Session 9

Session 9: Puzzled No More: Addressing the Burning Issues of GERD and Acid-Related Disorders Learning Objectives

• List conditions associated with or that aggravate symptoms of gastroesophageal reflux disease (GERD), and determine steps to diagnose GERD and GERD complications.

• Compare the efficacy of at least 2 therapeutic options for GERD in order to devise optimal treatment strategies for short- and long-term control of symptoms.

Faculty H. Juergen Nord, MD, MACG, FACP Professor of Medicine Division of the Digestive Diseases and Nutrition University of South Florida College of Medicine Tampa, Florida Dr H. Juergen Nord, a native of Germany, received his medical degree magna cum laude from J. W. Goethe University of Frankfurt. In 1965, he was awarded a Fulbright Scholarship. He completed his residency in internal medicine at Indiana University Medical Center in Indianapolis and his fellowship in gastroenterology at Washington University in St Louis. In 1973, Dr Nord moved to the University of South Florida College of Medicine in Tampa, where he is professor of medicine in the Division of Digestive Diseases and Nutrition, which he directed from 1990 to 2000. Dr Nord has a special interest in postgraduate education and has directed or co-directed 52 postgraduate courses. He has lectured at more than 400 local, regional, national, and international courses and scientific symposia. Dr Nord has co-edited 3 books/manuals and has more than 160 publications to his credit. He serves on the editorial boards of several scientific journals. Dr Nord is a past president of the American Society for Gastrointestinal Endoscopy, the Florida Gastroenterologic Society, and the Florida Society for Gastrointestinal Endoscopy. Dr Nord has been listed in Best Doctors in America since 1996 and, in 1998, received the Laureate Award of the Florida chapter of the American College of Physicians. The American College of Gastroenterology awarded him mastership in 2005. David A. Peura, MD Professor of Medicine University of Virginia Health Sciences Center Charlottesville, Virginia Dr David Peura earned his medical degree from the University of Vermont College of Medicine in Burlington. He completed his internal medicine training at Letterman Army Medical Center in San Francisco, where he also served as chief medical resident, followed by GI fellowship training at Walter Reed Army Medical Center in Washington, DC. He served on the clinical staff and later became chief of gastroenterology at Walter Reed and consultant in gastroenterology to the Army surgeon general. Retiring from the Army in 1990 with the rank of colonel, he joined the faculty at the University of Virginia in Charlottesville. Throughout his career, Dr Peura has been actively involved in clinical investigation relating to acid peptic disorders, particularly peptic ulcer disease. Most recently, his research has centered on Helicobacter pylori and its role in ulcer pathogenesis. A reviewer for most of the major medical and gastroenterology subspecialty journals, he has authored or coauthored more than 100 original articles, book chapters, and reviews on a wide range of digestive disease topics. Dr Peura has demonstrated expertise and innovation in the area of medical education. While chair of the American College of Gastroenterology Board of Governors and the American Gastroenterological Association (AGA) Clinical Practice Section, he assisted in the organizations’ annual clinical and scientific education program development. As chair of the AGA Education Committee and Digestive Health Initiative Ulcer Campaign, Dr Peura coordinated the planning and implementation of a number of highly regarded physician and lay education programs. He continues to serve as an advisor and faculty for regional, national, and international teaching projects. Dr Peura received the AGA’s annual Distinguished Educator Award in 2002 and served as the organization’s 100th president from 2005 to 2006. He is an internationally recognized clinician and educator, and a popular speaker on the subject of upper GI disease.

Faculty Financial Disclosure Statements The presenting faculty report the following: Dr Nord has nothing to disclose. Dr Peura is a speaker for, consultant to, and member of the advisory board for Takeda Pharmaceuticals North America, Inc.; and is a speaker for AstraZeneca Pharmaceuticals LP as well as a member of the advisory board for Novartis Pharmaceuticals Corporation. 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 metronidazole various misoprostol Cytotec nabumetone Relafen naproxen various nizatidine Axid omeprazole Prilosec, Zegerid pantoprazole Protonix piroxicam Feldene potassium chloride various quinidine Quinaglute rabeprazole Aciphex ranitidine Tritec, Zantac rifabutin Mycobutin sucralfate Carafate tetracycline various theophylline Theo-Dur tinidazole Tindamax vancomycin Vancocin

Generic Trade alendronate Fosamax amoxicillin Amoxil aspirin various baclofen Kemstro, Lioresal bismuth subcitrate + tetracycline Pylera + metronidazole celecoxib Celebrex clarithromycin Biaxin clopidogrel Plavix esomeprazole Nexium etodolac Lodine hydrochlorothiazide various ibuprofen various indomethacin Indocin ketorolac Toradol lansoprazole Prevacid levofloxacin Iquix, Levaquin metoclopramide Reglan Suggested Reading List Biskupiak JE, Brixner DI, Howard K, et al. Gastrointestinal complications of over-the-counter nonsteroidal antiinflammatory drugs. J Pain Palliat Care Pharmacother. 2006;20:7-14. 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 H-B. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol. 2007;5:17-26. Fass R, Quan SF, O’Connor GT, et al. Predictors of heartburn during sleep in a large prospective cohort study. Chest. 2005;127:1658-1666. Gunaratnam NT, Jessup TP, Inadomi J, et al. Sub-optimal proton pump inhibitor dosing is prevalent in patients with poorly controlled gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2006;23:1473-1477. Lee J, Anggiansah A, Anggiansah R, et al. Effects of age on the gastroesophageal junction, esophageal motility, and reflux disease. Clin Gastroenterol Hepatol. 2007;5:1392-1398. Pandolfino JE, El-Serag H-B, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006;130:639-649. Tytgat GN, McColl K, Tack J, et al. New algorithm for the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2008;27:249-256. 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

Addressing the Burning Addressing the Burning Issues of GERD and Issues of GERD and

AcidAcid--Related DisordersRelated Disorders

David A. Peura, MDProfessor of Medicine

University of Virginia Health Sciences CenterCharlottesville, VA

H. Juergen Nord, MD, MACG, FACPProfessor of Medicine

University of South Florida College of MedicineTampa, FL

H. Juergen Nord, MD, MACG, FACPProfessor of Medicine

University of South Florida College of MedicineTampa, FL

Learning Objectives

• List conditions associated with or that aggravate symptoms of GERD and determine steps to diagnose GERD and GERD complications

• Compare the efficacy of at least 2 therapeutic options for GERD in order to devise optimal treatment strategies for short- and long-term control of symptoms

Practice Pearls

• The prevalence of GERD is increasing across different geographic regions with various factors accounting for this rise

• Nocturnal acid exposure may be important in the development of GERD complications, nonesophageal symptoms, and sleep disturbances

• Even moderate weight gain among persons of normal weight can cause or worsen reflux symptoms

• Gastroprotection is necessary in older patients and those with GI risk who require NSAIDs

Prevalence of GERD Increasing Across Geographic Regions

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

Prevalence of GERD Symptoms in 17 Studies from 1980-2005

GERD = gastroesophageal reflux disease

Audience Question

• What factors are responsible for the changing epidemiology of GERD?

1. Increasing longevity

2. Increasing prevalence of obesity

3. Increasing prevalence of comorbidities affecting the esophagus

4. Use of drugs that affect lower esophageal sphincter pressure and gastric emptying

5. All of the above

?

2

Pathophysiology of GERD

Richter JE. Gastroesophageal reflux disease. In: Yamada T, et al, eds. Textbook of Gastroenterology. Vol. 1. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2003:1196-1224.

Delayed gastric emptying time

Transient lower esophageal sphincter relaxation (TLESR); decreased LES pressure

Impaired esophageal clearance, acid sensitivity

Reduced saliva

Increased gastric volume

Hiatal hernia

Factors Responsible for theChanging Epidemiology of GERD

• Increasing longevity

• Obesity epidemic

• Comorbid conditions affecting the esophagus

• Use of drugs that affect LES pressure and gastric emptying

Lee J, et al. Clin Gastroenterol Hepatol. 2007;5:1392-1398.Watanabe S, et al. J Gastroenterol. 2007;42:267-274.Bonatti H, et al. J Gastrointest Surg, 2007; in press.

Case: Claude III

• 16-year-old who complains of abdominal and esophageal pain for the past 5 months− Compounded by nighttime coughing that is

progressively worsening− Suffers from bouts of epigastric burning

• Height: 5’5; weight: 165 lbs.; body mass index (BMI): 28 kg/m2

• Diagnosed with asthma 5 years ago, which makes exercise and activity difficult− Takes an antihistamine daily

• Has self-medicated with over-the-counter (OTC) antacids, but is not satisfied with treatment results

• Denies tobacco use

NonesophagealManifestations of GERD

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

• Noncardiac chest pain (NCCP)• 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

GERD Symptoms Are Common Among Children With Asthma

5.3

9.5

3.1

10

4.9

12.3

17.8*

7.2*

10.8*

21.5

0

5

10

15

20

25 Healthy controls (n = 264)Asthma (n = 872)

Størdal K, et al. Acta Paediatrica. 2006;95:1197-1201.

Prev

alen

ce o

f sym

ptom

(%)

* P < .01 vs controls† P < .001 vs controls

†

†

Regurgitation/ vomiting

Nausea Heartburn/ retrosternal

pain

Acid regurgitation

Pain when swallowing

Aged 7–16 years

Treating Reflux Disorders at Primary Care Level: An Updated Algorithm*

Tytgat GN, et al. Aliment Pharmacol Ther. 2008;27:249-256.

† Always consider alternative diagnosis when treatment failure occurs

Patient self-care fails, symptoms indicate GERD, other conditions ruled out†

Optimize OTC and/or PPI + adjuvant therapy 4-8 weeks

Success

Step down and stop; restart on lowest effective

dose if relapse occurs

Success

Continue, aim for lowest effective dose

Failure*

BID PPI ±adjuvant therapy

4 weeks and review

Failure*

Success

Failure*

Refer to specialist

* This algorithm is for treatment of GERD in adults

3

Diagnostic Testing for GERD

• Endoscopy and biopsy– Useful to diagnose reflux esophagitis,

complications of GERD (stricture, Barrett’s esophagus), or GERD mimickers (eosinophilic esophagitis, peptic ulcer)

• pH and/or impedance monitoring– Measures reflux and its

association with symptoms

Rosen R, et al. Am J Gastroenterol. 2004;99:2452-2458.Stavroulaki P. Int J Pediatr Otorhinolaryngol. 2006;70:579-590.

Rudolph CD, et al. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1-S31.Photos 1 and 2 courtesy of Janet K. Harnsberger, MD.

Photos 3 and 4 courtesy of Benjamin D. Gold, MD.

1 2

3 4

• Barium swallow/upper gastrointestinal series– Useful to detect anatomic

abnormalities (eg, hiatal hernia, achalasia, stricture)

21

Role of Diagnostic Testing in Initial Management of GERD

• Assume GERD if symptoms consistent with GERD– Diagnosis “confirmed” by response to acid suppression therapy

• Endoscopy to document presence/absence of esophagitis or Barrett’s not necessary to direct therapy– Manage patient focusing on symptom relief

• Further tests (endoscopy, 24- or 48-hour pH metry) indicated if:– Symptoms suggest complicated disease

• Dysphagia • Weight loss • Bleeding• Odynophagia • Anemia

– Inadequate response to therapy (consider other conditions, eg, eosinophilic esophagitis, functional heartburn)

– Risk factors for Barrett’s, or patient and physician deem appropriate

DeVault KR, et al. Am J Gastroenterol. 2005;100:190-200.

Audience Question

• Which of the following lifestyle modifications has little discernable effect on GERD?

1. Weight loss

2. Alcohol/tobacco cessation

3. Elevation of head of bed

4. Sleeping in left lateral decubitus position

?

Evidence to support these measures is limited– Alone, they are unlikely to control symptoms– Can be recommended in conjunction with medical therapy

Lifestyle Modifications in the Management of GERD

Kaltenbach T, et al. Arch Intern Med. 2006;166:965-971.Peisman M, et al. Am J Gastroenterology. 2007;102:2128-2134.

Dietary Factors to Avoid

• Alcohol • Fatty foods

• Spicy foods • Chocolate

• Caffeine, coffee • Peppermint

• Citrus, fruit juices

• Carbonated beverages

• Eat meals earlier

Lifestyle

• Smoking/ tobacco cessation

• Sleeping in left lateral decubitus position

• Weight loss • Elevate head of bed

• Avoid LES-relaxing medications

Impact of Lifestyle Changes on GERD

• 16 trials examined effectiveness of lifestyle changes

Lifestyle change Effect

Weight loss Improved pH metry results and symptoms

Elevation of head of bed Improved pH metry results and symptoms

Left lateral decubitus position Raised LES pressure, improved pH metry results

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

Pharmacotherapy Options for GERD

Hassall E. J Pediatr. 2005;146(3 suppl):S3-S12.Physicians’ Desk Reference. Montvale, NJ. Thomson PDR; 2007.

Tipnis NA, et al. Curr Treat Options Gastroenterol. 2007;10:391-400.

Therapy Considerations

Histamine2-receptorantagonists(H2RAs)

• Available for infants (ranitidine), children, adolescents, and adults– Solution or suspension forms and effervescent tablet

• Less potent acid suppression compared with PPIs• Tachyphylaxis (ie, tolerance) is an issue

Proton pumpinhibitors (PPIs)

• Lansoprazole, esomeprazole, and omeprazole available for children, adolescents, and adults

• Rabeprazole available for patients 12 to 17 years• Pantoprazole and rabeprazole available for patients ≥ 18 years of age• Multiple formulations for ease of use; many PPIs are available OTC• Superior efficacy to H2RAs for healing, symptom relief, and pH

control• Cost and managed care restrictions

4

100

PPIs Are the Most Effective Acid-Suppressive Therapy

1. Chiba N, et al. Gastroenterology. 1997;112:1798-1810.2. Khan M, et al. Cochrane Database Syst Rev. 2007;(2):CD003244.

3. Havelund T, et al. Am J Gastroenterol. 1999;94:1782-1789.

0 2 4 6 8 10Time (weeks)

Perc

enta

ge o

f pat

ient

s to

tally

hea

led

PPIsH2RAPlacebo

80

60

40

20

0

• PPI therapy provides the most effective healing and symptom relief in GERD patients1,2

• PPIs improve qualityof life that has been impaired due to GERD symptoms3

Follow-up: Claude III

• Claude III is instructed on lifestyle modifications and is prescribed lansoprazole 30 mg QD− He takes the medication on an “as-

needed” basis, typically when he has a sore throat

• He still has intermittent bouts of nighttime coughing

• He has lost 10 pounds after beginning karate lessons

Audience Question

• Since Claude still experiences occasional nighttime coughing, how would you proceed with treatment?

1. Give PPI before dinner2. Switch PPIs3. Increase PPI dose, with one before

breakfast and one before dinner, and instruct him on the importance of complying with directions on taking medications

4. Increase PPI dose, with one before breakfast and one before bed

5. Add an H2RA before bed

? Improper Dosing of PPIs Is Prevalent Among “Nonresponders”

• 54% of patients on PPI therapy dosed suboptimally

• Only 12% dosed in a manner to maximize efficacy, 15-30 minutes prior to a meal

Gunaratnam NT, et al. Aliment Pharmacol Ther. 2006;23:1473-1477.

28%

4%

30%

38%

> 60 minutes before meal

After mealsAt bedtimeAs needed

Breakdown of Sub-Optimal Dosers

“Optimal” = taking a PPI with or up to 60 minutes prior to meal

Importance of Timing of PPI Dose

Ensures that maximum plasma concentration of PPI coincides with the activated proton pumps

Gunaratnam NT, et al. Aliment Pharmacol Ther. 2006;23:1473-1477.Rudolph CD, et al. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1-S31.

Dosing Administer PPI

QD 30 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 More than 50% of patients referred for persistent GERD symptoms are taking their PPI GERD symptoms are taking their PPI suboptimallysuboptimally

Symptoms Sometimes Persist Despite PPI Therapy

Patients with LA Grade C/D esophagitis unhealed after 8 weeks of PPI therapy

0

5

10

15

20

25

30

Richter 2001(N = 2425)

Kahrilas 2000(N = 1960)

Castell 2002(N = 5241)

Fennerty 2005(N = 999)

Labenz 2005(N = 2766)

Perc

ent o

f unh

eale

d pa

tient

s

Katz PO, et al. Aliment Pharmacol Ther. 2006;23(suppl 2):9-22.

5

If Increased Acid Suppression Does Not Improve Symptoms, Consider Alternate Etiologies

• BID PPI therapy is often the next step when symptoms do not respond1

• If symptoms do not improve on BID PPI, consider other etiologies2

– Functional heartburn– Nonacid reflux– Eosinophilic esophagitis– Hypersensitive esophagus– Pill-associated esophagitis– Acid hypersecretion

1. Richter JE. Nat Clin Pract Gastroenterol Hepatol. 2007;4:658.2. Charbel S, et al. Am J Gastroenterol. 2005;100:283.

Case Summary: Claude III

• Claude III is instructed on the importance of taking lansoprazole as often as prescribed, at the proper time

• Since taking his medication as prescribed, he still has occasional nighttime coughing episodes, but no longer suffers from a sore throat

• Because the severity of his asthma lessened through adolescence, he no longer requires asthma medication

Case: Claude Jr.

• Claude III’s father, a full-time bartender and restaurant owner, is 52 years old, overweight and smokes 1 pack of cigarettes per day– Waist circumference of 42 inches– Height: 5’10”; weight 225 lbs– Body mass index = 37 kg/m2

• Complains of substernal pain with a burning feeling for the last month to 6 weeks; takes rabeprazole 20 mg QD

• Has nighttime symptom breakthrough (2 to 4 nights a week), resulting in frequent bouts of insomnia

• Usually skips breakfast, but eats large meals at supper– He eats quickly due to work responsibilities

Audience Question

• How would you proceed with managing Claude Jr.’ssymptoms?

1.Order an endoscopy

2.Order an upper GI series

3.Obtain pH monitoring

4.Refer to surgery

5.Other

?

Higher Body Mass Index Increases Risk of GERD Symptoms

Regardless of Obesity• Even moderate weight gain among persons of normal weight

can cause or worsen reflux symptoms• Weight loss is associated with a decreased risk of symptoms

Mul

tivar

iate

odd

s ra

tio

for r

eflu

x sy

mpt

oms

Body mass index (kg/m2)

Jacobson BC, et al. N Engl J Med. 2006;354:2340-2348.

P < .001 for trend

N = 2306 women with at least weekly GERD symptoms and 3904 with no symptoms

Obesity as a Risk Factor: Severe Erosive Esophagitis

1. Labenz J, et al. Am J Gastroenterol. 2004;99:1652-1656.

2. Photos courtesy of Dr. M. Farivar.

Odds Ratio (95% CI) P Value*

BMI > 25-30 kg/m2

(overweight)1.70 (1.24-2.34) .0011

BMI > 30-40 kg/m2

(obese) 1.97 (1.33-2.93) .0008*P value compared to BMI < 25 kg/m2

Grade A Grade B Grade C Grade DLos Angeles Grade2

Obesity as a Risk Factor: Severe Erosive Esophagitis (LA Grade C or D)1

6

Obesity as a Risk Factor: Barrett’s Esophagus

Obesity Odds Ratio 95% CI

With GERD symptoms 34.4 6.3-188Without GERD symptoms 0.7 0.2- 2.4

Risk of Barrett’s Esophagus in Obesity with GERD Symptoms

N = 167 with histologically confirmed Barrett’s esophagus

Smith KJ, et al. Cancer Epidemiol Biomarkers Prev. 2005;14(11 pt 1):2481-2486.

Audience Question

• In addition to obesity, which of the following is a risk factor for Barrett’s esophagus?

1. Prior history of ulcers

2. Prior history of H2RA use

3. Nocturnal GERD symptoms

4. Hypertension

?

Risk Factors for Barrett’s Esophagus

Falk GW. Gastroenterology. 2002;122:1569-1591.El-Serag HB, et al. Am J Gastroenterol. 2005;100:2151-2156.

Ronkainen J, et al. Gastroenterology. 2005;129:1825-1831.

Risk Factors for BE

Long history of GERD symptoms

(> 5-10 years)

Nocturnal GERD symptoms

Caucasian, male gender, middle-agedDevelopment of

GERD symptoms at an early age

Obesity, particularly

visceral adiposity

GERD complications

(eg, ulceration, strictures, bleeding,

esophagitis)

Tobacco and alcohol use

Diagnostic Criteriafor Barrett’s Esophagus

Endoscopic Findings– Squamocolumnar junction is displaced

proximal to esophagogastric junction

Sampliner RE, et al. Am J Gastroenterol. 2002;97:1888-1895..Photos courtesy of Byron Cryer, MD.

GE junction

Squamocolumnarjunction

Columnar-lined epithelium

Systematic biopsy– Documentation of intestinal metaplasia and

detection of dysplasia (ie, goblet cells, brush border)

GERD: What Are the Risks for Esophageal Cancer?

Cohort N Number of Incident Cancers

Hazard Ratio(95% CI)

Standard reference 13,416 16 1.00

Simple reflux* 6328 6 1.7 (0.7–4.5)

Esophagitis 6392 8 2.2 (0.9–5.2)

Barrett’s esophagus 1677 13 10.6 (5.1–22.0)

Solaymani-Dodaran M, et al. Gut. 2004;53:1070-1074.Shaheen N, et al. JAMA. 2002;287:1972-1981.

* Subjects who had a record of gastroesophageal reflux and no record of any antireflux operations, Barrett’s esophagus, or esophagitis

The absolute risk of cancer in Barrett’s esophagus is 1 in 250 patient years

Endoscopic Healing and Symptom Relief with Esomeprazole

Perc

ent o

f pat

ient

s

* P < .0001 Malfertheiner P, et al. Gut. 2005;54:746-751.

The presence of Barrett’s mucosa exerts a negative impact on healing

7

David A. Peura, MDProfessor of Medicine

University of Virginia Health Sciences CenterCharlottesville, VA

Audience Question

• How would you proceed in managing Claude Jr.’s nocturnal symptom breakthrough?

1. Initiate lifestyle modifications and increase PPI dosing to BID

2. Initiate lifestyle modifications and add a bedtime H2RA to morning PPI

3. Initiate lifestyle modifications and increase PPI dosing but give it QD or switch PPIs

4. Refer to a gastroenterologist

?

Some Patients on PPI Therapy Have Breakthrough Symptoms

AGA Survey. http://www.gastro.org/wmspage.cfm?parm1=5287.

No breakthrough

symptoms

62%

Breakthrough symptoms

38%

N = 1064

Breakthrough symptoms often occur at night:

16%

45%

65%

28%

0 20 40 60 80

Morning

Afternoon

At night

Whilesleeping

Percent of patients with breakthrough symptoms

Follow-up Case: Claude Jr.

• Since he began taking omeprazole IR 40 mg at bedtime, Claude Jr.’snocturnal heartburn has improved considerably

• However, he stopped taking the medication 2 weeks ago after reading a newspaper article about a link between PPIs and hip fractures, and his nocturnal heartburn returned

Long-term Efficacy and Safety of PPIs

• Incidence of adverse events did not increase with long-term treatment

• No dysplasia or neoplasmswere observed

• In this study, PPI therapy appeared effective and safe when given to adults continuously for > 10 years

Klinkenberg-Knol EC, et al. Gastroenterology. 2000;118:661-669.

Number of patientsNumber of relapses

Years on omeprazole ≥ 20 mg daily

Num

ber o

f pat

ient

s or

re

laps

es

50

100

150

200

250

0 5 6 7 8 9 10 113 421 12

Safety of PPIs in Pregnancy

Treatment Group

Pregnancy Category

Number of Pregnancies

(Number in First Trimester)

Rate of Major Congenital

Abnormalities

Control Rate of Congenital

Abnormalities (N = 868)

Lansoprazole B 62 (55) 3.9% 3.8%

Omeprazole C 295 (233) 3.6% 3.8%

Pantoprazole B 53 (47) 2.1% 3.8%

• Multicenter prospective controlled study in Europe• Risk of major congenital abnormalities did not differ between

PPI and control groups

Diav-Citrin O, et al. Aliment Pharmacol Ther. 2005;21:269-275.Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.

8

Omeprazole Decreases Antiplatelet Action of Clopidogrel

Gilard M, et al. J Am Coll Cardiol. 2008;51:256-260.

0

-10

-30

-40

-50

-60

Perc

ent o

f pla

tele

t rea

ctiv

ity in

dex

(PR

I) va

riatio

n

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

on clopidogrel plus aspirin efficacy after 7 days of treatment

P < 0.0001

Placebo (n = 60)

Omeprazole (n = 64)

-20

-70

(–43.3)

(–32.6)

• On Day 1, mean PRI was similar: 83.2% (SD 5.6) and 83.9% (SD 4.6), respectively, in the placebo and omeprazole groups

• On Day 7, mean PRI was 39.8% (SD 15.4) and 51.4% (SD 16.4), respectively, in the placebo and omeprazole groups (P < 0.0001)

Controversy: Are PPIs Associated with an Increased Risk of

C. difficile–Associated Disease?• 317 cases of community-acquired C. difficile–associated

disease treated with oral vancomycin and 3167 controls

Dial S, et al. CMAJ. 2006;175:745-748.Cunningham R. CMAJ. 2006;175:757-758.

Exposure Within 90 Days

Adjusted Odds Ratio for C. difficile–Associated

Disease95% CI

Antibiotic 8.2 6.1 – 11.0

PPI 3.5 2.3 – 5.2

• Questions remain:– Epidemiologic studies have limitations– C. difficile–associated disease involves a complex interaction between

host, pathogen, and environment

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)

†

No Evidence of Increased Cancer Risk Associated with PPI Use

• PPI use does not appear to increase risk of colorectal or stomach cancer1-5

• No evidence of increased risk in either short-term or long-term studies (≥ 7 years exposure)1-4

– May increase fundic gland polyps but not neoplasm5

1. van Soest EM et al. Am J Gastro. 2008;103:966-973.2. Robertson DJ, et al. Gastroenterology. 2007;133:755-760.

3. Yang YX, et al. Gastroenterology. 2007;133:748-754.4. Singh M, et al. Aliment Pharmacol Ther. 2007;26:1051-1061.

5. Jalving M, et al. Aliment Pharmacol Ther. 2006;24:1341-1348.

Overall PPI Safety

• PPIs are well tolerated with a low incidence of adverse events

• Most common adverse events:

Scott LJ, et al. Drugs. 2002;62:1503-1538.Gold BD, et al. Pediatric Drugs. 2002;4:673-685.

Rudolph CD, et al. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1-S31.Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.

• Constipation (≤ 5%)

• Headache (< 10%)• Abdominal pain (≤ 5%)

• Nausea/vomiting (≤ 5%)• Diarrhea (≤ 5%)

• On the market for nearly 20 years• Not known to cause cancer• Weigh the risk of not treating versus risk of treatment

Facing Managed Care Challenges in Patients Requiring PPI Therapy

• Document – Severity/recurrences of symptoms– Failure of other therapies, especially OTC

• Encourage patients to become their own advocates– Impact on productivity/lack of sleep– Impact on quality of life– Direct and indirect cost associated with poor symptom control

• Use alternate strategies where appropriate– Start patient on QD– Step up to BID only if necessary– Consider on-demand therapy for maintenance of uncomplicated

reflux

DeVault KR. Am J Manag Care. 2000;6(16 suppl):S871-S875.

9

Unmet Needs in Management of GERD

How Can PPI Therapy Be Improved?

• Remove the necessity of dosing before meals

• Lengthen duration of effect– Lessen need for BID and additional OTC dosing

– Improve nocturnal acid control

• Decrease inter-patient variability

• Products under development

Boparai V, et al. Drugs. 2008;68:925-947.

� Combination therapies (PPI + histamine or gastrinantagonist combinations)

� Potassium-competitive acid blockers (P-CABs)

� Tenatoprazole� Dexlansoprazole

New AGA Evidence-Based Guidelines for Managing GERD

PPI therapy is preferable to anti-reflux surgery as initial therapy due to superior safety

Utilize BID PPI therapy as empirical trial for patients with suspected reflux chest pain after cardiac etiology has been considered

Long-term use of PPIs to treat patients with esophagitis is acceptable but titrate to lowest effective dose based on symptom control

PPIs are superior to H2RAs, and H2RAs are superior to placebo

“Grade A” recommendations*

* Strongly recommended based on good evidence that it improves important health outcomes AGA Institute. Gastroenterology. 2008;135:1383-1391.

New AGA Evidence-Based Guidelines for Managing GERD

When symptom control is the primary objective in patients with symptomatic esophageal syndromes, use antisecretory drugs on a short course or on an as-needed basis

Antireflux surgery is a viable option for patients with esophageal GERD syndromes with persistent troublesome symptoms (especially troublesome regurgitation) despite PPI therapy

Advise overweight or obese patients with esophageal GERD syndromes to lose weight

Use endoscopy with biopsy for patients with esophageal GERD syndromes with troublesome dysphagia or who fail empiric BID PPI.

Biopsies should target areas of suspected metaplasia, or in absence of visual abnormalities, normal mucosa to test for eosinophilic esophagitis

Use BID PPI therapy for patients with esophageal syndromes who do not adequately respond to QD PPI therapy

“Grade B” recommendations*

AGA Institute. Gastroenterology. 2008;135:1383-1391.* Recommended with fair evidence that it improves

important outcomes

Case Summary: Claude Jr.

• His endoscopy shows LA grade B esophagitis with no evidence of Barrett’s esophagus

• He restarted omeprazole IR 40 mg at bedtime, which provides heartburn relief

• Referral to weight management program

Case: Claude Sr.

• Claude Sr., the family patriarch, is 76 years old, lives independently, and complains of difficulty swallowing and chest pain

• Diagnosed with osteoporosis 2 years ago and has long standing hypertension

• He has undergone a cardiac workup, including a thallium stress test, which is negative

• An endoscopy reveals LA grade C esophagitis and midesophageal stricture

• He takes alendronate, hydrochlorothiazide, potassium chloride, low dose aspirin, and naproxen

10

Changes Underlying Increased Esophageal Acid Exposure in Elderly

• Older age associated with less effective esophageal motility and acid clearance mechanisms

• Structural degradation of gastroesophageal junction and decreased LES length may contribute n = 99 n = 255 n = 299 n = 313 n = 205 n = 96

P < 0.0001 on multivariate regression

Esop

hage

al a

cid

expo

sure

(% ti

me

pH <

4)

Age (in years)

Lee J, et al. Clin Gastroenterol Hepatol. 2007;5:1392-1398.

Typical GERD Symptoms Less Frequent in Older Patients

Yet Esophageal Injury More Severe

Esophagitis grade III - IV

Pilotto A, et al. J Am Geriatr Soc. 2006;54:1537-1542.

Perc

ent o

f pat

ient

s

N = 840P < .001 for age in all comparisons

0

10

20

30

40

50

60

70

80

Heartburn/acid reflux

Esophagitis grade I

Esophagitis grade II

Young (mean age 36.7 years)Adult (mean age 59.1 years)Elderly (mean age 77.3 years)Very elderly (mean age 88.4 years)

Atypical Symptoms More Common in Older Patients with

Reflux Esophagitis

0

5

10

15

20

25

30

35

Dysphagia Anorexia Anemia Weight loss Vomiting

Young (mean age 36.7 years)Adult (mean age 59.1 years)Elderly (mean age 77.3 years)Very elderly (mean age 88.4 years)

Perc

ent o

f pat

ient

s

Pilotto A, et al. J Am Geriatr Soc. 2006;54:1537-1542.N = 840P < .05 for age in all comparisons

Effect of Pantoprazole in Older Patients with Erosive Esophagitis

0

20

40

60

80

100

0

20

40

60

80

100

Grade 2 Grade 3/4

Healing rates of erosive esophagitis at 8 weeks

Perc

ent o

f pat

ient

s he

aled

(95%

CI)

n = 44 n = 210 n = 13 n = 69n = 11

n = 71

≥ 65 years

< 65 years

P < 0.00186

83

46

3527

34

Healing rates of pantoprazole* by erosive esophagitis grade

Perc

ent o

f pat

ient

s he

aled

(95%

CI)

* Patients received pantoprazole 40 mg once daily. Healing rates were measured after 8 weeks.

≥ 65 years

< 65 years

n = 23 n = 140 n = 21 n = 70

96

87 76 74

DeVault KR, et al. Dis Esophagus. 2007;20:411-415.

Pantoprazole 40 mg

once daily

Nizatidine 150 mg

twice dailyPlacebo

Drug-Induced Esophageal Injury: Offending Medications

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

4%

22% 8%

40%

7%10%

9%

NSAIDs (including aspirin)

Quinidine

Potassium chloride

Alendronate

Ascorbic acid

TetracyclinesOther

antibiotics

Audience Question

• Which of the following is a risk factor for a serious upper GI event with NSAID use?

1. Advancing age

2. Concomitant use of H2RA

3. Prior use of oral antacids

4. Smoking

5. All of the above

?

11

Risk Factors for Serious Upper GI Events with NSAID Use

Risk Factor• Prior complicated ulcer • Concomitant SSRI use

• Advancing age (> 65 years) • Multiple NSAID use

• Concomitant anticoagulant use • High-dose NSAIDs

• Concomitant corticosteroid use • Selection of NSAID (eg, ketorolac, indomethacin, or piroxicam vs. etodolac or nabumetone )

• Concomitant aspirin use (including low dose)

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

Concomitant Aspirin Use Is Common Among OTC NSAID Users

Biskupiak J, et al. J Pain Palliat Care Pharmacother. 2006;20:7-14.

05000

1000015000200002500030000350004000045000

Naproxen 220 mg Ibuprofen 200 mg

OTC NSAID aloneConcomitant aspirin

Num

ber o

f ind

ivid

uals

19.5%

12.6%

Retrospective review of database containing information for > 3.2 million individuals

Ibuprofen May Reduce the Cardioprotective Effects of Aspirin

• Reported to block aspirin from binding to platelets in vitro

• Retrospective analysis of 7107 patients:– Ibuprofen + aspirin was associated with a higher mortality than

aspirin alone

Catella-Lawson F, et al. N Engl J Med. 2001;345:1809-1817.MacDonald TM, et al. Lancet. 2003;361:573-574.

Adjusted Hazard Ratio 95% CI P Value

All-cause mortality 1.93 1.30 - 2.87 .001

Cardiovascular mortality 1.73 1.05 - 2.84 .03

CV Risks Are the Limitation with COX-2 Inhibitors

Bertagnolli MM, et al. N Engl J Med. 2006;355:873-884.Arber N, et al. N Engl J Med. 2006;355:885-895.

Laine L, et al. Gastroenterology. 2004;127:395-402.

Trial Dose Number of Patients

Relative Risk of CV Events vs Placebo

(95% CI)

APC study

Celecoxib 200 mg

twice daily685 2.6 (1.1 – 6.1)

Celecoxib 400 mg

twice daily671 3.4 (1.5 – 7.9)

PreSAP trialCelecoxib

400 mg once daily

933 1.3 (0.65 – 2.62)

Also, COX-2 inhibitors offer no GI benefit compared to traditional NSAIDs in the presence of aspirin

Lansoprazole and MisoprostolProvide Gastric Protection

from NSAID Use

Perc

ent o

f pat

ient

s

* P < .001 vs placebo

537 long-term NSAID users with a history of gastric ulcer(all H. pylori negative)

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

*

*

**

Tips for Prevention of Pill-Related GI Injury in the Aging Population

• Reinforce importance of medication administration schedules and directions– Take medication upright– Swallow of water prior to medication and at least 4 ounces after

• Use alternative medication formulations in high-risk patients or those with dysphagia– A variety of chewable, liquid, or crushable forms available

• Educate patients on signs and symptoms of esophageal injury and dysphagia

• Prescribe gastroprotective cotherapy for patients with GI risk requiring NSAIDs

O’Neill JL, et al. Ann Pharmacother. 2003;37:1675-1684.

12

Case Summary: Claude Sr.

• Claude Sr’s. dysphagia resolved after his stricture was dilated and he was started on orally disintegrating lansoprazole 30 mg tablet once daily to treat his esophagitis

• He was also instructed on correct methods for taking his medication and his alendronate was discontinued

Overall Take-Home Points

• The prevalence of GERD is increasing across different geographic regions with various factors accounting for this rise

• Nocturnal acid exposure may be important in the development of GERD complications, nonesophageal symptoms, and sleep disturbances

• Even moderate weight gain among persons of normal weight can cause or worsen reflux symptoms

• Gastroprotection is necessary in older patients and those with GI risk who require NSAIDs