1. Clinical Management Course
Acid Peptic Diseases
Clinical Management Course
February 2007
Walter Smalley, MD MPH

2. 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 1

3. Antacids Immediate effect on gastric pH Effect is short-lived
Typical dose cc
Frequent use may cause diarrhea

4. 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 5

5. 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 7

6. H2 blockers : No difference in efficacy within group8

7. 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)

8. 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

9. Case 1 35 year old healthy man Occasional heartburn
Occurs only with large meals, EtOH ingestion
No dysphagia

10. Heartburn : Summary How soon does the patient want relief ?
How long does it need to last ?
How much are they willing to pay ? 41

11. 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 40

12. 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

13. Case 2 50 yo with frequent nocturnal heartburn No dysphagia
Trial of lifestyle modification only minimally effective
Antacids ineffective

14. 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

15. 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 2

16. 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 3

17. Case 2 50 yo with frequent nocturnal heartburn No dysphagia
Trial of lifestyle modification only minimally effective
Antacids ineffective
EGD - distal esophageal erosions

18. Antacids: temporary relief H2-antagonists:
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 4

19. GERD: H2-antagonists NO BETWEEN - DRUG DIFFERENCES IN EFFICACY
symptomatic relief < % cases
endoscopic improvement < symptomatic relief
higher doses (>2X ulcer doses) improve efficacy slightly 6

20. GERD : Prokinetic Agents
Metoclopramide
As effective as H2RAs
Adverse reactions:
fatigue, lethargy, extrapyramidal symptoms occur in 10% - 30%. 9

21. Case 2 Continue lifestyle modification
Trial of H2 blockers at high doses

22. Case 3 Patient #2 returns after 8 week trial of H2 blockers
Therapy only minimally effective

23. GERD : Proton Pump Inhibitors
Causes healing and resolution of symptoms in 80% of patients with disease resistant to H2-blockers
Expensive, single source drugs ($ / day)
Over the counter more expensive than prescription
Not on Wal-mart list
Generic omeprazole still > $1 per day 12

24. Case 3
Proton pump inhibitor

25. Case 4 Patient from Case 3 returns
Symptoms well controlled on omeprazole
Symptoms recur immediately after stopping drug
“Hates taking meds”

26. 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
% of cases have some improvement 13

27. GERD: Anti - Reflux Surgery
Side effects: about 10 % cases
"gas bloat"
dysphagia
strictures
other
Usually won’t work if PPI’s don’t work 14

28. Utilization of GERD pharmaceuticals in patients
treated medically and surgically
Acid suppression days
per quarter
Most fundoplication
patients end up taking
some acid meds
after operation
Khaitan et al, Arch Surgery 2003

29. 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

30. 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)

31. Case 5
40 yo with epigastric pain

32. “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

33. 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

34. Case 5 40 yo with epigastric pain 8 week trials of PPI fails
EGD : duodenal ulcer
H pylori positive
no NSAIDs confirmed

35. 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 15

36. H pylori : Concepts H pylori infection is chronic
Prevalence in US adults = %
Lifetime risk of ulcer disease = 10%
Associated with chronic gastritis - a histological diagnosis
H pylori is a risk factor for gastric adenocarcinoma 16

37. 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. 17

38. 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 18

39. 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 20

40. Peptic Ulcer: Treatment Outcomes28

41. Case 5 QD H2 blockers, or proton pump inhibitor Amoxicillin 1000 BID
Treatment with acid suppression
QD H2 blockers, or
proton pump inhibitor
Treat H pylori
Amoxicillin 1000 BID
Clarithromycin 500 BID
Omeprazole 20 BID

42. Case 6 65 yo male with osteoarthritis with recent ulcer
On ibuprofen 1800 mg per day
Ulcer has healed
H pylori negative

43. 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 22

44. NSAIDs and PUD : Treatment
Stop NSAIDs
Acid suppression
Drug Healing at weeks
Omeprazole > 90%
H2-Blockers %
Misoprostol %
Sucralfate not effective 23

45. 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". 24

46. 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 ( %)
Causes spontaneous abortions - do not use in potentially fertile women 25

47. 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)

48. 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

49. Results from a polyp prevention trial

50. Case 6 narcotics non-narcotics physical therapy topical therapy
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

51. Peptic Ulcer Disease Stop NSAIDs. Acid suppression acutely
Test for H pylori and treat if present. 27

52. 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

53. 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)

54. 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 %CI 0.46 to 0.76
NNT = 20
treatment had no significant effect on mortality
OR 1.11, 95%CI to 1.57
NNT = incalculable
Lancet 2005

55. 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

56. Case 7 Start IV Pantoprazole (80 mg bolus followed by 8 mg per hour)
Start PPI of choice after patient is taking oral meds