 2007;133:748-754.

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1

Randolph V. Fugit, PharmD, BCPSInternal Medicine Clinical Specialist

Veterans Affairs Medical Center, DenverAdjoint Assistant Professor, Pharmacy PracticeUniversity of Colorado Health Sciences Center

Denver, CO

Today’s Focus

• Discuss risk factors and current strategies for treating patients with gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD)

• Compare and contrast the efficacy of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) for the treatment of GERD and PUD

• Evaluate issues surrounding the long-term use of PPIs and their potential to cause adverse effects

• Discuss pharmacogenomics, drug interactions, and dosing associated with PPI therapy

• Identify PPI administration options and the rationale(s) for their use in patients with acid-related disorders

Section 1: An Overview of GERD

Randolph V. Fugit, PharmD, BCPSInternal Medicine Clinical Specialist

Veterans Affairs Medical Center, DenverAdjoint Assistant Professor, Pharmacy PracticeUniversity of Colorado Health Sciences Center

Denver, CO

Case: Daniel

• 55-year-old attorney presents with heartburn that has occurred on and off for the past year– Heartburn occurs 3 to 5 times a week

• Symptoms primarily occur after eating and when lying down

• Initially treated with lansoprazole 30 mg twice daily for Los Angeles (LA) Grade C esophagitis

• Prescribed lansoprazole 30 mg once daily, but admits he takes medication only as needed and that he sometimes takes an H2RA instead of his PPI

• Often eats high-fat meals• Takes theophylline daily for asthma

Audience Question

• Which of the following most likely contributed to Daniel’s recurrent heartburn?

1. Takes PPI only when needed

2. Tolerance to antisecretory effect of PPI

3. Timing of PPI dose in relationship to meals

4. Genetic polymorphism related to PPI

?

1Fass R, et al. Aliment Pharmacol Ther. 2005;22:79-94.2Shapiro M, et al. Aliment Pharmacol Ther. 2006;23:321-329.

60% - 70%1,2of GERD patients

are diagnosed with nonerosive reflux disease

(NERD)

20% - 30%1 of GERD patients

are diagnosed with erosive

esophagitis (EE)

GERD Is a Heterogeneous Disorder

6% - 10%1,2

of GERD patients are diagnosed with

Barrett’s esophagus

2

The Prevalence of GERD Is Increasing Across Different Geographic Regions

El-Serag HB. Clin Gastroenterol Hepatol, 2007;5:17-26.

• Patients worldwide are reporting more GERD symptoms over the last 2 decades

• Overall, GERD symptoms increased approximately 4% per year worldwide– 5% in North America

(P = 0.0005)– 27% in Europe

(P < 0.0001)– 1% in Asia

(P = 0.49)

Prevalence of GERD Symptoms in 17 Studies from 1980-2005 • Increasing longevity1

– Increased acid exposure occurs more in older patients

• Obesity epidemic2

– Changes in lower esophageal sphincter (LES) pressure– High-fat diet, delayed gastric emptying, visceral obesity

• Comorbid conditions affecting the esophagus3

– Diabetes, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis

• Use of drugs that affect LES pressure and gastric emptying3

– Theophylline, calcium antagonists, benzodiazepines, nitrates, anticholinergics, antidepressants

Factors Responsible for theChanging Epidemiology of GERD

1Lee J, et al. Clin Gastroenterol Hepatol. 2007;5:1392-1398.2Watanabe S, et al. J Gastroenterol. 2007;42:267-274.

3Bonatti H, et al. J Gastrointest Surg. 2008;12:373-381.

4237.5

32.53130

24.527

05

1015202530354045

< 21 21-30 31-40 41-50 51-60 61-70 > 70

Prevalence of Severe Erosive Esophagitis Increases Among Older

Patients with Severe Heartburn

Johnson DA, et al. Gastroenterology. 2004;126:660-664.

Age (years)

Perc

enta

ge o

f (LA

Gra

de

C/D

) ero

sive

eso

phag

itis

A post hoc analysis of the baseline characteristics from 5 prospective, randomized, controlled clinical trials assessing effect of PPIs

on healing of erosive esophagitis (N = 11,945)

P < 0.0001

Older patients with severe

heartburn had more severe esophagitis

than younger patients

Poor Control of Intragastric pH Is a Risk Factor for Persistent Erosive Esophagitis

Katz PO, et al. Aliment Pharmacol Ther. 2007;25:617-628.

• Double-blind, multicenter, 4-week, proof-of-concept study of adults (N = 103; mean age 48.7 years; 65% men) with endoscopically verified LA grade C or D esophagitis

• Patients randomly assigned to oral esomeprazole 10 mg or 40 mg once daily for 4 weeks, then endoscopically assessed

Time pH > 4.0 (%)

Hea

ling

rate

(%)

Erosive esophagitis healing rates were positively related to the percent of time intragastric pH was > 4.0

P = 0.0002

0

20

40

60

80

100

0 to < 25 25 to < 50 50 to < 75 ≥ 75

pH Control Over Time: PPI Versus H2RA

Miner PB Jr, et al. Aliment Pharmacol Ther. 2007;25:103-109.N = 31

Study day

Mea

n tim

e pH

> 4

(%)

P < 0.001 omeprazole vs famotidine at all time points except day 1

0

10

20

30

40

50

60

70

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Omeprazole 20 mgFamotidine 20 mgFamotidine 10 mg

Donnellan C, et al. Cochrane Database Syst Rev. 2004;4.

• 38 randomized controlled trials• Follow-up time 24 – 52 weeks

Rel

apse

of e

soph

agiti

s (%

)

N = 5964 P = 0.02

N = 1583 P = 0.004

N = 1156 P = 0.06

1823

39

29

58

66

0

10

20

30

40

50

60

70 PPI healing dose

H2RAPPI maintenance dose

Comparison of Maintenance Therapies for Erosive Esophagitis

3

Audience Question ?• Which of the following is a

misconception about appropriate dosing patterns for PPIs?

1. On-demand therapy is effective in patients with severe esophagitis

2. The ideal BID dosing schedule for PPIsis 30 minutes before breakfast and 30 minutes before evening meal

3. Taking a PPI when eating a high-fat meal may reduce its bioavailability

4. PPI dosing more than once per day may decrease adherence

Maintenance Treatment of GERD With PPIs Taken on Demand*

1Kaspari S, et al. Eur J Gastroenterol Hepatol. 2005;17:935-941.2Sjöstedt S, et al. Aliment Pharmacol Ther. 2005;22:183-191.

On-demand PPI therapy is noteffective in patients with severe

erosive esophagitis2

90

80

5144

0

25

50

75

100

LA Grade D(P = 0.09)

LA Grade C(P = 0.0002)

Endo

scop

ic re

mis

sion

at 6

mon

ths

(%)

Esomeprazole20 mg once daily

Esomeprazole20 mg on-demand

(n = 79) (n = 24)

1.5 1.4

2.2 2.3

0

0.5

1.0

1.5

2.0

2.5

Perc

eive

d av

erag

e da

ily

sym

ptom

load

*

Pantoprazole 20 mg on demand

Placebo

P < 0.05

On-demand PPI therapy is effective in the long-term management of

patients with NERD or mild GERD1

† Symptom load: heartburn, acid regurgitation, pain in swallowing

Intent to treat (n = 439)

Per protocol (n = 357)

P < 0.05

* On-demand = taking PPIs when symptoms arise

Compliance with Medications

Coping with GERD Internet Survey (n = 587)

MedicineNet.com Web site.http://www.medicinenet.com/pdf/hr0505gerd.pdf. Accessed March 17, 2008.

6%

17%

22%

55%

Regularly asprescribed bytheir physicianAs needed

Do not takemedication

Fairly regularlybut sometimesforget

Importance of Timing of PPI Dose

1Gunaratnam NT, et al. Aliment Pharmacol Ther. 2006;23:1473-1477.2Rudolph CD, et al. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1-S31.

3Welage LS. Gastroenterol Clin North Am. 2003;32(3 suppl):S25-S35.

Dosing Administer PPI1,2

QD30 minutes before breakfast or 30 minutes before evening meal

BID 30 minutes before breakfast and evening meal

More than 50% of patients referred for persistent GERD symptoms are taking their PPI suboptimally1

PPIs are only able to bind to proton pumps when the pumps are active (about 75% of pumps are activated

after stimulation, usually meal-related)3

Effects of Pharmacogenetic Polymorphism of CYP 2C19 on PPI Metabolism

and Treatment OutcomesGERD patients treated with lansoprazole 30 mg/day for 8 weeks1

Cur

e ra

te (%

)

Rapid(n = 24)

Intermediate(n = 28)

Poor(n = 13)

0

25

50

75

100

45.8

67.9

84.6

Rapid(n = 10)

Intermediate(n = 10)

Poor(n = 7)

Plas

ma

lans

opra

zole

(n

g/m

L)

312

440

745

0

200

400

600

800

1000

P < 0.05

P < 0.05

P < 0.005

1Furuta T, et al. Drug Metab Pharmacokinet. 2005;20:153-167.

2Robinson M, et al. Drugs. 2003;63:2739-2754.

Poor metabolizers: 3%-5% of Caucasians and African-Americans; 12%-25% of Asian populations2

Rapid metabolizers may require higher PPI doses2

Dietary and Lifestyle Modifications in the Management of GERD

Kaltenbach T, et al. Arch Intern Med. 2006;166:965-971.

Evidence to support these measures is limited– Alone, they are unlikely to control symptoms in patients with moderate to

severe GERD– Recommend in conjunction with medical therapy

Dietary Factors to Avoid

• Alcohol • Fatty Foods

• Spicy foods • Chocolate

• Caffeine, coffee • Peppermint

• Citrus, fruit juices

• Carbonated beverages

Lifestyle

• Smoking/ tobacco cessation

• Do not eat at least 3 hours before bedtime

• Weight loss

• Elevate head of bed

• Avoid LES-relaxing medications− Nitrates− Calcium channel blockers

4

Case Follow-up: Daniel

• Takes lansoprazole 30 mg once daily • Importance of compliance to drug

regimen discussed as well as when to take dose in relationship to meal

• Heartburn symptoms have been reduced to once a month

• Pharmacist recommends that Daniel avoid eating 2 to 3 hours before bedtime and modifying his diet to decrease high-fat foods

• Pharmacist requests Daniel keep a diary for one week on dietary and lifestyle triggers that exacerbate his heartburn, and requests he return one week later to review these triggers

Case: Martin

• 69-year-old retired accountant, was diagnosed with nonerosive reflux disease 6 months ago– Treated with once-daily PPI

• About 3 months ago, he began to complain of coughing and wheezing (asthma-like) as well as nocturnal heartburn to the point that the heartburn woke him up 3 or 4 nights a week

• Pantoprazole 40 mg once daily has not relieved his nocturnal heartburn or his coughing and wheezing

Nighttime Heartburn VersusNo Nighttime Heartburn in GERD

Chen C-L, et al. J Clin Gastroenterol. 2008;42:13-17.

Nighttime heartburn (n = 18) No nighttime heartburn (n = 15)

7.0

1.6

5.5

2.8

0.9

2.0

0

1

2

3

4

5

6

7

8

Total Recumbent Upright

Mea

n nu

mbe

r of p

rolo

nged

re

flux

even

ts (>

5 m

inut

es)

P = 0.004

16.3

10.7

17.8

7.05.7

8.4

0

4

8

12

16

20

Total Recumbent Upright

Aci

d co

ntac

t tim

e (%

) P = 0.001

Nighttime heartburn is associated with excessive gastroesophageal reflux

0

10

20

30

40

50

60

NERD EE

36.7

Persistent Symptoms Are Common on PPIs After 4 Weeks of Treatment

Dean BB, et al. Clin Gastroenterol Hepatol. 2004;2:656-664.

Perc

ent o

f pat

ient

s w

ith s

ympt

om re

spon

se

9.5

55.5

7.5

Symptom response to PPI therapy among patients with NERD and EE

n = 1854 n = 705

PPI response (P < 0.0001)

Placebo response (P > 0.05)

• PPI response rate after 4 weeks of treatment: − 36.7% for NERD

− 55.5% for erosive esophagitis

Audience Question ?• Which of the following is

an “atypical” or extraesophageal manifestation of GERD?

1. Chronic cough

2. Chronic hoarseness

3. Asthma

4. Chronic sinusitis

5. All of the above

Atypical or Extraesophageal Manifestations of GERD

• Noncardiac chest pain• Atypical loss of dental

enamel• Sudden infant death• Halitosis• Sleep apnea

• Asthma• Chronic bronchitis • Aspiration pneumonia• Idiopathic pulmonary

fibrosis

Pulmonary • Hoarseness• Chronic cough• Chronic laryngitis• Chronic posterior

pharyngitis• Globus sensation• Otitis media• Chronic sinusitis• Otalgia• Aphthous ulcers

Ear, Nose, and Throat

Other

Poelmans J, et al. Gut. 2005;54:1492-1499.

5

Effect of PPI Therapy in Patients with GERD-Related Asthma and Cough

20 19 18.5

5*

0

5

10

15

20

25

Asthmatics withGERD

Asthmaticswithout GERD

PretreatmentPosttreatment

• Esomeprazole 40 mg/day for 3 months

• GERD group experienced significant improvements in:

– Forced expiratory volume– Peak expiratory flow– Asthma symptom scores– Asthma medication use

Böcskei C, et al. Lung. 2005;183:53-62.

n = 94 n = 26

Short-acting β2-agonist use in 2-week period

Mea

n nu

mbe

r

*P < 0.001 vs pretreatment

Case Follow-up: Martin

• Pantoprazole increased to 40 mg twice daily with second dose to be taken at dinner

• Nocturnal heartburn has been resolved and patient is asymptomatic during the night

• Cough and wheezing decrease after 3 months of empiric treatment with twice-daily pantoprazole

• Referral to ENT for further evaluation

Moderate/severe GERD (frequent or severe symptoms)

Expert’s Algorithm for Treating Mild and Moderate/Severe GERD

Mild GERD (occasional or

mild symptoms)

Testing or referral to specialist

Alarm symptoms

Yes

No Extra-esophageal symptoms

Yes

No

NO RESPONSE

Maintenance acid suppression therapy

Assess compliance, increase dose, or refer for testing

Lifestyle modifications + trial of acid suppression

(OTC H2RA or PPI)

Empiric PPI therapy

(4 – 8 weeks)

Empiric PPI therapy

(2 – 3 months)

RESPONSE

Section 2: Exploring Peptic Ulcer Disease

Randolph V. Fugit, PharmD, BCPSInternal Medicine Clinical Specialist

Veterans Affairs Medical Center, DenverAdjoint Assistant Professor, Pharmacy PracticeUniversity of Colorado Health Sciences Center

Denver, CO

Case: Margaret

• 48-year-old woman diagnosed with H. pylori–positive duodenal ulcer– Presents with gnawing, burning epigastric

pain that occurs daily

– Symptoms frequently occur several hours following a meal

• Allergic to penicillin - hives

• Admits to being noncompliant with medications

• Currently takes calcium carbonate, levothyroxine for hypothyroidism, hydrochlorothiazide and lisinopril for hypertension

• Which of the following is the preferred eradication regimen for treating this patient?

1. PPI + clarithromycin

2. PPI + clarithromycin + metronidazole

3. PPI + metronidazole + tetracycline + bismuth subsalicylate

4. 2 and 3

5. All of the above

Audience Question ?

6

Helicobacter pylori

• Most people infected with H. pylori are asymptomatic1

• Associated with chronic gastritis, duodenal ulcer, gastric ulcer, gastric cancer, and gastric B-cell lymphoma1,2

• Association between H. pylori and GERD remains unclear1

• H. pylori eradication heals ulcers and decreases ulcer recurrence1

• Up to 20%-40% of patients fail eradication therapy2

• Diagnosis1

– Nonendoscopic: antibody testing, urea breath testing, fecal antigen test– Endoscopic: histology, rapid urease testing, culture, polymerase chain

reaction

1Chey WD, et al. Am J Gastroenterol. 2007;102:1808-1825.2Vilaichone R-K, et al. Gastroenterol Clin North Am. 2006;35:229-247.

Recommended Treatment Plan for H. pylori Infection

• First line of defense– PPI + clarithromycin + amoxicillin1-4

– (For penicillin-allergic patients): PPI + clarithromycin + metronidazole2

• Second line of defense– PPI + amoxicillin + metronidazole1-3

– PPI (H2RA) + bismuth + metronidazole + tetracycline1-3

• Third line of defense (rescue treatment)– PPI + amoxicillin + rifabutin1-3

– PPI + amoxicillin + levofloxacin1-3

1Vilaichone R-K, et al. Gastroenterol Clin North Am. 2006;35:229-247.2Collins J, et al. Med Clin North Am. 2006;90:1125-1140.

3Malfertheiner P, et al. Gut. 2007;56:772-781.4Vakil N. Am J Gastroenterol. 2006;101:497-499.

Duck WM, et al. Emerg Infect Dis. 2004;10:1088-1094.

* Based on the H. pylori Antimicrobial Resistance Monitoring Program in United States, of 347 clinical H. pylori isolates collected from 1998 through 2002

H. pylori Antimicrobial Resistance in Adults*

NoneTetracycline

0.9Amoxicillin

12.9Clarithromycin

25.1Metronidazole

Antimicrobial Resistance (%)Medication

Sequential Therapy

• Rationale:– Initial treatment with drugs that rarely promote resistance– Reduce bacterial load and preexisting resistant organisms– Follow with different antibiotics to kill remaining organisms

• Regimen (dual treatment followed by triple therapy):– Days 1 through 5: PPI + amoxicillin 1 g, both taken twice daily– Day 6: Discontinue amoxicillin; add clarithromycin + tinidazole– Days 6 through 10: PPI + clarithromycin 250-500 mg

+ tinidazole 500 mg, all taken twice daily

Chey WD, et al. Am J Gastroenterol. 2007;102:1808-1825.

Newer treatments such as sequential therapy require validation in the United States before they can be

recommended as a standard first-line therapy

0

1

2

3

4

5

6

Study (n = 37) Control (n = 55)

Effect of PPIs on Thyrotropin Values in Patients With Hypothyroidism

Sachmechi I, et al. Endocr Pract. 2007;13:345-349.

• Control group: euthyroid patients who received LT4(levothyroxine) therapy who did not receive PPI therapy

• Study group: euthyroid patients who received LT4therapy for ≥ 6 months and in whom PPI therapy was later initiated

* Group differences compared with use of Student t test† Or equivalent study period for control group

Patients with hypothyroidism and normal TSH values during LT4 replacement therapy may need additional thyroid function testing after treatment with PPIs and may need LT4 dose adjustment (7 patients in study group needed dose adjustment)

Mea

n th

yroi

d-st

imul

atin

g ho

rmon

e (T

SH) (

µIU

/mL)

val

ue Post-PPI†Baseline

Change = 0.69 ± 1.9 P = 0.035*

Change = 0.11 ± 1.06 P = 0.45*

Factors That May Affect Treatment Success

• Duration of treatment– 10-day treatment

associated with fewertreatment failures than 7-day treatment2

– 14-day treatment associated with fewertreatment failures than 7-day treatment3

• Side effects1

– Nausea– Diarrhea– Short-term use of metronidazole can

cause a disulfiram-like reaction when taken with alcohol

– Pseudomembranous colitis and allergic reactions (rare)

• Drug interactions1• Antimicrobial resistance1

• Nonadherence to drug regimen1

• Selection of eradication regimen1

1Vilaichone R-K, et al. Gastroenterol Clin North Am. 2006;35:229-247.2Broutet N, et al. Aliment Pharmacol Ther. 2003:17:99-109.3Calvet X, et al. Aliment Pharmacol Ther. 2000;14:603-609.4Chey WD, et al. Am J Gastroenterol. 2007;102:1808-1825.

Treatment duration recommendation: 10 to 14 days (preferably 14 days) in the United States4

7

Case: Veronica

• 72-year-old woman with chronic osteoarthritis and a history of ulcer-related bleeding− Takes naproxen twice daily− Also takes aspirin 81 mg daily for

cardioprotection post–myocardial infarction• Other medications include:

− Over-the-counter omeprazole 20 mg per day (but stopped taking medication 2 weeks ago because she read a newspaper article questioning the long-term safety of PPIs)

− Alendronate weekly− Calcium plus vitamin D

• Because it is easier for her to swallow liquid than to take a tablet or capsule, she wants to know if PPIs come in a liquid

Incidence of Drug-Induced Esophageal Injury

Abid S, et al. Endoscopy. 2005;37:740-744.N = 92NSAID = nonsteroidal anti-inflammatory drug

7%

10%9%4%

22%

8% 40%NSAIDs

(including aspirin)

Quinidine

Potassium chlorideAlendronate

Ascorbic acid

Tetracyclines

Other antibiotics

Risk Factors for Serious Upper GI Events with NSAID Use

• Concomitant SSRI use• Concomitant corticosteroid use

• Selection of NSAID (eg, etodolac or nabumetone vsketorolac, indomethacin, or piroxicam)

• Concomitant anticoagulant use

Risk Factor• Prior ulcer or complicated ulcer • Multiple NSAID use

• Advancing age (> 65 years) • High-dose NSAIDs

• Concomitant aspirin use (including low-dose)

Wilcox CM, et al. Clin Gastroenterol Hepatol. 2006;4:1082-1089.SSRI = selective serotonin reuptake inhibitor

Patients May Underreport NSAID Use

• 18% of respondents to survey noted use of an NSAID that had not been reported verbally to nursing staff1

− 8% reported daily use• 22% of respondents did not think the medications were important

enough to list1

• 30% of respondents cited the fact that the drugs were not prescribed by a physician1

Survey of patients in private GI practice after a written and verbally confirmed report of current medications to nursing staff1

“This reflects a common misperception that these medications are insignificant or benign when actually their chronic use, particularly among the elderly…is linked to serious and potentially fatal GI injury and bleeding”

– Dr. David Johnson, study coauthor2

1Majithia RT, et al. Am J Gastroenterol. 2007;102(suppl 2):S431. Abstract 849. 2ACG Web site. www.gi.org/media/releases/2007am/NSAIDs%20Risks%20and%20Cost%20Benefits.pdf.

Accessed March 17, 2008.

Therapy Advantages Disadvantages

Misoprostol1-3• FDA labeled for reducing risk of

gastric ulcers• Reduces ulcer complications

• Poor compliance• Diarrhea in 20% of patients• Contraindicated in women of

childbearing age

H2RAs1,2• Alleviate dyspeptic symptoms• Heal active ulcers only if NSAID

discontinued

• Double dosages (eg, famotidine 40 mg BID) required to reduce risk of gastric ulcer

• Less effective than standard PPI dosages

PPIs1,3

• FDA labeled for reducing risk of gastric ulcers

• Alleviate dyspeptic symptoms• Heal active ulcers even when

NSAID is continued

• Fewer years on the market than H2RAs

• Cost

Gastroprotection Strategies for Patients Taking Chronic NSAIDs

1Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.2Lazzaroni M, et al. Dig Liver Dis. 2001;33(suppl 2):S44-S58.

3Graham DY, et al. Arch Intern Med. 2002;162:169-175.

Underutilization of Gastroprotective Measures in Patients Receiving NSAIDs

517 (1%)Less than recommended dose of misoprostol51 (< 1%)Less than recommended dose of PPIs

16,395 (23%)Less than recommended dose of H2RAsSpecific therapy

Therapy Traditional NSAIDs(n = 71,839)

Antiulcer therapyNone 48,182 (67%)Recommended protection 7322 (10%)Less than recommended protection 16,335 (23%)

Concurrent use of traditional NSAIDs and gastroprotective drugs among study cohort

Smalley W, et al. Arthritis Rheum. 2002;46:2195-2200.

8

COX-2/COX-1 Selectivity Ratio In Vitro

Adapted from US FDA Web site. http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4090S1_02_FDA-Cryer.ppt#624,26,Slide 26. Accessed March 17, 2008.

Warner TD, et al. FASEB J. 2004:18:790-804.

Increasingly COX-2 Selective Increasingly COX-1 Selective3

ketorolac210-3 -2 -1

etodolacdiclofenac

flurbiprofen

ibuprofentolmetin

naproxenaspirin

indomethacinketoprofen

fenoprofen

rofecoxibvaldecoxib

celecoxibmeloxicam

> 50-fold COX-2 selective

5- to 50-fold COX-2 selective

< 5-fold COX-2 selective

lumiracoxib*

fenoprofen

*Not FDA approved

Long-Term PPI Use and Hip Fractures

• Nested case-control study of patients aged > 50 years• 13,556 patients with hip fracture and 135,386 controls

Yang Y-X, et al. JAMA. 2006;296:2947-2953.

Exposure Group Adjusted Odds Ratio for Hip Fracture 95% CI

> 1 year of PPI therapy 1.44 1.30 – 1.59

Long-term high-dose PPI therapy 2.65 1.80 – 3.90

• Association stronger in men than women• Possible mechanisms:

– Calcium malabsorption secondary to acid suppression– Reduction in bone resorption through inhibition of osteoclastic vacuolar

proton pumps

• Did not include information on OTC calcium and vitamin D use

Use of PPIs and Risk of Osteoporosis-Related Fractures

Targownik LE, et al. CMAJ. 2008;179:319-326.

* Adjusted for income, region of residence, diagnoses (short- or long-term diabetes, epilepsy, ischemic heart disease, myocardial infarction, hypertension, arthritis, solid organ transplant, chronic obstructive pulmonary disease, substance use, depression, schizophrenia, dementia), home care use, and multiple medications

Odds ratio (95% CI)

Decreased risk of fracture

Increased risk of fracture

PPI exposure (years)

≥ 1

≥ 2

≥ 3

≥ 4

≥ 5

≥ 6

≥ 7

Unadjusted OR

Adjusted OR*

0.1 0.5 1.0 5.0 10.0

• 15,792 patients with osteoporosis-related fracture (hip, vertebra, or wrist) matched against 47,289 controls

• Adjusted odds ratios (OR) for the risk of all osteoporosis-related fractures calculated for duration of PPI exposure ranging from ≥ 1 year to ≥ 7 years

† Adjusted OR for PPI exposure ≥ 7 years = 1.92

(95% CI, 1.16-3.18; P = 0.011)

†

P = not significant

Influence of Omeprazole on Antiplatelet Action of Clopidogrel

1Gilard M, et al. J Am Coll Cardiol. 2008;51:256-260.2Gurbel PA, et al. J Am Coll Cardiol. 2008;51:261-263.

• VASP (vasodilator-stimulated phosphoprotein) provides an index of platelet reactivity to clopidogrel: the higher the platelet reactivity index (PRI), the more frequently thrombosis occurs under clopidogrel

• CYP2C19 seems to be one of the determinants of the pharmacodynamic response to clopidogrel

Double-blind, placebo-controlled trial of patients undergoing coronary artery stent implantation to assess effect of omeprazole on clopidogrel efficacy1

Mea

n pl

atel

et re

activ

ity

inde

x (P

RI)

(%)

100

Clopidogrel + Omeprazole (n = 64)

Clopidogrel + Placebo (n = 60)

80

60

40

20

0VASP PRI (%) on Day 1VASP PRI (%) on Day 7

P < 0.0001

Pharmokinetic/pharmacodynamic investigations are required before any clinical significance can be attributed to this drug interaction and suggestions that cardiologists

delete omeprazole when indicated in patients treated with dual antiplatelet therapy2

PPIs and Risk of Community-Acquired Clostridium difficile–Associated Disease

1Dial S, et al. JAMA. 2005;294:2989-2995. 2Lowe DO, et al. Clin Infect Dis. 2006;43:1272-1276.

1Association between medications and CDAD based on clinical diagnosis and/or positive toxin assay1233 cases vs 12,330 controls

2Association between outpatient PPI use and hospitalization for CDAD 1389 cases vs 12,303 controls

Antibiotic Exposure Within 90 Days

Adjusted Odds Ratio for CDAD 95% CI

Antibiotics 3.1 2.7-3.6PPI 2.9 2.4-3.4

H2RA 2.0 1.6-2.7

Timing of Most Recent PPI Exposure

Adjusted Odds Ratio for CDAD 95% CI

≤ 90 days 0.9 0.8-1.191-180 days 0.7 0.5-1.0181-365 days 0.9 0.6-1.3

CDAD = C. difficile–associated disease

Long-Term Use of PPIs and Risk of Colorectal Cancer (CRC)

1Robertson DJ, et al. Gastroenterology. 2007;133:755-760.2Yang Y-X, et al. Gastroenterology. 2007;133:748-754.

Study Comparison Adjusted OR 95% CI

Ever vs never or rare PPI users 1.11 0.97-1.27

Short-term* vs never or rare users 1.07 0.86-1.34

Long-term† vs never or rare users 1.09 0.58-2.06

• No statistically significant increase in CRC after ≥ 5 years of PPI use (adjusted OR 1.1; 95% CI, 0.7-1.9)2

• Recent studies show that the long-term use of PPI therapy does not have an association with a significantly increased risk of CRC1,2

*Short-term = < 7 years of PPI use† Long-term = ≥ 7 years of PPI use

1Denmark5589 CRC cases55,890 controls

9

No Current CV Risk in PPI Use of Omeprazole and Esomeprazole

• The FDA recently reviewed a 14-year omeprazole study and 5-year ongoing analysis of esomeprazole– Patients randomly received treatment with either PPI versus those who

received surgery for severe GERD– Initial results raised concerns that long-term use may increase the risk

of heart attack, heart failure, and heart-related sudden death compared to patients receiving surgery

• Supported data via patient follow-up and studies (including 2-year placebo-controlled trials) concluded there was no such related CV risk of either PPI

“The FDA does not believe that health care providers or patients should change either their prescribing

practices or their use of these products at this time”

US FDA Web site. http://www.fda.gov/cder/drug/early_comm/omeprazole_esomeprazole.htm. Accessed March 17, 2008.

Audience Question

• Which of the following is an FDA-approved alternative PPI formulation that you could recommend for this patient?

1. Pantoprazole granules sprinkled on soft foods

2. Omeprazole capsule opened and chewed followed by a full glass of water

3. Rabeprazole oral suspension 4. Lansoprazole orally disintegrating tablet

?

When Additional PPI Formulations May Be Needed

• Difficulty swallowing tablets or capsules– As high as 22% in patients aged > 50 years– Up to 60% of the nursing home population– Causes: stricture, esophageal motility disorders, strokes

• Aversion to swallowing tablets or capsules• Nothing by mouth (NPO) patients

– In hospital– Tube feedings

• High-risk bleeding ulcers• Children

Howden CW. Am J Med. 2004;117(suppl 5A):44S-48S.

FDA-Approved Alternative PPI Formulations and

Administration OptionsEsomeprazole Lansoprazole Omeprazole Pantoprazole

Capsule granules sprinkled on selected soft foods

Applesauce

Applesauce, nutritional pudding, cottage cheese, yogurt, strained pears

Applesauce

Capsule granules mixed into selected beverages

Apple, orange, or tomato juice

Nasogastric (NG) tube administration

Capsule granules in water

Capsule granules in apple juice or ODT in water (≥ 8 Fr)

Yes

IV formulation Yes YesPacket for oral suspension Yes Yes Yes Yes

Orally disintegrating tablet (ODT)

Orally with or without water, dispersed in water through NG tube or oral syringe

Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.Contents of PPI capsules are delayed-release and should not be chewed or crushed

*Rabeprazole is available in tablet form only

Case Summary: Veronica

• After speaking with her physician about the benefits versus risks of PPI therapy, Veronica agrees to resume taking PPI

• Options such as oral PPI tablets and capsules discussed with patient

• Veronica decides to try an alternative form of PPI

• Pharmacist instructs Veronica on properly preparing and administering orally disintegrating tablet formulation of lansoprazole

Clinical Pearls

• PPIs are effective for GERD treatment and maintenance therapy, H. pylori ulcers (when combined with antimicrobials), and the treatment and prophylaxis of NSAID ulcers and ulcer-related bleeding– Should only be used when indicated, in the lowest effective dose and for

shortest period of time

• PPIs are superior to H2RAs in relieving symptoms, preventing and healing NSAID ulcers and esophagitis, and tolerance does not develop to antisecretory effect

• Patients must be educated on the proper usage and timing of PPIs

• There are many PPI dosing and formulation options to meet every patient’s needs

• Drug interactions, side effects, pharmacogenomics, and dosing should be considered with PPI therapy