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2. 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
3. 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
5. 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
6. H2RAs are effective only in mild
erosive esophagitis
Isolated erosions
78
Longitudinally confluent
erosions
38
p < 0.001
23
Circumferential erosions
0
20
40
60
80
6-week healing rate (%)
Koelz et al. Gastroenterology 1986
100
7. Doubling the dose is ineffective
in patients refractory to H2RAs
% patients with
mild or no heartburn
50
40
30
Standard dose
Double dose
20
10
0
Week 4
Week 8
Kahrilas et al. Am J Gastroenterol 1999
8. 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
9. % esophagitis cases healed
PPIs are the most effective drugs for
the initial treatment of GERD
100
PPIs
80
60
H2RAs
40
Placebo
20
0
2
4
6
8
Weeks of treatment
10
Chiba et al. Gastroenterology 1997
12
p < 0.0005
10. 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?
11. 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
12. 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
13. Pathogenesis of Ulcers
Therapy is directed at enhancing host defense or
eliminating aggressive factors; i.e., H. pylori.
Aggressive Factors
Acid, pepsin
Bile salts
Drugs (NSAIDs)
H. pylori
Defensive Factors
Mucus, bicarbonate layer
Blood flow, cell renewal
Prostaglandins
Phospholipid
Free radical scavengers
14. 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
15. H. pylori –protection against
reflux esophagitis?
Patients cured of H. pylori infection (n =
244)
25.8%
% patients with
erosive esophagitis
30
25
20
Patients remaining infected (n =
216)
12.9%
15
10
5
p < 0.001between groups
0
2
6
12
18
24
30
36
Months
Labenz et al. Gastroenterology 1997
16. H. pylori – improvement of the
efficacy of PPIs?
p = 0.002
Median 24-hour
intragastric pH with PPI
10
8
6
5.51
5.3
5.07
3.53
4
2
0
Hp Placebo
Rx
Pre–Hp Rx
Hp Placebo
Rx
Post–Hp Rx
Van Herwaarden et al. Aliment Pharmacol Ther 1999
18. Prevention of ulcers in NSAID Users
50
Ulcer Recurrence (%)
Placebo n = 155
40
32
Misoprostol 200 ug bid
n = 296
Omeprazole 20 mg qd
n = 274
30
20
*
10
*
13
10
**
10
0
12
3
Gastric Ulcer
Duodenal Ulcer
P<0.001 omeprazole & misoprostol vs placebo
P<0.001 omeprazole vs placebo & misoprostol
Hawkey et al, 1998
19. Prevention of ulcers in NSAID Users
Ulcer Recurrence (%)
30
Ranitidine 150 mg bid
n = 215
Omeprazole 20 mg qd
n = 210
16.3
20
*
5.2
10
5.7
*
0.5
0
Gastric Ulcer
Yeomans et al, 1998
Duodenal Ulcer
* p< 0.05
20. H. pylori & NSAID Ulcers
Ulcers
Naproxen
Naproxen
P value
HP+ (n=43) HP- (n=38)
Gastric
9
2
Duodenal 2
0
Both
1
0
Total
12 (28%)
2 (5%)
Chan et al, 1997
0.04
0.007
21. H. pylori and ulcer relapse in
patients with healed duodenal
ulcer: 6 month double-blind trial
Ulcer Relapse (%)
100
80
60
H. pylori-negative
H. pylori-positive
40
20
0
Placebo
Omeprazole Misoprostol
20mg qd 200mg bid
Hawkey et al, Gut 1996
22. 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
23. Tests For Initial Diagnosis
of Infection
Urea Breath Test and Stool Assay
Serology
Non-invasive, sensitive and specific
O.K. for initial diagnosis
Fair sensitivity and specificity
Endoscopy Not necessary for
diagnosis
24. 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
25. 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
26. H. pylori Infection and
Ulcer Recurrence
100
Recurrence (%)
80
Twelve-month rates of
duodenal ulcer recurrence
in patients whom H. pylori
was eradicated and those
in whom it was not.
60
40
(Walsh JH. N.E.J.M.
1995;333:984)
20
0
Not
Eradicated
Eradicated
27. 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.
28. 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
29. H. pylori: Treatment
Agents Which Inhibit H. pylori In Vivo
Antibiotic Resistance
Resistance
No Antibiotic
- metronidazole
subcitrate
- tinidazole
subsalicylate
- erythromycin base
- clarithromycin
- ciprofloxacin
- colloidal bismuth
- ofloxacin
- bismuth
- tetracycline
- nitrofurantoin
- furazolidone
30. Monotherapy for H. pylori Infection
Drug
Azithromycin
Doxycycline
Metronidazole
Tinidazole
Tetracycline
Bismuth subsalicylate
Quinolones
Erythromycin
Amoxicillin
Nitrofurantoin
Furazolidone
Colloidal bismuth subcitrate
Clarithromycin
(Blecker U, Gold B. Pediatr Infect Dis J 1997;16:391)
Cure Rate (%)
5
5
5
5
5
5-10
10
15
15
20
20-40
30-40
40-60
31. H. pylori Treatment:
Resistance in Pediatric Strains
State
No of Strains
Tested
Resistance
(mean %)
Antibiotic
Georgia
15
Alabama
4
5
20
25
Clarithromycin
Metronidazole
Metronidazole
Florida
12
South Carolina
3
25
60
1
15
Clarithromycin,
Metronidazole
Amoxicillin
Metronidazole
Ohio
10
10
Metronidazole
32. 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
33. 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
Lifestyle measures
Lifestyle measures that are sometimes recommended to GERD patients include avoiding factors that are known to aggravate GERD symptoms, such as certain foods, avoiding lying down after meals, raising the head of the bed to reduce nocturnal reflux, and losing weight.
Role of lifestyle measures
Although many physicians feel that advice about lifestyle measures is worthwhile, the value of this approach in the management of GERD remains controversial. Discussion at the Genval Workshop, for example, suggested that the possibility of patients deriving adequate benefit from lifestyle alterations alone is significantly over-estimated (1).
Objective evidence for the efficacy of lifestyle measures is lacking. Avoidance of alcohol and certain foods that provoke reflux symptoms can provide symptomatic relief, but is of no benefit in healing erosive esophagitis (1). Moreover, as described in the following two slides, lifestyle modifications such as weight reduction or smoking cessation may not reduce esophageal acid exposure.
It is widely accepted that lifestyle measures alone are insufficient, except possibly in patients with mild, infrequent symptoms. Indeed, many patients presenting with GERD symptoms may have already tried lifestyle alterations and found them to be ineffective (1).
Lifestyle measures may themselves have a negative impact on patient lifestyle. For example, some patients may have to give up favorite foods.
(1) Dent et al. Gut 1999; 44 (Suppl. 2): S1–S16.
Evolution of pharmacological therapy
Four types of drug are used in the management of GERD:
antacids
prokinetic agents
histamine H2-receptor antagonists (H2RAs)
proton pump inhibitors (PPIs).
Pharmacological therapy – antacids, prokinetics and H2RAs
Antacids are widely used as first-line treatment for GERD, and many patients will use such remedies before consulting their doctors. These agents can provide prompt symptom relief, but their effect is only temporary due to rapid gastric emptying (1). There is little objective evidence that they are superior in efficacy to placebo (1–4).
Prokinetic agents act by increasing LES pressure and stimulating esophageal peristalsis and gastric emptying. These agents are as effective as antacids and H2RAs in relieving symptoms in patients with mild GERD, but are only effective in healing mild degrees of erosive esophagitis (2). Furthermore, their usefulness is limited by adverse effects (2).
H2RAs act by inhibiting histamine-stimulated gastric acid secretion. Placebo-controlled studies have shown that these agents relieve reflux symptoms in approximately 50% of patients, but are less effective in healing erosive esophagitis (2).
(1) Tytgat, Nio. Baillière’s Clin Gastroenterol 1987; 1: 791–807.
(2) Klinkenberg-Knol et al. Drugs 1995; 49: 695–710.
(3) Furman et al. Gastroenterology 1982; 82: 1062.
(4) Wolfe, Sachs. Gastroenterology 2000; 118: S9–S31.
Antacids may be no more effective than placebo
This slide and the one that follows provide data supporting statements made on the previous slide.
Although antacids have been the traditional therapy for GERD for many years and are still widely used, there is little evidence concerning their efficacy. Indeed, the results of some studies suggest that antacids may be no more effective than placebo in alleviating symptoms and influencing the natural history of the disease.
For example, in one study, an antacid was compared with placebo in 32 patients with symptomatic gastroesophageal reflux (1). The two test treatments, each taken 7 times daily, both produced significant increases in the time needed to reproduce heartburn with a timed acid perfusion (Bernstein) test. However, the mean increase was somewhat greater with placebo (169 +/- 66 versus 41 +/- 20 seconds, or 4.1-fold) than with the antacid (120 +/- 57 versus 42 +/- 16 seconds, or 2.9-fold).
(1) Graham, Patterson. Dig Dis Sci 1983; 28: 559–63.
H2RAs are effective only in mild erosive esophagitis
A number of studies have shown that treatment with H2RAs promotes healing of erosive esophagitis. However, the evidence also suggests that these benefits are largely confined to individuals with only mild degrees of erosive esophagitis. In a study of 108 patients with erosive esophagitis, the effects of treatment with an H2RA on the healing of esophageal lesions were compared with those of placebo. After 6 weeks, those patients with the mildest degree of esophagitis (isolated erosions), as assessed endoscopically, showed a healing rate of 78 %. The frequency of healing was considerably lower in individuals with more extensive lesions: 38 % in those with longitudinally confluent lesions and 23 % in those with circumferential erosions of the distal esophagus (1).
(1) Koelz et al. Gastroenterology 1986; 91: 1198–205.
Doubling the dose is ineffective in patients refractory to H2RAs
One approach that has been used in an attempt to improve treatment outcomes in patients refractory to H2RAs is doubling of the dose. The data shown here demonstrate that this approach is ineffective.
Kahrilas et al. gave 481 GERD patients with moderate or severe heartburn a standard dose of an H2RA for 6 weeks (1). They then randomized patients who were still symptomatic (n = 271) to receive standard- or double-dose treatment with the same H2RA for a further 8 weeks. As shown on the slide, the proportion of these patients with mild or no heartburn after 4 or 8 weeks was no greater with the double dose than with the standard dose. This proportion was less than 40% in both treatment groups after 4 weeks and less than 50% in both groups after 8 weeks.
(1) Kahrilas et al. Am J Gastroenterol 1999; 94: 92–7. Reproduced with permission from the American College of Gastroenterology.
Pharmacological therapy – PPIs
PPIs provide prolonged inhibition of acid secretion, irrespective of the stimulus, and are significantly more effective than H2RAs in controlling gastric acid (1). Comparative trials have consistently shown that these agents are more effective than H2RAs in relieving GERD symptoms and healing erosive esophagitis (1). Furthermore, PPIs are effective in patients with severe erosive esophagitis or Barrett’s esophagus (1).
Although most patients can be treated effectively with PPI therapy, there is some variability in response. As a result, some patients, particularly those with nocturnal reflux, may require prolonged therapy, higher doses, or both (1).
(1) Klinkenberg-Knol et al. Drugs 1995; 49: 695–710.
PPIs are the most effective drugs for the initial treatment of GERD
The ACG guidelines state that acid suppression is the mainstay of therapy for GERD, and that “proton pump inhibitors provide rapid symptomatic relief and healing in the highest percentage of patients” (1).
This conclusion is based on the evidence from 33 randomized trials involving more than 3000 patients. In these trials, symptom control was achieved in 83% of patients treated with PPIs, compared with 60% of patients receiving H2RAs and 27% of placebo-treated patients. Healing of erosive esophagitis was achieved in 78%, 50% and 24% of patients respectively.
(1) DeVault et al. Am J Gastroenterol 1999; 94: 1434–42.
PPIs are the most effective drugs for the initial treatment of GERD
This figure is taken from a meta- analysis of randomized, single- or double-blind clinical trials conducted in GERD patients with endoscopically proven erosive or ulcerative esophagitis (1). The meta-analysis incorporated a total of 43 studies involving 7635 patients treated for 2–12 weeks.
The figure shows that, for all time points between 2 and 12 weeks, the mean percentage of patients in whom esophagitis was healed was considerably higher with PPIs than with H2RAs. Notably, the mean proportion healed after 2 weeks with PPIs (63.4%) was similar to the mean proportion healed after 12 weeks with H2RAs (60.2%). The overall proportion of cases healed, regardless of the duration of treatment, was 83.6% with PPIs, 51.9% with H2RAs and 28.2% with placebo (p < 0.0005 between groups).
(1) Chiba et al. Gastroenterology 1997; 112: 1798–810. Reproduced with permission from the American Gastroenterological Association.
Helicobacter pylori in GERD
In general, infection with the bacterium H. pylori is detrimental to health. This bacterium has been implicated in a variety of gastric diseases, including chronic active gastritis, peptic ulcer disease, ulcer bleeding, mucosa-associated lymphoid tissue (MALT) lymphoma and distal gastric cancer.
In the context of GERD, H. pylori may have certain beneficial effects: protection against reflux esophagitis, protection against serious complications of GERD and improvement of the efficacy of PPI therapy. These effects are described in more detail on the slides that follow.
It is important to note that the relationship between H. pylori and GERD is complex and not yet fully understood. This is why the titles of the following slides end with a question mark.
H. pylori – protection against reflux esophagitis?
The data shown here indicate that H. pylori may be protective against reflux esophagitis. They are taken from a study in which patients with duodenal ulcer but no erosive esophagitis were followed up prospectively after cure of H. pylori infection (n = 244) or after diagnosis of persisting infection (n = 216) (1). Over 3 years, the incidence of erosive esophagitis was 25.8% in H. pylori-negative patients but only 12.9% in H. pylori-positive patients (p < 0.001).
These data are contradicted by others showing that eradication of H. pylori has little effect on the incidence of GERD. In a study involving 242 patients with endoscopically documented duodenal ulcers, for example, only one patient showed evidence of erosive esophagitis 6 months after treatment to eradicate H. pylori (2). Moreover, the proportion of patients experiencing new heartburn 1 month and 6 months after treatment was not significantly higher in patients in whom H. pylori was eradicated than in those in whom infection persisted.
(1) Labenz et al. Gastroenterology 1997; 112: 1442–7. Reproduced with permission from the American Gastroenterological Association.
(2) Vakil et al. Aliment Pharmacol Ther 2000; 14: 45–51.
H. pylori – improvement of the efficacy of PPIs?
These data suggest an explanation for the findings shown on the previous slide. They indicate that the efficacy of PPIs in healing esophagitis may be improved in the presence of H. pylori because infection with this bacterium enhances the ability of PPIs to control acid secretion.
The data come from a study carried out in 19 healthy volunteers infected with H. pylori (1). These volunteers were randomized to receive either placebo or H. pylori eradication therapy. Before treatment, median 24-hour intragastric pH during the administration of a PPI was approximately 5.5 in both groups. After treatment, this variable was not significantly changed in the placebo group but was reduced to 3.53 in the eradication group (p = 0.002). Therefore, it appears that eradication of H. pylori reduced the ability of the PPI to elevate intragastric pH.
These results are supported by findings from a study conducted in healthy volunteers by Katsube et al, which show that the absence of H. pylori is associated with nocturnal acid breakthrough (2). At night, median intragastric pH was significantly lower in H. pylori-negative subjects than in H. pylori-positive subjects, and the proportion of the time for which intragastric pH was below 4 was significantly higher – regardless of whether subjects were given a PPI or not.
(1) Van Herwaarden et al. Aliment Pharmacol Ther 1999; 13: 731–40.
(2) Katsube et al. Aliment Pharmacol Ther 2000; 14: 1049–56.