Acid-Peptic Disease

PUD/GERD/NSAIDs

Duane T. Smoot, M.D., FACP,

FACG
Associate Professor and Chief
Gastroenterology Division
Howard University
 Lifestyle measures
• Raise the head of the bed, or lie on left side
• Decrease fat intake
• Avoid certain foods
• Avoid lying down for 3 hours after eating
• Stop smoking
• Lose weight if appropriate
 Role of lifestyle measures
• Role in GERD debatable
• Many physicians feel that lifestyle advice is
worthwhile
• Lifestyle measures are generally insufficient
by themselves
• Lifestyle measures may have a negative
impact on patient lifestyle
 Evolution of pharmacological
therapy
• Antacids

• Prokinetics

• H2-receptor antagonists

• Proton pump inhibitors

 Pharmacological therapy –
antacids, prokinetics and H2RAs
• Antacids
– Prompt but temporary relief
– No objective proof of superiority to placebo
• Prokinetics
– Improvement of symptoms in mild GERD
– Effective for healing only mild erosive esophagitis
– Can be useful in a select patient population
• H2RAs
– Relief of symptoms in ~50% of patients
– Effective for healing only mild erosive esophagitis

Tytgat and Nio. Baillière’s Clin Gastroenterol 1987; Klinkenberg-Knol et al. Drugs 1995;
Furman et al. Gastroenterology 1982; Wolfe and Sachs. Gastroenterology 2000
 Antacids may be no more
effective than placebo
x5 *
x 4.1
to reproduce heartburn
Mean increase in time

x4
with Bernstein test

*
x 2.9
x3
*p < 0.05
x2 versus
pre-
x1 treatment

x0
Placebo Antacid

Graham and Patterson. Dig Dis Sci 1983

 H2RAs are effective only in mild
erosive esophagitis
Isolated erosions 78

Longitudinally confluent
38 p < 0.001
erosions

Circumferential erosions 23

0 20 40 60 80 100
6-week healing rate (%)

Koelz et al. Gastroenterology 1986

Doubling the dose is ineffective
in patients refractory to H2RAs
50
mild or no heartburn

40
% patients with

30
Standard dose
20 Double dose

10

0
Week 4 Week 8

Kahrilas et al. Am J Gastroenterol 1999

 Pharmacological therapy –
PPIs
• Significantly more effective than H2RAs for
both symptom resolution and healing of
erosive esophagitis
• Also effective in more severe cases of GERD
• Most patients respond well to standard
therapy, but some require prolonged and/or
high-dose treatment

Klinkenberg-Knol et al. Drugs 1995

PPIs are the most effective drugs
for the initial treatment of GERD

• “PPIs provide rapid symptomatic relief and

healing of erosive esophagitis in the highest
percentage of patients”

DeVault et al. Am J Gastroenterol 1999

 PPIs are the most effective drugs for
the initial treatment of GERD
100
% esophagitis cases healed

PPIs
80

60 H2RAs p < 0.0005

40
Placebo

20

0
2 4 6 8 10 12
Weeks of treatment
Chiba et al. Gastroenterology 1997
H. pylori: Clinical Manifestations in
Children Compared to Adults

● Chronic-active/chronic gastritis - different

histopathology; neutrophils much less frequent
● Duodenal ulceration - less frequent than adults
● Gastric ulceration - occurs but uncommon
● MALT lymphoma - 6 case reports in literature
● Gastric cancer - one case reported
● Controversial: recurrent abdominal pain (RAP),
non-ulcer dyspepsia; others?
 Age, HP & Acid secretion
• Subjects with a mean age of 57 when
compared to subjects with a mean age of 33
– higher mean basal
– higher meal-stimulated
– higher pepsinogen I & II levels
• Age positively effected acid secretion
• H. pylori negatively effected acid secretion
Goldschmiedt, et al., Gastro, 1991
 Age, HP & Acid secretion

• The decline in acid output in the elderly was

primarily due to atrophic gastritis and
partially to tobacco smoking
• After adjusting for histology, H. pylori and
other variables, age had no independent
effect on acid secretion.
• Age is associated with reduced pepsin
output.
Feldman, et al., Gastro, 1996
 Pathogenesis of Ulcers
Therapy is directed at enhancing host defense or
eliminating aggressive factors; i.e., H. pylori.

Aggressive Factors Defensive Factors


Acid, pepsin 
Mucus, bicarbonate layer

Bile salts 
Blood flow, cell renewal

Drugs (NSAIDs) 
Prostaglandins

H. pylori 
Phospholipid

Free radical scavengers
 Helicobacter pylori in GERD

• Infection with H. pylori

may cause a variety of
gastric diseases
• In the context of GERD,
however, H. pylori may
have some beneficial
effects
 H. pylori –protection against
reflux esophagitis?
Patients cured of H. pylori infection (n =
30 244)
25 25.8%
erosive esophagitis
% patients with

20
15 Patients remaining infected (n =
216)
10 12.9%
5

0 p < 0.001between groups

2 6 12 18 24 30 36
Months

Labenz et al. Gastroenterology 1997

H. pylori – improvement of the
efficacy of PPIs?
p = 0.002
10
intragastric pH with PPI

8
Median 24-hour

6 5.51 5.3 5.07

4 3.53

0
Hp Placebo Hp Placebo
Rx Rx
Pre–Hp Rx Post–Hp Rx
Van Herwaarden et al. Aliment Pharmacol Ther 1999
NSAIDs and H. pylori
Prevention of ulcers in NSAID Users
50
Placebo n = 155
40
Ulcer Recurrence (%)

32
Misoprostol 200 ug bid
30 n = 296
Omeprazole 20 mg qd
20 * n = 274
* 13 12
10 10
10 **
3
0
Gastric Ulcer Duodenal Ulcer

P<0.001 omeprazole & misoprostol vs placebo

P<0.001 omeprazole vs placebo & misoprostol Hawkey et al, 1998
Prevention of ulcers in NSAID Users
30

Ranitidine 150 mg bid

Ulcer Recurrence (%)

n = 215
20 16.3
O meprazole 20 mg qd
n = 210
10 * 5.7
5.2
* p< 0.05
*
0.5
0
Gastric U lcer D uodenal U lcer

Yeomans et al, 1998

 H. pylori & NSAID Ulcers
Ulcers Naproxen Naproxen P value
HP+ (n=43) HP- (n=38)
Gastric 9 2 0.04

Duodenal 2 0
Both 1 0
Total 12 (28%) 2 (5%) 0.007

Chan et al, 1997

 H. pylori and ulcer relapse in
patients with healed duodenal
ulcer: 6 month double-blind trial
100

80
Ulcer Relapse (%)

60
H . pylori-negative
40
H . pylori-positive
20

0
Placebo OmeprazoleMisoprostol
20mg qd 200mg bid

Hawkey et al, Gut 1996

 NSAID Use in the Arthritis
Patient with a History of
Bleeding Ulcer

• Treating H. pylori is likely to be of benefit

if there was a duodenal ulcer; test and treat
for H. pylori is recommended.
• Use COX2 Inhibitor
• Add a PPI or Misoprostol
Tests For Initial Diagnosis
of Infection

Urea Breath Test and Stool Assay
 Non-invasive, sensitive and specific
 Serology
 O.K. for initial diagnosis
 Fair sensitivity and specificity
 Endoscopy Not necessary for
diagnosis
 Diagnostic Tests to Evaluate
Treatment Success
• Urea Breath Test and Stool Assay
– Can be done 4 weeks post treatment
– PPIs can interfere with the Breath Test, not with Stool
Assay
• Endoscopy (antral and fundal biopsies)
– Also allows for bacterial Culture and Sensitivity
• Rapid Urease Assays
– Also influenced by PPIs, biopsy from antrum and fundus
 What Diseases Have Evidence-Based
Justification For Treating H. pylori
• Peptic ulcer disease: duodenal (67%) and gastric ulcers
(59%) recur if no eradication
• Bleeding duodenal ulcer: rebleeding in 30% if no eradication
with 1 year follow up
• MALT lymphoma: justified based on best-available
evidence to treat in low-grade MALT lymphoma
• Gastric cancer: justified in early gastric cancer; 9%
recurrence incidence in untreated controls
• Non-ulcer dyspepsia: evidence not yet definitive; up to 40%
with abdominal pain recurrence with . H. pylori eradication
 H. pylori Infection and
Ulcer Recurrence
100

80
Twelve-month rates of
Recurrence (%)

duodenal ulcer recurrence

60
in patients whom H. pylori
was eradicated and those
40 in whom it was not.
(Walsh JH. N.E.J.M.
20 1995;333:984)

0
Not Eradicated
Eradicated
Known Factors Which Determine
Success of H. pylori Therapy

 Patient compliance or non-compliance


Medicine complications or side effects
 Antimicrobial resistance of infecting H. pylori strains
 Duration of Therapy

Correct dosing

Clearance of H. pylori infection is not equivalent to

eradication.
 Who Should Be Treated For
H. pylori Infection?

 Patients who have documented H. pylori infection and:

 Definitely had or has a duodenal or stomach ulcer
 Have had stomach lymphoma or family hx of stomach cancer
 Consider treatment if:
 Presence of “severe histologic” gastritis and H. pylori infection
 Ulcer-like dyspepsia in the absence of an ulcer or prior to endoscopy
in a young patient

Source: 1997 Digestive Health Initiative International Update Conference, 1997 Canadian Consensus
Conference
 H. pylori: Treatment
Agents Which Inhibit H. pylori In Vivo
Antibiotic Resistance No Antibiotic Resistance
- metronidazole - colloidal bismuth subcitrate
- tinidazole - bismuth subsalicylate
- erythromycin base - tetracycline
- clarithromycin - nitrofurantoin
- ciprofloxacin - furazolidone
- ofloxacin
- norfloxacin
- amoxicillin (rare)
 Monotherapy for H. pylori
Infection
Drug Cure Rate (%)
Azithromycin 5
Doxycycline 5
Metronidazole 5
Tinidazole 5
Tetracycline 5
Bismuth subsalicylate 5-10
Quinolones 10
Erythromycin 15
Amoxicillin 15
Nitrofurantoin 20
Furazolidone 20-40
Colloidal bismuth subcitrate 30-40
Clarithromycin 40-60

(Blecker U, Gold B. Pediatr Infect Dis J 1997;16:391)

 H. pylori Treatment:
Resistance in Pediatric Strains
No of Strains Resistance
State Tested (mean %) Antibiotic

Georgia 15 5 Clarithromycin
20 Metronidazole
Alabama 4 25 Metronidazole

Florida 12 25 Clarithromycin,
60 Metronidazole
1 Amoxicillin
South Carolina 3 15 Metronidazole

Ohio 10 10 Metronidazole
 FDA-Approved Treatment
Regimes
for H. pylori Infection
 Omeprazole 20 mg BID + Clarithromycin 500
mg BID + Amoxicillin 1 g BID for 10 days

Lansoprazole 30 mg BID +Clarithromycin 500
mg BID + Amoxicillin 1 g BID for 10 days
 Bismuth subsalicylate (Pepto Bismol) 525 mg
QID + Metronidazole 250 mg QID + Tetracycline
500 mg QID X 14 days + H2 receptor antagonist x
4 wks
 H. pylori: Pediatric Treatment

 Pediatric Treatment Recommendations

◆ 2 wks omeprazole (1 - 3 mg/kg/D bid) + clarithromycin (15
mg/kg/D bid) + metronidazole (15 mg/kg/D tid)
◆ followed by 2 wks of omeprazole (2 mg/kg/D qd)
◆ 2 wks omeprazole (1 - 3 mg/kg/D bid) + clarithromycin (15
mg/kg/D bid) + amoxicillin (50 mg/kg/D tid)
◆ followed by 2 wks of omeprazole (2 mg/kg/D qd)
◆ 2 wks amoxicillin (50 mg/kg/D tid) + metronidazole (15
mg/kg/D tid) + bismuth subsalicylate (qid) + H2 receptor
antagonist (e.g., ranitidine 5 mg/kg/D bid)
◆ possible to substitute lansoprazole for omeprazole