Acid Peptic Diseases

Clinical Management Course

February 2007

Walter Smalley, MD MPH

Acid - Peptic Diseases

• Drugs• Antacids• H2RAs (“H-2 blockers”)• Proton Pump Inhibitors (PPI’s)• Selective COX-II inhibitors

• Conditions Covered• Heartburn • Gastroesophageal Reflux (GERD)• Peptic Ulcer Disease

• H. Pylori• NSAIDs

Antacids

• Immediate effect on gastric pH• Effect is short-lived• Typical dose 30-60 cc• Frequent use may cause diarrhea

H-2 Receptor Antagonists

• Inhibit H-2 receptors (competitive inhibition)• Partially inhibit acid production• Relatively safe drugs• Less effective than PPI’s• Less expensive than PPI’s• Available over the counter: at prices more expensive

than prescription costs

Cimetidine : Safety Considerations

• Brand name Tagamet• Induces cytochrome p450 system• Drug interactions with coumadin, theophylline,

dilantin and others• Rarely clinically relevant

• But “why not use ranitidine”

• Confusion in the elderly• Thrombocytopenia

H2 blockers : No difference in efficacy within group

Ulcer treatment

Ulcer maintenance

GE Reflux treatment (BID to QID)

Cimetidine (Tagamet)

800 - 900mg QHS 300 mg QHS > 1200 mg QD

Ranitidine (Zantac)

300 mg QHS 150 mg QHS > 300 mg QD

Nizatidine (Axid)

300 mg QHS 150 mg QHS > 300 mg QD

Famotidine (Pepcid)

40 mg QHS 20 mg QHS > 40 mg QD

Proton Pump Inhibitors

• Raise gastric pH to > 5 for several hours• Binds covalently to H+/K+ pump• Prodrugs: bioavailable at acid pH• Maximal effectiveness

• After several doses• When taken before meals• After a long fast• (Prior to breakfast)

Proton Pump Inhibitors

• Omeprazole • (generic cost about 80% of prescription costs )

• Immediate release omeprazole• Lansoprazole• Rabeprazole• Pantoprozole – oral and IV form• Esomeprazole

• Very effective, no important predictable differences in efficacy

• Very expensive ($2-4/day)• ~ $1 per day generic

Case 1

• 35 year old healthy man• Occasional heartburn• Occurs only with large meals, EtOH ingestion• No dysphagia

Heartburn : Summary

• How soon does the patient want relief ?• How long does it need to last ?• How much are they willing to pay ?

Heartburn : Summary

• Prevention

• Antacids are effective immediately in reducing acid - work for 1-2 hours

• H2-blockers are effective in 1-2 hours - they work for > 6-8 hours• Available over the counter

Case 1

• Consider not eating large meals• Consider PRN antacids• Consider OTC H2 blockers

• On the horizon ?• Immediate release omeprazole –

• Direct to consumer marketing• Marginal benefit vs other PPIs

Case 2

• 50 yo with frequent nocturnal heartburn• No dysphagia• Trial of lifestyle modification only minimally

effective• Antacids ineffective

GERD: When to perform diagnostic tests

• Endoscopy• Dysphagia• Weight loss• Age > 50• Failure of medical therapy

• Motility : prior to fundoplication• pH monitoring: might resolve diagnostic uncertainty in

absence of esophagitis

Gastroesophageal Reflux

• Reflux of gastroduodenal contents • Acid ( gastric)• Alkaline (biliary, pancreatic)

• Decreased lower esophageal sphincter (LES) tone• Decreased rate of gastric emptying• Increased intra-abdominal pressure• Decreased salivary clearance

GERD: Lifestyle Modification

• weight loss, avoid tight-fitting clothes• NPO 3-4 hours before bedtime• elevate head of bed 8''• avoid foods and drugs that decrease LES pressure or

gastric emptying rate• fat, EtOH, tobacco , peppermint, garlic, onions,

chocolate, Ca++channel blockers, nitrates, theophylline, antidepressants

• No strong RCT evidence to support important effect of lifestyle modification

Case 2

• 50 yo with frequent nocturnal heartburn• No dysphagia• Trial of lifestyle modification only minimally

effective• Antacids ineffective

• EGD - distal esophageal erosions

GERD : Overview

• Antacids: temporary relief

• H2-antagonists:

• high (“double”) doses, frequent dosing

• Prokinetics: as effective as H2RA’s

• Metoclopramide

• Proton pump inhibitors:

• most effective

• most expensive

GERD: H2-antagonists

• NO BETWEEN - DRUG DIFFERENCES IN EFFICACY• symptomatic relief < 60 - 70% cases• endoscopic improvement < symptomatic relief• higher doses (>2X ulcer doses) improve efficacy

slightly

GERD : Prokinetic Agents

• Metoclopramide • As effective as H2RAs• Adverse reactions:– fatigue, lethargy, extrapyramidal symptoms

occur in 10% - 30%.

Case 2

• Continue lifestyle modification• Trial of H2 blockers at high doses

Case 3

• Patient #2 returns after 8 week trial of H2 blockers• Therapy only minimally effective

GERD : Proton Pump Inhibitors

• Causes healing and resolution of symptoms in 80% of patients with disease resistant to H2-blockers

• Expensive, single source drugs ($ 2 - 4 / day)

• Over the counter more expensive than prescription• Not on Wal-mart list

• Generic omeprazole still > $1 per day

Case 3

• Proton pump inhibitor

Case 4

• Patient from Case 3 returns• Symptoms well controlled on omeprazole• Symptoms recur immediately after stopping drug• “Hates taking meds”

GERD: Anti - Reflux Surgery

• Indications: • patient preference over drug treatment• young patients with severe esophagitis• difficult to dilate strictures• recurrent esophageal ulcers• GER-respiratory/ENT syndromes• 80 - 90% of cases have some improvement

GERD: Anti - Reflux Surgery

• Side effects: about 10 % cases• "gas bloat"• dysphagia• strictures• other

• Usually won’t work if PPI’s don’t work

Utilization of GERD pharmaceuticals in patients treated medically and surgically

Khaitan et al, Arch Surgery 2003

Acid suppression days per quarter

Most fundoplication patients end up taking some acid meds after operation

Endoscopic therapies for GERD

• Stretta: radiofrequency destruction of GEJ myenteric plexus

• Endoscopic Plication: sewing gastric cardia mucosa to augment GEJ

• Injection of GEJ with plastic (removed from market)

• All should be considered experimental at this point

Case 4

• Consider anti reflux procedure• Weighing potential benefits of not taking medication

vs. risk of side effects from surgery (probably 1- 3% in experienced hands)

Case 5

• 40 yo with epigastric pain

“ALARM FEATURES” •unexplained weight loss• anorexia• early satiety• vomiting• progressive dysphagia• odynophagia• bleeding• anemia• jaundice• abdominal mass• lymphadenopathy• family history of upper GI cancer• history of peptic ulcer, previous gastric surgery or malignancy.

ACG dyspepsia management guidelines

Case 5

• 40 yo with epigastric pain

• Relieved with meals

• No clinical signs of bleeding

• No vomiting

• Reasonable approaches

• Empiric trial of acid suppression

• “Test and treat” for H pylori

• Refer for endoscopy

Case 5

• 40 yo with epigastric pain

• 8 week trials of PPI fails

• EGD : duodenal ulcer• H pylori positive• no NSAIDs confirmed

Ulcer Disease : Basic Concepts

• H. pylori is associated with GU and DU• NSAID use is associated with GU and DU• Most ulcers are not the result of excess acid • Acid suppression aids in healing ulcers• Prior to the H pylori era: most of the cost of ulcer

disease had been in “maintenance” therapy

H pylori : Concepts

• H pylori infection is chronic• Prevalence in US adults = 50 - 80%• Lifetime risk of ulcer disease = 10%• Associated with chronic gastritis - a histological

diagnosis• H pylori is a risk factor for gastric adenocarcinoma

H pylori - Diagnosis

• EGD – • Biopsy for histology and CLO

• Breath Tests – • commercially available• big hassle

• Serology – • widely available, • followup is problematic (positivity persists

months after eradication)• Stool antigen test:

• problem = it’s stool.

H pylori. treatment - Efficacy

• For treatment of duodenal ulcer > gastric ulcer• Eradication of H.pylori alone = treatment with H2-

blockers alone• For preventing recurrent duodenal ulcer:

• Eradication of H.pylori >> continuous H2-blocker therapy

• Marginal (if any) benefit in treating non ulcer dyspepsia

H pylori. treatment - Options

• Many different regimens • No "standard of care"• Best therapy yet to be determined• Big problems

• compliance• resistance

• Current (2/07) favorite combination• Amoxicillin, PPI, Clarithromycin• Metrondazole, PPI, Clarithromycin

Peptic Ulcer: Treatment Outcomes

Efficacy : 8 weeks

Efficacy : 1 year chronic acid suppression

Efficacy : 1 year without acid suppression

Sucralfate 70 - 90% NA 60 - 70%

H2-antagonists 70 - 90% 70 - 90% 50 - 75%

Omeprazole > 95% 70 - 90% 50 - 75%

H. pylori eradication

> 95% >90% > 90%

Case 5

• Treatment with acid suppression

• QD H2 blockers, or

• proton pump inhibitor• Treat H pylori

• Amoxicillin 1000 BID

• Clarithromycin 500 BID

• Omeprazole 20 BID

Case 6

• 65 yo male with osteoarthritis with recent ulcer• On ibuprofen 1800 mg per day• Ulcer has healed• H pylori negative

NSAIDs and Ulcers - Concepts

• Higher doses ---> greater risk• Long time users still have increased risk after 12

months• Absolute risk is high

• about one ulcer hospitalization per 100 person years in the elderly

• About 2/3 of ulcers in NSAID users are due to the NSAID use

• By far our most important complication of pharmaceutical use

NSAIDs and PUD : Treatment

• Stop NSAIDs• Acid suppression

Drug Healing at 6 - 8 weeks• Omeprazole > 90%• H2-Blockers 70-90%• Misoprostol 70-90%• Sucralfate not effective

NSAIDs and Ulcers - Prevention

• Does the patient really need NSAIDs ?• objective = pain control• NSAIDs do not prevent progression in

osteoarthritis• little evidence demonstrating superiority of

NSAIDs over acetaminophen in osteoarthritis patients.

• No NSAID is "safe".

NSAIDs and Ulcers - Prevention

• Misoprostol - a synthetic PGE analog• Prevents GU and DU• Expensive therapy - for prevention.• Debate on cost effectiveness continues.• Side effects: diarrhea (10%), abdominal pain (10 -

20%)• Causes spontaneous abortions - do not use in

potentially fertile women

NSAIDs and Ulcers - Prevention

• H-2 blockers at high doses may be reliable preventive agents for DU prevention

• Misoprostol is very effective in preventing ulcers in clinical trials.

• PPI’s are as probably as effective as misoprostol and better tolerated

• Eradicating H pylori is helpful in preventing recurrence (RCT evidence)

Selective COX-II Inhibitors: COXIBs

• Celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib

• NO more effective than traditional NSAIDs• Potential benefit is GI safety

• Still have renal toxicity, other toxicities ?• Large trials demonstrate decreased ulcer rate

• Decrease of about 50% • Do high-risk patients still need acid suppression ?

• Risk of cardiac events has led to the removal of rofecoxib and valdecoxib

Results from a polyp prevention trial

Case 6

• Consider alternatives to NSAIDs

• narcotics

• non-narcotics

• physical therapy

• topical therapy• Consider misoprostol• Consider acid suppression with PPI• For now would not consider any COXIB drugs left on

the market

Peptic Ulcer Disease

• Stop NSAIDs.• Acid suppression acutely• Test for H pylori and treat if present.

Case 7

• 75 yo admitted with hematemesis, shock• Intubated for airway protection (NPO)• EGD reveals gastric ulcer with visible vessel

• Treatment with heater probe controls bleeding

Acid Suppression

• There is evidence that acid suppression may decrease rebleeding rates, surgical rates, and hospital days

• There is no evidence that it saves lives • (studies would have to be huge)

• Most IV PPI data is based on trials using IV OMEPRAZOLE which is not available in the US

• Most studies involved bleeding ulcers requiring endoscopic therapeutic interventions (injection therapy or heater probe)

Lancet 2005

Proton pump inhibitor (IV or PO)

Moderate effects on:•reduced rebleeding (table left)

•OR 0.46, 95%CI 0.33 to 0.64•NNT =12

•surgery •OR 0.59 95%CI 0.46 to 0.76•NNT = 20

treatment had no significant effect on mortality

•OR 1.11, 95%CI 0.79 to 1.57•NNT = incalculable

PPI’s Summary

• In the select group of patients who require endoscopic therapy the few published studies demonstrated potential advantage for IV Omeprazole

• In our settings most endoscopies will be done quite early - there is little advantage in starting IV PPI’s prior to EGD in most cases

• Oral PPIs may have some protective effect compared to placebo

Case 7

• Start IV Pantoprazole (80 mg bolus followed by 8 mg per hour)

• Start PPI of choice after patient is taking oral meds