Clinical trial: factors associated with freedom from relapse of heartburn in patients with healed reflux oesophagitis - results from the maintenance phase of the EXPO study

Background  A bility to predict freedom from heartburn relapse during maintenance therapy for healed reflux oesophagitis may facilitate optimal treatment choices for individual patients.
Aim  To determine factors predicting freedom from heartburn relapse during maintenance proton pump inhibitor therapy in patients with healed reflux oesophagitis.
Methods  This post-hoc analysis used data from the maintenance phase of the EXPO study (AstraZeneca study code: SH-NEG-0008); 2766 patients with healed reflux oesophagitis and resolved heartburn received once-daily esomeprazole 20 mg or pantoprazole 20 mg for 6 months. Multiple logistic regression analysis determined factors associated with freedom from heartburn relapse.
Results  Heartburn relapse rates were lower with esomeprazole than pantoprazole in all subgroups analysed. Esomeprazole treatment was the factor most strongly associated with freedom from heartburn relapse (odds ratio 2.08; P  <   0.0001). Other factors significantly associated with freedom from heartburn relapse were Helicobacter pylori infection, greater age, non-obesity, absence of epigastric pain at baseline, pre-treatment nonsevere heartburn and GERD symptom duration ≤5 years.
Conclusions  Several factors predict freedom from heartburn relapse during maintenance proton pump inhibitor therapy for healed reflux oesophagitis, the strongest being choice of proton pump inhibitor. These findings outline the importance of optimizing acid control and identifying predictors of relapse for effective long-term symptom management in reflux oesophagitis patients.     

Current practice and future perspectives in the management of gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD) is primarily due to incompetence of the lower oesophageal sphincter (LOS) and crural diaphragm, with transient LOS relaxation frequently accounting for daytime reflux. In the absence of drugs that adequately correct the motility defects of GERD, treatment is directed towards decreasing gastric acidity. Oesophageal healing is related to control of 24-h intragastric acidity, the degree of acid suppression and duration of treatment.
H₂-receptor antagonists are generally less effective in GERD than in peptic ulcer disease. While providing symptomatic relief in non-erosive GERD, they are often ineffective in healing erosive oesophagitis. Proton pump inhibitors provide more rapid and complete healing and symptom resolution. They are superior to H₂-receptor antagonists in the long-term management of erosive oesophagitis and in reducing recurrence of oesophageal stricture following mechanical dilatation. In Barrett's oesophagus, high-dose proton pump inhibitors in combination with laser/photodynamic ablation therapy can produce metaplastic regression, although this does not preclude future emergence of adenocarcinoma.
Surgical morbidity and mortality rates in GERD generally remain higher than those associated with long-term pharmacotherapy. However, direct comparisons between laparascopic anti-reflux surgery and proton pump inhibitor maintenance therapy remain to be performed.
Although there is no evidence that H. pylori infection worsens the severity of oesophagitis or that H. pylori is carcinogenic in the metaplastic oesophageal mucosa, it has been suggested that H. pylori -positive patients requiring long-term proton pump inhibitor therapy receive bacterial eradication therapy to reduce the risk of developing atrophic gastritis.     

Comparison of the efficacy of pantoprazole vs. nizatidine in the treatment of erosive oesophagitis: a randomized,active-controlled,double-blind study

BACKGROUND: Pantoprazole is a proton pump inhibitor approved for the treatment of erosive oesophagitis and gastro-oesophageal reflux disease. AIM: To compare the efficacy and safety of pantoprazole vs. nizatidine for the treatment of symptomatic gastro-oesophageal reflux disease and endoscopically documented erosive oesophagitis (grade > or = 2). METHODS: A multicentre, double-blind, randomized, active-controlled study (221 patients) was performed to compare 20 and 40 mg pantoprazole daily with nizatidine 150 mg b.d. (maximum, 8 weeks). The primary end-point was endoscopic healing of erosive oesophagitis (grade 1 or 0). The secondary end-point was symptomatic improvement. RESULTS: Healing averaged 61%, 64% and 22% for pantoprazole 20 mg, pantoprazole 40 mg and nizatidine 150 mg, respectively, at 4 weeks, and 79%, 83% and 41% at 8 weeks (P < 0.05, differences between groups at both points). Starting on day 1 of symptom assessment, significantly fewer pantoprazole-treated patients reported night-time heartburn and regurgitation compared with nizatidine-treated patients. Symptoms of gastro-oesophageal reflux disease were completely eliminated in 68% and 65% of patients in the pantoprazole 20-mg and 40-mg groups and in 28% of patients in the nizatidine group at study completion. The difference between each pantoprazole group and the nizatidine group was significant (P < 0.05). CONCLUSIONS: Pantoprazole, at single daily doses of 20 mg and 40 mg for up to 8 weeks, provides more rapid relief of symptoms and superior healing of erosive oesophagitis than nizatidine 150 mg b.d., and is well tolerated.     

Ninety-six-hour wireless oesophageal pH monitoring following proton pump inhibitor administration in NERD patients

Background Comparative studies of proton pump inhibitors (PPIs) have revealed that acid reflux is influenced by PPI treatment, formulations and dosing regimens. Wireless pH capsules have circumvented some of the limitations of conventional catheter‐based pH testing with the additional advantage of 96‐h recording periods. Aim To clarify the effectiveness of intra‐oesophageal acid suppression by omeprazole, pantoprazole and lansoprazole in non‐erosive reflux disease patients through a 4‐day monitoring of oesophageal pH and related symptoms. Methods Twenty‐four patients with typical symptoms of gastro‐oesophageal reflux disease were enrolled and administered upper endoscopy and placement of a wireless pH capsule. Patients randomly received omeprazole, pantoprazole or lansoprazole for 3 days after the first 24 h. Symptom–reflux associations were expressed using the symptom index (SI). Results All patients completed the study. Significant decrease in acid exposure occurred on day 2 and in each successive day in all groups. Pantoprazole and omeprazole are more effective than lansoprazole at inducing a normalization of intra‐oesophageal acid exposure at days 2 and 3. Significant reduction in SI at day 2 was observed. Conclusions Four‐day ambulatory oesophageal pH monitoring is feasible and safe. Omeprazole, pantoprazole and lansoprazole have an equivalent potency for normalizing intra‐oesophageal acid exposure after 3 days of treatment in non‐erosive reflux disease patients.     

Non-erosive reflux disease (NERD)--acid reflux and symptom patterns

BACKGROUND: Recent reports suggest that patients with non-erosive reflux disease (NERD) treated with anti-reflux medications show lower symptom improvement rates than patients with erosive oesophagitis treated with the same medications. AIM: To determine the acid reflux and symptom patterns of patients with NERD in comparison with those with erosive oesophagitis and Barrett's oesophagus, and to identify different NERD subgroups. METHODS: One hundred and forty-nine consecutive patients seen for classic heartburn symptoms were evaluated for the study. Oesophageal mucosal injury was assessed by upper endoscopy and classified by Hetzel-Dent criteria. Patients with Hetzel-Dent grades 0-1 were considered to have NERD. The extent of oesophageal acid exposure was determined by ambulatory 24-h oesophageal pH monitoring. RESULTS: Seventy-one patients were found to have NERD, 36 erosive oesophagitis and 42 Barrett's oesophagus. Compared with patients with erosive oesophagitis (75%) and Barrett's oesophagus (93%), those with NERD (45%) were significantly less likely to have an abnormal pH test (P = 0.0001). Patients with Barrett's oesophagus had the highest mean number of acid reflux events (210 +/- 17.7), compared with those with erosive oesophagitis (139.7 +/- 15.2) and NERD (95.3 +/- 9.4) (P = 0.0001); however, the rate of perceived acid reflux events was similar and very low in all groups (NERD, 3.6%; erosive oesophagitis, 2.9%; Barrett's oesophagus, 2.17%). NERD-positive patients (abnormal pH test) had a similar extent of oesophageal acid exposure to those with erosive oesophagitis. NERD-positive patients were more likely to demonstrate a symptom index greater than 75% than NERD-negative patients (normal pH test) (61.9% vs. 10.5%; P = 0.0001). In the NERD-negative group, those with a negative symptom index reported having heartburn at pH < 4 only 12.7% of the time, compared with 70.7% of the time in those with a positive symptom index, despite a similar mean number of heartburn episodes. CONCLUSIONS: Patients with NERD commonly demonstrate a negative pH test. Acid reflux characteristics and symptom patterns suggest a heterogeneous group of patients.     

Dysfunction of oesophageal motility in Helicobacter pylori-infected patients with reflux oesophagitis

BACKGROUND: Helicobacter pylori infection has been suggested to be protective against gastro-oesophageal reflux disease. However, a significant proportion of patients with gastro-oesophageal reflux disease are infected by H. pylori. AIM: To study oesophageal motor function in H. pylori-infected patients with reflux oesophagitis. METHODS: Patients with erosive reflux oesophagitis were recruited prospectively for stationary oesophageal manometry and 24-h ambulatory oesophageal pH monitoring. H. pylori status was determined by biopsy urease test. Non-reflux volunteers were recruited as controls. RESULTS: Seventy-four patients with erosive oesophagitis (34 H. pylori-positive, 40 H. pylori-negative) and 48 non-reflux patient controls (22 H. pylori-positive, 26 H. pylori-negative) were recruited. There was no difference in severity of oesophagitis (median grade, 1; P=0.53) or oesophageal acid exposure (total percentage time oesophageal pH < 4, 7.6% vs. 6.8%; P=0.57) between H. pylori-positive and H. pylori-negative groups. Compared to H. pylori-negative patients, H. pylori-positive patients had significantly lower basal lower oesophageal sphincter pressure (12.2 mmHg vs. 15.3 mmHg; P=0.03) and amplitude of distal peristalsis (56.9 mmHg vs. 68.4 mmHg; P=0.03). Ineffective oesophageal motility (14% vs. 7%; P=0.02) and failed oesophageal peristalsis were also significantly more prevalent in H. pylori-positive patients. CONCLUSIONS: Among patients with a similar degree of reflux oesophagitis, H. pylori-infected patients have more severe oesophageal dysmotility and lower oesophageal sphincter dysfunction. Oesophageal motor dysfunction probably plays a dominant role in the development of gastro-oesophageal reflux disease in patients with H. pylori infection.     

Systematic review: the efficacy of intermittent and on-demand therapy with histamine H2-receptor antagonists or proton pump inhibitors for gastro-oesophageal reflux disease patients

AIM: To perform a systematic review on the efficacy of intermittent and on-demand therapy with either histamine H2-receptor antagonists or proton pump inhibitors for patients with erosive oesophagitis or symptomatic heartburn. METHOD: We conducted randomized-controlled trials of non-continuous therapy in gastro-oesophageal reflux disease patients. RESULTS: Fourteen studies met inclusion criteria. Because of variation in outcome measures statistical pooling of results was not possible. Results were analysed qualitatively. Four studies evaluated intermittent therapy of treatment 3 days a week with omeprazole 20 mg or daily with ranitidine which were not efficacious compared to a daily proton pump inhibitor. Famotidine 10 and 20 mg, ranitidine 75 mg and cimetidine 200 mg were efficacious in five on-demand studies for relief of symptomatic heartburn episodes. In three of four studies, evaluating only non-erosive (endoscopy-negative) gastro-oesophageal reflux disease patients, esomeprazole 20 and 40 mg and omeprazole 10 and 20 mg a day were efficacious using willingness to continue as an endpoint. Lansoprazole 30 mg and omeprazole 20 mg maintained symptom control in 60-70% of healed oesophagitis patients. CONCLUSIONS: Intermittent proton pump inhibitor or H2-receptor antagonist therapy is not effective in maintaining control in oesophagitis patients. H2-receptor antagonists are effective for relief of heartburn episodes. On-demand proton pump inhibitor therapy may work in a proportion of non-erosive gastro-oesophageal reflux disease patients.     

Clinical trial: factors associated with resolution of heartburn in patients with reflux oesophagitis – results from the EXPO study

Background The ability to predict symptom response to reflux oesophagitis‐healing therapy may optimize treatment decisions. Aim To identify factors associated with heartburn resolution in patients receiving acid‐suppressive therapy for reflux oesophagitis. Methods In this multicentre, randomized, double‐blind trial (EXPO; AstraZeneca study code: SH‐NEG‐0008), patients with endoscopically confirmed reflux oesophagitis and reflux symptoms received once‐daily proton pump inhibitor therapy [esomeprazole 40 mg (n = 1562) or pantoprazole 40 mg (n = 1589)] for ≥4 weeks. Factors associated with heartburn resolution after 4 weeks were identified by multiple logistic regression analysis. Results Esomeprazole therapy, positive Helicobacter pylori status and greater age were associated with an increased likelihood of heartburn resolution [odds ratio (95% confidence interval): 1.31 (1.12, 1.54), 1.44 (1.19, 1.74) and 1.013 (1.007, 1.019) per year, respectively; all P < 0.001]. Men and patients with no acid regurgitation or epigastric pain pre‐treatment were also more likely to achieve heartburn resolution (all P < 0.05). Conclusions The use of esomeprazole rather than pantoprazole increases the probability of achieving resolution of heartburn during reflux oesophagitis‐healing therapy. Other factors, including H. pylori status, age, gender and symptom profile may be helpful in determining the likelihood of heartburn resolution in such patients.     

The extent of oesophageal acid exposure overlap among the different gastro-oesophageal reflux disease groups

BACKGROUND: Studies have demonstrated that patients with Barrett's oesophagus have the highest oesophageal acid exposure profile, followed by erosive oesophagitis and non-erosive reflux disease patients, but the exact extent of overlap remains unknown. AIM: To determine the extent of overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups. METHODS: A total of 121 patients with gastro-oesophageal reflux disease underwent an upper endoscopy and were classified as having Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-all (non-erosive reflux disease-positive and functional heartburn). Subsequently, patients underwent pH testing and overlap in oesophageal acid exposure among the different gastro-oesophageal reflux disease groups was determined. RESULTS: Of those enrolled, 24 had Barrett's oesophagus, 30 erosive oesophagitis and 28 were non-erosive reflux disease-positive. Mean oesophageal acid exposure time was 224.8 +/- 35, 134.3 +/- 21.9 and 141.3 +/- 19.8 min for Barrett's oesophagus, erosive oesophagitis and non-erosive reflux disease-positive respectively. Per cent overlap for total, upright and supine time between non-erosive reflux disease-positive and erosive oesophagitis was 47.4%, 64.7% and 81.8%, between Barrett's oesophagus and erosive oesophagitis was 47.8%, 40.7% and 24%, and between Barrett's oesophagus and non-erosive reflux disease-positive was 31.6%, 37.5% and 20.8% respectively. CONCLUSIONS: Our study demonstrated a high oesophageal acid exposure overlap between patients with non-erosive reflux disease-positive and erosive oesophagitis, Barrett's oesophagus and erosive oesophagitis, as well as Barrett's oesophagus and non-erosive reflux disease-positive patients.     

Effect of Helicobacter pylori eradication on oesophageal acid exposure in patients with reflux oesophagitis

BACKGROUND: The effect of Helicobacter pylori eradication on reflux oesophagitis is unclear. AIM: To study the effect of H. pylori eradication on oesophageal acid exposure and disease severity in patients with reflux oesophagitis. METHODS: Patients with reflux oesophagitis and H. pylori infection were recruited for 24-h oesophageal pH-metry. They were then randomly assigned to receive either treatment for H. pylori eradication (1-week omeprazole-based triple therapy, followed by 7-week omeprazole) or omeprazole alone (8-week omeprazole). Uninfected patients were recruited as controls. Endoscopy, pH monitoring and symptom assessment were repeated at 26 weeks. RESULTS: Forty patients (25 H. pylori-positive and 15 uninfected) with erosive oesophagitis were studied. Fourteen were randomized to receive treatment for H. pylori eradication and 11 to receive omeprazole alone. There was no difference in the percentage of time the oesophageal pH < 4 before and 26 weeks after treatment among the three groups. However, the percentage of time the oesophageal pH < 2 (P=0.01) and pH < 3 (P=0.02) was significantly increased in patients receiving treatment for H. pylori eradication. Three (21%) patients in the group receiving treatment for H. pylori eradication had worsening of reflux oesophagitis. CONCLUSIONS: H. pylori eradication increases oesophageal acid exposure and may adversely affect the clinical course of reflux disease in a subset of patients.     

Reflux and Barrett's oesophagitis after gastric surgery--long-term follow-up and implications for the roles of gastric acid and bile in oesophagitis

BACKGROUND: The role of gastric acid is difficult to separate from that of bile in oesophageal reflux, and the complications of this can take many years to develop. Gastric surgery patients provide a good model for both significant bile reflux and marked gastric acid inhibition. AIM: To study the oesophageal abnormalities in gastric surgery patients undergoing long-term follow-up, compared with patients with intact stomachs. METHODS: Two hundred and forty adult patients were endoscoped regardless of their age, sex or type of surgical procedure. Oesophageal damage was graded on a scale of 0-5, and biopsies were taken to exclude neoplasia, to diagnose Barrett's oesophagus and to identify Helicobacter pylori. RESULTS: Of the 240 patients studied, 140 had undergone gastric surgery 27 years (19-31 years) [median (interquartile range)] prior to endoscopy, and these patients had milder oesophageal scores and fewer cases of Barrett's oesophagitis. Of the 119 patients with post-surgical bile reflux gastritis, 31 (26%) had oesophagitis, two (1.7%) had Barrett's oesophagitis and oesophageal scores of 0 (0-1) were found. These results compared with corresponding values of 37 (37%; P = 0.11), 11 (11%; P = 0.007) and 0 (0-2) (P = 0.046), respectively, in 100 patients with intact stomachs. In addition, of the 83 patients with vagotomy, 19 had oesophagitis (23%; P = 0.05), none had Barrett's oesophagitis and lower oesophageal scores (P = 0.02) were found. CONCLUSIONS: The prevalence and severity of reflux and Barrett's oesophagitis are not increased in patients with a long history of gastric surgery, particularly after vagotomy, and despite being at risk of bile reflux.     

The basis for the decreased response to proton pump inhibitors in gastro-oesophageal reflux disease patients without erosive oesophagitis

BACKGROUND: The reason why heartburn in gastro-oesophageal reflux disease subjects without oesophagitis is less responsive to proton pump inhibitors than heartburn in those with erosive oesophagitis is not known. METHODS: Gastric and oesophageal pH were determined in 26 subjects with gastro-oesophageal reflux disease at baseline and on days 1, 2 and 8 of treatment with 20 mg omeprazole or 20 mg rabeprazole in a randomized, two-way cross-over fashion. The presence or absence of erosive oesophagitis at baseline was documented by upper gastrointestinal endoscopy. RESULTS: At a given value of the integrated gastric acidity during treatment with a proton pump inhibitor, the probability of pathological oesophageal reflux was significantly higher in subjects with no oesophagitis than in those with erosive oesophagitis. This occurred because the post-prandial gastric acidity in subjects with no oesophagitis showed a decreased response to the antisecretory agent. CONCLUSIONS: Compared with gastro-oesophageal reflux disease subjects with erosive oesophagitis, those with no oesophagitis are relatively refractory to the pharmacodynamic effects of proton pump inhibitors on the post-prandial integrated gastric acidity.     

Oesophageal motility defects associated with nocturnal gastro-oesophageal reflux on proton pump inhibitors

BACKGROUND: Recent studies from our laboratory reveal that 70% of patients with gastro-oesophageal reflux disease (GERD) on proton pump inhibitors twice daily (b.d.) have nocturnal gastric acid breakthrough (gastric pH < 4 > 1 h) which is often accompanied by oesophageal acid exposure. The pathogenesis of GER during gastric acid breakthrough is not clear. AIM: To determine the prevalence of oesophageal motility abnormalities in patients with nocturnal GER associated with nocturnal acid breakthrough on proton pump inhibitor b.d. METHODS: We reviewed the pH-metry and manometric studies of 100 consecutive patients with GERD who were on proton pump inhibitor b.d. pH tracings were analysed for the nocturnal period (10.00 hours until 06.00 hours). Nocturnal GER was defined as> 0.5% time distal oesophageal pH < 4. Manometric tracings were reviewed for lower oesophageal sphincter (LES) pressure and oesophageal body motility. Chi-squared and Fischer's test were used for statistical analysis. RESULTS: Of the 100 patients, 74 (74%) had nocturnal gastric acid breakthrough. Thirty-one (42%) had concurrent abnormal nocturnal GER (refluxers) and 43 out of 74 (58%) had no GER (non-refluxers). The prevalence of ineffective oesophageal motility, and low LES pressure was significantly higher in refluxers than in non-refluxers (P < 0. 05, P < 0.001, respectively). Ineffective-oesophageal motility has a high specificity (91%), but low sensitivity (45%) as a diagnostic predictor for patients who are more likely to develop nocturnal GER on proton pump inhibitor b.d. CONCLUSION: Ineffective oesophageal motility is a risk factor for proton pump inhibitor refractory GER.     

The effect of over-the-counter ranitidine 75 mg on night-time heartburn in patients with erosive oesophagitis on daily proton pump inhibitor maintenance therapy

BACKGROUND: H2-receptor antagonists are widely used with proton pump inhibitors. AIM: To determine if H2-receptor antagonists used in conjunction with proton pump inhibitors were effective for nocturnal heartburn in patients taking proton pump inhibitors. METHODS: We evaluated 386 patients with erosive oesophagitis documented at endoscopy who were receiving single daily maintenance proton pump inhibitor therapy to determine if they had symptoms of nocturnal heartburn. Patients with two or more episodes of night-time a week were invited to participate in the study. Patients were randomly assigned to a single dose of an over-the-counter preparation of ranitidine 75 mg at bedtime or matching placebo for 14 days. RESULTS: The prevalence of nocturnal symptoms was 10.6%. Mean symptom scores on the first day of the trial (baseline) were similar between the treatment group (1.1 +/- 0.9) and the placebo group (1.1 +/- 1.1). On day 3, symptom scores were significantly lower in the ranitidine group (0.71 +/- 0.69) compared with the control group (1.4 +/- 1.2; P = 0.045). On day 14, mean symptom scores were similar in the ranitidine group (0.82 +/- 0.95) and the control group (1 +/- 0.84). CONCLUSIONS: Nocturnal heartburn is uncommon on proton pump inhibitor therapy; the addition of ranitidine at bedtime resulted in a decrease in symptom scores on day 3 but there were no differences on day 14.     

Comparable clinical efficacy and tolerability of 20 mg pantoprazole and 20 mg omeprazole in patients with grade I reflux oesophagitis

BACKGROUND: Several clinical trials have shown that pantoprazole (40 mg) and omeprazole (40 or 20 mg) have similar efficacy and safety in the treatment of grade II-IV reflux oesophagitis (Savary-Miller classification). AIM: To compare the efficacy and safety of once-daily doses of pantoprazole (20 mg) and omeprazole (20 mg) with respect to symptom relief and healing of patients with grade I reflux oesophagitis. METHODS: Patients with endoscopically established grade I reflux oesophagitis (non-confluent, patchy red lesions with/without white fibrin coating) were enrolled into this randomized, open, parallel-group, multicentre study. A total of 328 patients (n=166 in the pantoprazole group, n=162 in the omeprazole group) were recruited in 23 centres. Patients received 4 weeks of treatment. If the reflux oesophagitis was not completely healed, the treatment was extended to 8 weeks. RESULTS: After 2 and 4 weeks of treatment with either pantoprazole or omeprazole, the rate of symptom relief was similar (70% vs. 79% and 77% vs. 84%, respectively). High healing rates were observed after 4 and 8 weeks (pantoprazole: 84% and 90%, respectively; omeprazole: 89% and 95%, respectively). Both treatments were well tolerated. The most frequently reported adverse events on pantoprazole and omeprazole, respectively, were nausea (8% vs. 7%), diarrhoea (5% vs. 6%) and headache (6% vs. 3%). CONCLUSIONS: After 4 and 8 weeks of treatment with pantoprazole (20 mg) or omeprazole (20 mg), patients with mild gastro-oesophageal reflux disease (grade I) showed comparably high rates of symptom relief and healing. Both treatments were safe and well tolerated.     

Approaches to endoscopic‐negative reflux disease: part of the GERD spectrum or a unique acid‐related disorder?

Endoscopic-negative reflux disease (ENRD) is the most common presentation of gastro-oesophageal reflux disease (GERD)-affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD-related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high-dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial.     

Efficacy and tolerability of pantoprazole 40 mg versus 80 mg in patients with reflux oesophagitis.

BACKGROUND: Pantoprazole is a substituted benzimidazole which is a potent inhibitor of gastric acid secretion by its action upon H+, K+- ATPase. METHODS: Pantoprazole 40 mg and 80 mg were compared in a randomized double-blind study in 192 out-patients with stage II or III (Savary-Miller classification) reflux oesophagitis. Patients received either pantoprazole 40 mg (n = 97) or pantoprazole 80 mg (n = 95), once daily before breakfast for 4 weeks. Treatment was extended for a further 4 weeks if the oesophagitis had not healed. RESULTS: After 4 weeks complete healing of the reflux oesophagitis was seen in 78% of protocol-correct patients given pantoprazole 40 mg daily (n = 86), and in 72% in the 80 mg (n = 87) group. The cumulative healing rates after 8 weeks were 95 and 94%, respectively (P > 0.05, Cochran-Mantel- Haenszel), and time until healing of oesophagitis comparable in both groups. Differences between doses were also not significant in an intention-to-treat analysis. Both dosing schedules were well tolerated and the patients experienced remarkable symptom relief. No adverse event or changes in laboratory values of clinical significance could definitely be ascribed to the trial medication. CONCLUSION: The 40 mg pantoprazole dosage is comparable to 80 mg in reflux oesophagitis, both in efficacy and tolerability.     

Review article: acid suppression in the management of gastro-oesophageal reflux disease--an appraisal of treatment options in primary care

Gastro-oesophageal reflux disease (GERD) is one of the most common conditions presenting to the primary care physician. Despite progress in understanding and treatment of the disease, strategies for capitalizing on these advances are less well developed. In many practices, H2-receptor antagonists still remain the most widely prescribed treatment for GERD, despite the availability of the more effective acid-suppressant proton pump inhibitors. This review examines the relative efficacies of acid-suppressant drugs in minimizing oesophageal acid exposure and outlines the evidence for the superiority of proton pump inhibitors over standard-dose H(2)-antagonists in symptom relief, erosion healing and prevention of relapse in GERD. Current prescribing patterns and considerations for the general practitioner are also examined. The availability and impact of over-the-counter H(2)-antagonists on the treatment of GERD and their relative cost-effectiveness vs. proton pump inhibitors are also addressed. A hierarchy of drug efficacy (full-dose proton pump inhibitor > half-dose proton pump inhibitor > high-dose H(2)-antagonist > standard-dose H(2)-antagonist or prokinetic) applies in principle to all GERD patients, (with or without oesophagitis). The most effective initial therapy for GERD is also likely to be the most cost-effective one, if treatment failure leads to higher utilization of medical resources. The application of these recommendations to the management of non-endoscoped GERD, endoscopy-negative GERD and low-grade oesophagitis as well as higher grade oesophagitis is also reviewed.     

Pantoprazole: an update of its pharmacological properties and therapeutic use in the management of acid-related disorders

Pantoprazole (Protonix) is an irreversible proton pump inhibitor (PPI) that reduces gastric acid secretion. In combination with two antimicrobial agents (most commonly metronidazole, clarithromycin or amoxicillin) for 6-14 days, pantoprazole 40 mg twice daily produced Helicobacter pylori eradication rates of 71-93.8% (intent-to-treat [ITT] or modified ITT analysis) in patients without known antibacterial resistance. Pantoprazole-containing triple therapy was at least as effective as omeprazole- and similar in efficacy to lansoprazole-containing triple therapy in large trials. In the treatment of moderate to severe gastro-oesophageal reflux disease (GORD), oral pantoprazole 40 mg/day was as effective as other PPIs (omeprazole, omeprazole multiple unit pellet system, lansoprazole and esomeprazole) and significantly more effective than histamine H(2)-antagonists. Pantoprazole 20 mg/day provided effective mucosal healing in patients with GORD and mild oesophagitis. Intravenous pantoprazole 40 mg/day can be used in patients who are unable to take oral medication. Oral pantoprazole 20-40 mg/day for up to 24 months prevented relapse in most patients with healed GORD. According to preliminary data, oral pantoprazole 20 or 40 mg/day was effective at healing and preventing non-steroidal anti-inflammatory drug (NSAID)-related ulcers, and intravenous pantoprazole was at least as effective as intravenous ranitidine in preventing ulcer rebleeding after endoscopic haemostasis. Oral or intravenous pantoprazole up to 240 mg/day maintained target acid output levels in most patients with hypersecretory conditions, including Zollinger-Ellison syndrome. Oral and intravenous pantoprazole appear to be well tolerated in patients with acid-related disorders in short- and long-term trials. Tolerability with oral pantoprazole was similar to that with other PPIs or histamine H(2)-antagonists in short-term trials. Formal drug interaction studies have not revealed any clinically significant interactions between pantoprazole and other agents. In conclusion, pantoprazole is an effective agent in the management of acid-related disorders. As a component of triple therapy for H. pylori eradication and as monotherapy for the healing of oesophagitis and maintenance of GORD, pantoprazole has shown similar efficacy to other PPIs and greater efficacy than histamine H(2)-antagonists. Limited data suggest that it is also effective in Zollinger-Ellison syndrome and in preventing ulcer rebleeding. Pantoprazole is well tolerated with minimal potential for drug interactions. The availability of pantoprazole as both oral and intravenous formulations provides flexibility when the oral route of administration is not appropriate. Thus, pantoprazole is a valuable alternative to other PPIs in the treatment of acid-related disorders.     

The effect of Helicobacter pylori eradication on gastro-oesophageal reflux

BACKGROUND: Increased prevalence of oesophagitis has been reported following eradication of Helicobacter pylori. We hypothesized that H. pylori eradication might increase gastro-oesophageal acid reflux in patients with reflux oesophagitis. METHODS: Twenty-five consecutive patients (13 male, 12 female) with H. pylori infection and reflux oesophagitis grade I (22 patients) or II (three patients) were enrolled; mean age 49.9 (range 33-75) years. Twenty-four hour intra-oesophageal pH recording was performed before and 12 weeks after eradication of H. pylori, which was achieved using bismuth subnitrate suspension 150 mg q.d.s., oxytetracycline 500 mg q.d.s. and metronidazole 400 mg t.d.s. for 10 days. Eradication was confirmed by 14C-urea breath test 12 weeks after completion of treatment. The patients did not receive acid-suppressive medication. RESULTS: All patients had abnormal gastro-oesophageal reflux before anti-H. pylori treatment. After treatment, there was no significant change in the percentage of total time oesophageal pH < 4 (P=0.46) in the 23 patients in whom the infection had been cured. Nine of the cured patients had increased acid exposure, whereas 14 had decreased acid exposure. No significant change in reflux symptom scores was found. There was no relationship between change in acid exposure and symptom improvement. CONCLUSIONS: Twelve weeks after H. pylori eradication there was no consistent change in gastro-oesophageal acid reflux in patients with mild or moderate reflux oesophagitis.