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 H 2 -receptor antagonists (H 2 RAs) proton pump inhibitors (PPIs).
Pharmacological therapy – antacids, prokinetics and H 2 RAs 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 H 2 RAs 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). H 2 RAs 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.
H 2 RAs are effective only in mild erosive esophagitis A number of studies have shown that treatment with H 2 RAs 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 H 2 RA 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 H 2 RAs One approach that has been used in an attempt to improve treatment outcomes in patients refractory to H 2 RAs 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 H 2 RA for 6 weeks (1). They then randomized patients who were still symptomatic (n = 271) to receive standard- or double-dose treatment with the same H 2 RA 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 H 2 RAs in controlling gastric acid (1). Comparative trials have consistently shown that these agents are more effective than H 2 RAs 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 H 2 RAs 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 H 2 RAs. Notably, the mean proportion healed after 2 weeks with PPIs (63.4%) was similar to the mean proportion healed after 12 weeks with H 2 RAs (60.2%). The overall proportion of cases healed, regardless of the duration of treatment, was 83.6% with PPIs, 51.9% with H 2 RAs 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.
Lifestyle measures <ul><li>Raise the head of the bed, or lie on left side </li></ul><ul><li>Decrease fat intake </li></ul><ul><li>Avoid certain foods </li></ul><ul><li>Avoid lying down for 3 hours after eating </li></ul><ul><li>Stop smoking </li></ul><ul><li>Lose weight if appropriate </li></ul>www.freelivedoctor.com
Role of lifestyle measures <ul><li>Role in GERD debatable </li></ul><ul><li>Many physicians feel that lifestyle advice is worthwhile </li></ul><ul><li>Lifestyle measures are generally insufficient by themselves </li></ul><ul><li>Lifestyle measures may have a negative impact on patient lifestyle </li></ul>www.freelivedoctor.com
Pharmacological therapy – antacids, prokinetics and H2RAs <ul><li>Antacids </li></ul><ul><ul><li>Prompt but temporary relief </li></ul></ul><ul><ul><li>No objective proof of superiority to placebo </li></ul></ul><ul><li>Prokinetics </li></ul><ul><ul><li>Improvement of symptoms in mild GERD </li></ul></ul><ul><ul><li>Effective for healing only mild erosive esophagitis </li></ul></ul><ul><ul><li>Can be useful in a select patient population </li></ul></ul><ul><li>H 2 RAs </li></ul><ul><ul><li>Relief of symptoms in ~50% of patients </li></ul></ul><ul><ul><li>Effective for healing only mild erosive esophagitis </li></ul></ul>Tytgat and Nio. Baillière’s Clin Gastroenterol 1987; Klinkenberg-Knol et al. Drugs 1995; Furman et al. Gastroenterology 1982; Wolfe and Sachs. Gastroenterology 2000 www.freelivedoctor.com
Antacids may be no more effective than placebo Graham and Patterson. Dig Dis Sci 1983 www.freelivedoctor.com Placebo Mean increase in time to reproduce heartburn with Bernstein test x 4.1 x 2.9 x 0 x 1 x 2 x 3 x 4 x 5 Antacid * * * p < 0.05 versus pre-treatment
H 2 RAs are effective only in mild erosive esophagitis Koelz et al. Gastroenterology 1986 www.freelivedoctor.com 23 38 78 0 20 40 60 80 100 6-week healing rate (%) p < 0.001 Isolated erosions Longitudinally confluent erosions Circumferential erosions
Doubling the dose is ineffective in patients refractory to H2RAs Kahrilas et al. Am J Gastroenterol 1999 www.freelivedoctor.com 0 10 20 30 40 50 Week 4 Week 8 % patients with mild or no heartburn Standard dose Double dose
Pharmacological therapy – PPIs <ul><li>Significantly more effective than H2RAs for both symptom resolution and healing of erosive esophagitis </li></ul><ul><li>Also effective in more severe cases of GERD </li></ul><ul><li>Most patients respond well to standard therapy, but some require prolonged and/or high-dose treatment </li></ul>Klinkenberg-Knol et al. Drugs 1995 www.freelivedoctor.com
PPIs are the most effective drugs for the initial treatment of GERD <ul><li>“ PPIs provide rapid symptomatic relief and healing of erosive esophagitis in the highest percentage of patients” </li></ul>DeVault et al. Am J Gastroenterol 1999 www.freelivedoctor.com
PPIs are the most effective drugs for the initial treatment of GERD Chiba et al. Gastroenterology 1997 % esophagitis cases healed 0 20 40 60 80 100 2 4 6 8 10 Weeks of treatment 12 PPIs H 2 RAs Placebo p < 0.0005 www.freelivedoctor.com
H. pylori : Clinical Manifestations in Children Compared to Adults <ul><li>Chronic-active/chronic gastritis - different histopathology; neutrophils much less frequent </li></ul><ul><li>Duodenal ulceration - less frequent than adults </li></ul><ul><li>Gastric ulceration - occurs but uncommon </li></ul><ul><li>MALT lymphoma - 6 case reports in literature </li></ul><ul><li>Gastric cancer - one case reported </li></ul><ul><li>Controversial : recurrent abdominal pain (RAP), non-ulcer dyspepsia; others? </li></ul>www.freelivedoctor.com
Age, HP & Acid secretion <ul><li>Subjects with a mean age of 57 when compared to subjects with a mean age of 33 </li></ul><ul><ul><li>higher mean basal </li></ul></ul><ul><ul><li>higher meal-stimulated </li></ul></ul><ul><ul><li>higher pepsinogen I & II levels </li></ul></ul><ul><li>Age positively effected acid secretion </li></ul><ul><li>H. pylori negatively effected acid secretion </li></ul>Goldschmiedt, et al., Gastro, 1991 www.freelivedoctor.com
Age, HP & Acid secretion <ul><li>The decline in acid output in the elderly was primarily due to atrophic gastritis and partially to tobacco smoking </li></ul><ul><li>After adjusting for histology, H. pylori and other variables, age had no independent effect on acid secretion. </li></ul><ul><li>Age is associated with reduced pepsin output. </li></ul>Feldman, et al., Gastro, 1996 www.freelivedoctor.com
Pathogenesis of Ulcers <ul><li>Aggressive Factors </li></ul><ul><li>Acid, pepsin </li></ul><ul><li>Bile salts </li></ul><ul><li>Drugs (NSAIDs) </li></ul><ul><li>H. pylori </li></ul><ul><li>Defensive Factors </li></ul><ul><li>Mucus, bicarbonate layer </li></ul><ul><li>Blood flow, cell renewal </li></ul><ul><li>Prostaglandins </li></ul><ul><li>Phospholipid </li></ul><ul><li>Free radical scavengers </li></ul>Therapy is directed at enhancing host defense or eliminating aggressive factors ; i.e., H. pylori. www.freelivedoctor.com
Helicobacter pylori in GERD <ul><li>Infection with H. pylori may cause a variety of gastric diseases </li></ul><ul><li>In the context of GERD, however, H. pylori may have some beneficial effects </li></ul>www.freelivedoctor.com
H. pylori –protection against reflux esophagitis? % patients with erosive esophagitis Labenz et al. Gastroenterology 1997 www.freelivedoctor.com Patients remaining infected (n = 216) 12.9% p < 0.001between groups 0 10 15 20 25 30 5 6 2 18 12 30 24 36 Months Patients cured of H. pylori infection (n = 244) 25.8%
H. pylori – improvement of the efficacy of PPIs? Van Herwaarden et al. Aliment Pharmacol Ther 1999 www.freelivedoctor.com Median 24-hour intragastric pH with PPI 10 8 6 4 2 0 5.51 Hp Rx Hp Rx Placebo Placebo 5.3 3.53 5.07 Pre– Hp Rx Post– Hp Rx p = 0.002
Prevention of ulcers in NSAID Users Hawkey et al, 1998 * * ** P<0.001 omeprazole & misoprostol vs placebo P<0.001 omeprazole vs placebo & misoprostol www.freelivedoctor.com
Prevention of ulcers in NSAID Users Yeomans et al, 1998 * * * p< 0.05 www.freelivedoctor.com
H. pylori & NSAID Ulcers Chan et al, 1997 www.freelivedoctor.com
H. pylori and ulcer relapse in patients with healed duodenal ulcer: 6 month double-blind trial Hawkey et al, Gut 1996 www.freelivedoctor.com
NSAID Use in the Arthritis Patient with a History of Bleeding Ulcer <ul><li>Treating H. pylori is likely to be of benefit if there was a duodenal ulcer; test and treat for H. pylori is recommended. </li></ul><ul><li>Use COX2 Inhibitor </li></ul><ul><li>Add a PPI or Misoprostol </li></ul>www.freelivedoctor.com
Tests For Initial Diagnosis of Infection <ul><li>Urea Breath Test and Stool Assay </li></ul><ul><ul><li>Non-invasive, sensitive and specific </li></ul></ul><ul><li>Serology </li></ul><ul><ul><li>O.K. for initial diagnosis </li></ul></ul><ul><ul><li>Fair sensitivity and specificity </li></ul></ul><ul><li>Endoscopy Not necessary for diagnosis </li></ul>www.freelivedoctor.com
Diagnostic Tests to Evaluate Treatment Success <ul><li>Urea Breath Test and Stool Assay </li></ul><ul><ul><li>Can be done 4 weeks post treatment </li></ul></ul><ul><ul><li>PPIs can interfere with the Breath Test, not with Stool Assay </li></ul></ul><ul><li>Endoscopy (antral and fundal biopsies) </li></ul><ul><ul><li>Also allows for bacterial Culture and Sensitivity </li></ul></ul><ul><li>Rapid Urease Assays </li></ul><ul><ul><li>Also influenced by PPIs, biopsy from antrum and fundus </li></ul></ul>www.freelivedoctor.com
What Diseases Have Evidence-Based Justification For Treating H. pylori <ul><li>Peptic ulcer disease: duodenal (67%) and gastric ulcers (59%) recur if no eradication </li></ul><ul><li>Bleeding duodenal ulcer: rebleeding in 30% if no eradication </li></ul><ul><li>with 1 year follow up </li></ul><ul><li>MALT lymphoma: justified based on best-available evidence to treat in low-grade MALT lymphoma </li></ul><ul><li>Gastric cancer: justified in early gastric cancer; 9% recurrence incidence in untreated controls </li></ul><ul><li>Non-ulcer dyspepsia : evidence not yet definitive; up to 40% with abdominal pain recurrence with . H. pylori eradication </li></ul>www.freelivedoctor.com
H. pylori Infection and Ulcer Recurrence Twelve-month rates of duodenal ulcer recurrence in patients whom H. pylori was eradicated and those in whom it was not. (Walsh JH. N.E.J.M. 1995;333:984) Recurrence (%) Not Eradicated Eradicated www.freelivedoctor.com
Known Factors Which Determine Success of H. pylori Therapy <ul><li>Patient compliance or non-compliance </li></ul><ul><ul><li>Medicine complications or side effects </li></ul></ul><ul><li>Antimicrobial resistance of infecting H. pylori strains </li></ul><ul><li>Duration of Therapy </li></ul><ul><li>Correct dosing </li></ul><ul><li>Clearance of H. pylori infection is not equivalent to eradication. </li></ul>www.freelivedoctor.com
Who Should Be Treated For H. pylori Infection ? <ul><li>Patients who have documented H. pylori infection and : </li></ul><ul><ul><li>Definitely had or has a duodenal or stomach ulcer </li></ul></ul><ul><ul><li>Have had stomach lymphoma or family hx of stomach cancer </li></ul></ul><ul><li>Consider treatment if: </li></ul><ul><ul><li>Presence of “severe histologic” gastritis and H. pylori infection </li></ul></ul><ul><ul><li>Ulcer-like dyspepsia in the absence of an ulcer or prior to endoscopy in a young patient </li></ul></ul><ul><ul><li>Source : 1997 Digestive Health Initiative International Update Conference, 1997 Canadian Consensus Conference </li></ul></ul>www.freelivedoctor.com
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) www.freelivedoctor.com
Monotherapy for H. pylori Infection 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) Drug Cure Rate (%) www.freelivedoctor.com
H. pylori Treatment: Resistance in Pediatric Strains No of Strains State Tested Georgia 15 Alabama 4 Florida 12 South Carolina 3 Ohio 10 Resistance (mean %) Antibiotic 5 Clarithromycin 20 Metronidazole 25 Metronidazole 25 Clarithromycin, 60 Metronidazole 1 Amoxicillin 15 Metronidazole 10 Metronidazole www.freelivedoctor.com
FDA-Approved Treatment Regimes for H. pylori Infection <ul><li>Omeprazole 20 mg BID + C larithromycin 500 mg BID + Amoxicillin 1 g BID for 10 days </li></ul><ul><li>Lansoprazole 30 mg BID + Clarithromycin 500 mg BID + Amoxicillin 1 g BID for 10 days </li></ul><ul><li>Bismuth subsalicylate (Pepto Bismol) 525 mg QID + Metronidazole 250 mg QID + Tetracycline 500 mg QID X 14 days + H 2 receptor antagonist x 4 wks </li></ul>www.freelivedoctor.com