A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO study

AIM: To assess the efficacy of the 8-week therapy with esomeprazole 40 mg vs. pantoprazole 40 mg for healing erosive oesophagitis (EE) as part of a management study. METHODS: Patients had a history of gastro-oesophageal reflux disease symptoms (> or =6 months) and had suffered heartburn on at least 4 of the 7 days preceding enrollment. Endoscopies were performed to grade EE severity using the Los Angeles (LA) classification system at baseline, 4 and 8 weeks (if unhealed at 4 weeks). Heartburn severity was recorded by patients on diary cards. The primary end point was healing of EE by week 8 of treatment. RESULTS: Of 3170 patients randomized, the intent-to-treat population consisted of 3151 patients (63% male, mean age: 50.6 years, 27% Helicobacter pylori-positive). Esomeprazole 40 mg healed a significantly greater proportion of EE patients than pantoprazole 40 mg at both 4 weeks (life table estimates: esomeprazole 81%, pantoprazole 75%, P < 0.001) and 8 weeks (life table estimates: esomeprazole 96%, pantoprazole 92%, P < 0.001). The median time to reach sustained heartburn resolution was 6 days in patients receiving esomeprazole and 8 days with pantoprazole (P < 0.001). CONCLUSION: Esomeprazole 40 mg is more effective than pantoprazole 40 mg for healing EE and providing resolution of associated heartburn.     

Intravenous esomeprazole 40 mg vs. intravenous lansoprazole 30 mg for controlling intragastric acidity in healthy adults

Background  Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral therapy is not appropriate.
Aim  To compare IV esomeprazole and IV lansoprazole for the control of intragastric pH.
Methods  In this open-label crossover study, healthy, Helicobacter pylori -negative adults were randomized to one of two treatment sequences, each consisting of two 5-day dosing periods of IV esomeprazole 40 mg or IV lansoprazole 30 mg. Twenty-four-hour intragastric pH monitoring was conducted on days 1 and 5 of each dosing period.
Results  On days 1 and 5, intragastric pH was >4.0 significantly longer with esomeprazole than lansoprazole (least-squares means: day 1, 40.0% vs. 33.6%; day 5, 61.9% vs. 45.4%; both P  <   0.0001). During the first 4 h of pH monitoring, intragastric pH was >4.0 significantly longer on days 1 and 5 with esomeprazole than lansoprazole ( P  <   0.0001). Kaplan–Meier estimates of median hours to stable pH >4.0 were 4.92 for esomeprazole and 5.75 for lansoprazole ( P  =   0.0014 for test on Gehan scores).
Conclusion  In healthy adults, IV esomeprazole 40 mg controlled intragastric acidity faster and more effectively than IV lansoprazole 30 mg.     

Randomised clinical trial: a novel rabeprazole extended release 50 mg formulation vs. esomeprazole 40 mg in healing of moderate-to-severe erosive oesophagitis - the results of two double-blind studies

Aliment Pharmacol Ther 2011; 33: 203–212

Summary

Background Current PPIs may not achieve desired outcomes in some GERD patients due to limited duration of acid inhibition. Aim To evaluate a novel rabeprazole extended release (ER), which provides longer duration of drug exposure and acid suppression, in healing and symptomatic resolution of moderate‐severe erosive oesophagitis. Methods Patients with LA grade C or D oesophagitis were randomised to rabeprazole‐ER 50 mg or esomeprazole 40 mg once daily in two identical 8‐week double‐blind trials (N = 2130). Two primary endpoints were tested sequentially: (1) healing by 8 weeks [hypothesis: rabeprazole‐ER non‐inferior to esomeprazole (non‐inferiority margin = 8%)], (2) healing by 4 weeks [hypothesis: rabeprazole‐ER superior to esomeprazole (P < 0.05)]. The secondary endpoint was sustained heartburn resolution at 4 weeks. Results Rabeprazole‐ER was non‐inferior to esomeprazole in week‐8 healing (80.0% vs. 75.0%; 77.5% vs. 78.4%). Week‐4 healing (54.8% vs. 50.3%; 50.9% vs. 50.7%) and sustained heartburn resolution (48.3% vs. 48.2%; 53.2% vs. 52.5%) were not significantly different. Post hoc combined results for grade D revealed rabeprazole‐ER vs. esomeprazole differences in week‐8 healing = 10.4% (95% CI: ?1.4%, 22.2%) and week‐4 healing = 12.0% (P = 0.048). Conclusions Rabeprazole‐ER is as effective as esomeprazole in healing moderate‐severe oesophagitis and achieves similar rates of heartburn resolution. Subgroup analysis suggests the possibility of benefit in severe oesophagitis, but this requires further evaluation (ClinicalTrials.gov: NCT00658528 and NCT00658775).

     

Relationship between intragastric acid control and healing status in the treatment of moderate to severe erosive oesophagitis

Aim To assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis. Methods In this proof‐of‐concept study, adults with endoscopically verified Los Angeles grade C or grade D erosive oesophagitis were randomly assigned to oral esomeprazole 10 or 40 mg once daily for 4 weeks. On day 5, patients underwent 24‐h pH monitoring. At 4 weeks, erosive oesophagitis healing status was endoscopically assessed. Investigators scored gastro‐oesophageal reflux disease symptoms on a 4‐point scale [none to severe (0–3)] before and 4 weeks after treatment. The percentage of time intragastric pH was >4.0 and healing status were correlated and tested for significance using a Spearman rank correlation (r). Results 103 patients had evaluable data (mean age, 48.7 years; 65% men). Mean percentages of time with intragastric pH >4.0 on day 5 in patients with healed and unhealed erosive oesophagitis were 61% and 42%, respectively (P = 0.0002), indicating that erosive oesophagitis healing rates were positively related to the percentage of time intragastric pH was >4.0. Greater intragastric acid control correlated with lower final daytime and night‐time heartburn and acid regurgitation symptom scores (r = −0.029, −0.029 and −0.021; P = 0.003, 0.003 and 0.032, respectively). Conclusion A positive relationship between intragastric acid control and erosive oesophagitis healing was demonstrated.     

Ranitidine 300 mg twice daily and 150 mg four-times daily are effective in healing erosive oesophagitis.

BACKGROUND: Ranitidine 150 mg q.d.s. is the currently recommended dosage in the United States for the treatment of erosive oesophagitis. To determine whether a higher dose of ranitidine administered less frequently would also be effective in healing erosive oesophagitis, we compared ranitidine 300 mg b.d. with ranitidine 150 mg q.d.s. in the treatment of erosive oesophagitis. METHODS: This multicentre, double- blind, randomized, placebo-controlled study conducted in the United States compared two dosages of ranitidine in 772 patients with endoscopically diagnosed erosive oesophagitis. Patients were treated with ranitidine 300 mg b.d., ranitidine 150 mg q.d.s. or placebo for up to 12 weeks. Endoscopies were repeated after 4, 8 and 12 weeks of treatment. RESULTS: Ranitidine 300 mg b.d. was significantly more effective than placebo in healing erosive oesophagitis at weeks 8 and 12 (51 vs. 36% and 66 vs. 52%, respectively; P < or = 0.004). Significantly higher healing rates were also achieved with ranitidine 150 mg q.d.s. compared with placebo at 4, 8 and 12 weeks (37 vs. 21%, 62 vs. 36% and 77 vs. 52%, respectively; P < 0.001). Healing rates were significantly higher with ranitidine 150 mg q.d.s. than with ranitidine 300 mg b.d. at all scheduled endoscopies (P < or = 0.041). CONCLUSIONS: Ranitidine 300 mg b.d. is effective in healing erosive oesophagitis and may be appropriate as an alternative dosage regimen to ranitidine 150 mg q.d.s. in some patients with erosive oesophagitis.     

Randomised clinical trial: twice daily esomeprazole 40 mg vs. pantoprazole 40 mg in Barrett's oesophagus for 1 year

Aliment Pharmacol Ther 2011; 33: 1019–1027

Summary

Background Barrett’s oesophagus is regarded as the most important risk factor for development of oesophageal adenocarcinoma. According to current guidelines, treatment should be limited to symptomatic Barrett’s oesophagus. Aim To evaluate the expression of Ki67, cyclooxygenase‐2 (COX‐2) and apoptosis in Barrett’s oesophagus after 12 months of double‐dose proton pump inhibitor therapy. The effectiveness of esomeprazole and pantoprazole was also compared. Methods Seventy‐seven nondysplastic Barrett’s oesophagus patients underwent baseline upper endoscopy. Patients were then randomised into two groups: one group was allocated to receive esomeprazole 40 mg b.d. and the other group pantoprazole 40 mg b.d. for 12 months. A follow‐up endoscopy was performed at the end of treatment. Sixty‐five of 77 patients agreed to undergo oesophageal manometry and 24‐h pH‐metry. Barrett’s oesophagus biopsies, obtained at baseline and after treatment, were analysed using immunohistochemistry to assess Ki67 and COX‐2 expression; apoptosis was evaluated using TUNEL. Results In the esomeprazole group, a significant decrease in Ki67 and COX‐2 expression, as well as an increase in apoptosis, were observed (P < 0.05). By contrast, in the pantoprazole group Ki67, COX‐2 and apoptosis did not vary significantly from baseline. By 24‐h oesophageal pH‐monitoring, a normal acid exposure time was recorded in patients treated with esomeprazole, while those allocated to pantoprazole displayed abnormal acid exposure (P < 0.05). Conclusions Treatment of Barrett’s oesophagus patients with high‐dose esomeprazole, but not pantoprazole, promoted a decrease in proliferative markers, concomitantly with a decrease in apoptotic cell death. Moreover, esomeprazole allowed a better oesophageal acid control than pantoprazole.     

Esomeprazole 20 mg vs. pantoprazole 20 mg for maintenance therapy of healed erosive oesophagitis: results from the EXPO study

BACKGROUND: Following initial healing of erosive oesophagitis, most patients require maintenance therapy to prevent relapse. AIM: To compare endoscopic and symptomatic remission rates over 6 months' maintenance therapy with esomeprazole or pantoprazole (both 20 mg once daily) in patients with healed erosive oesophagitis. METHODS: Patients with symptoms of gastro-oesophageal reflux disease and endoscopically confirmed erosive oesophagitis at baseline were randomized to receive esomeprazole 40 mg or pantoprazole 40 mg for up to 8 weeks. Patients with healed erosive oesophagitis and free of moderate/severe heartburn and acid regurgitation at 4 weeks or, if necessary, 8 weeks entered the 6-month maintenance therapy phase of the study. RESULTS: A total of 2766 patients (63% men; mean age 50 years) received esomeprazole 20 mg (n = 1377) or pantoprazole 20 mg (n = 1389) and comprised the intention-to-treat population. Following 6 months of treatment, the proportion of patients in endoscopic and symptomatic remission was significantly greater for those receiving esomeprazole 20 mg (87.0%) than pantoprazole 20 mg (74.9%, log-rank test P < 0.0001). Esomeprazole 20 mg produced a higher proportion of patients free of moderate to severe gastro-oesophageal reflux disease symptoms and fewer discontinuations because of symptoms than pantoprazole 20 mg (92.2% vs. 88.5%, P < 0.001). CONCLUSIONS: Esomeprazole 20 mg is more effective than pantoprazole 20 mg for maintenance therapy following initial healing of erosive oesophagitis and relief of gastro-oesophageal reflux disease symptoms.     

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.     

Control of intragastric pH with omeprazole 20 mg, omeprazole 40 mg and lansoprazole 30 mg

BACKGROUND: Single daily doses of proton pump inhibitors, omeprazole and lansoprazole provide effective acid suppression and equal healing and symptom relief in patients with GERD. Despite this, controversy exists as to the efficacy of available proton pump inhibitors in the control of gastric acidity. AIM: To assess the efficacy of omeprazole 20 mg vs. lansoprazole 30 mg and omeprazole 40 mg vs. lansoprazole 30 mg in intragastric pH control. METHODS: Study I: 12 Helicobacter pylori-negative volunteers (mean age 33 years) were treated with omeprazole 20 mg and lansoprazole 30 mg in random order before breakfast for 7 days. Study II: 24 subjects (mean age 36 years) were similarly treated with omeprazole 40 mg and lansoprazole 30 mg for 7 days after a baseline pH study. One week washout was allowed between studies. Subjects had the same meal on each study day. On day seven, a 24-h intragastric pH study was performed. The percentage time for which gastric pH > 4 was analysed (Gastrosoft, Synectics Medical Inc.) and expressed as mean +/- s.d. RESULTS: (1) Omeprazole 20 mg and lansoprazole 30 mg showed no significant difference in the percentage time for which gastric pH > 4 in the daytime and night-time periods. (2) The percentage time for which pH > 4 with omeprazole 40 mg was significantly greater than lansoprazole 30 mg in both daytime (61 +/- 19% vs. 48 +/- 14%, P < 0.001), and night-time periods (34 +/- 21% vs. 26 +/- 14%, P < 0.05). (3) A large inter-subject variation existed in both studies. (4) In 10 subjects who participated in both studies, omeprazole 40 mg showed a significantly higher percentage time for which pH > 4 in the daytime (69 +/- 18% vs. 51 +/- 15%, P=0.015) than omeprazole 20 mg. CONCLUSION: These pH data support the therapeutic equivalency of FDA approved doses of omeprazole and lansoprazole.     

Randomized, placebo-controlled comparison of famotidine 20 mg b.d. or 40 mg b.d. in patients with erosive oesophagitis

Methods: this US multicentre, randomized, double-blind, placebo-controlled, parallel group study determined the effects of two twice daily oral famotidine regimens on symptom relief and healing of erosive oesophagitis in patients with gastro-oesophageal reflux disease. Three hundred and eighteen patients were enrolled: 66 received placebo, 125 received famotidine 20 mg b.d., and 127 received famotidine 40 mg b.d. Patients maintained diaries of their symptoms. Endoscopy was performed at weeks 0 and 6, and again at week 12 if healing had not occurred. Results: healing at 6 and 12 weeks was (respectively) 48% (P < 0.01 vs. placebo) and 69% (P? 0.01 vs.placebo) for famotidine 40 mg b.d.; 32% and 54% (P? 0.01 vs. placebo) for famotidine 20 mg b.d., and 18% and 29% for placebo. At both 6 and 12 weeks the healing rates of famotidine 40 mg b.d. were significantly greater than placebo and famotidine 20 mg b.d. Compared to placebo, famotidine produced more frequent global symptom improvement and more rapid heartburn relief. There were no significant differences among treatment groups in the incidence of clinical or laboratory adverse events. Conclusions: famotidine 40 mg b.d. was a better regimen than famotidine 20 mg b.d. or placebo. The clinical efficacy paralleled the previously documented effect of the famotidine regimens on decrease of oesophageal acid exposure.     

The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis

Background  The clinical safety of long-term lansoprazole therapy for the maintenance of healed erosive oesophagitis has not been extensively studied in clinical trials.
Aim  To assess the long-term clinical safety of dose-titrated lansoprazole as maintenance therapy for up to 82 months in subjects with healed erosive oesophagitis.
Methods  Clinical safety was assessed by monitoring adverse events (AEs), laboratory data including serum gastrin levels, and endoscopy.
Results  Mean duration (± s.d.) of lansoprazole treatment during the titrated open-label period was 56 ± 24 months (range <1–82 months). Overall, 189 of 195 (97%) subjects experienced a total of 2825 treatment-emergent AEs. Most AEs occurred during the first year of treatment, were mild-to-moderate in severity and resolved while on treatment. Of 155 serious AEs (in 74 subjects), only two (colitis and rectal haemorrhage in one subject) were considered treatment-related. Sixty-nine of 195 subjects (35%) experienced 187 treatment-related AEs, with diarrhoea (10%), headache (8%) and abdominal pain (6%) being the most common. Gastrin levels ≥400 pg/mL were seen in 9% of subjects; hypergastrinemia was not associated with gastro-intestinal AEs or nodules/polyps.
Conclusions  Lansoprazole maintenance therapy for up to 6 years is safe and well tolerated in subjects with healed erosive oesophagitis.     

Daily treatment with esomeprazole is superior to that taken on-demand for maintenance of healed erosive oesophagitis

BACKGROUND: On-demand therapy with esomeprazole is effective for long-term treatment of non-erosive gastro-oesophageal reflux disease, but it has not been evaluated in erosive gastro-oesophageal reflux disease. AIMS: To compare endoscopic and symptomatic remission over a 6-month period when patients with healed erosive gastro-oesophageal reflux disease are treated with esomeprazole 20 mg, either once daily or on-demand. METHODS: Patients with verified erosive reflux oesophagitis of Los Angeles grades A-D were enrolled. Following 4-8 weeks treatment with esomeprazole 40 mg daily, those who were endoscopically healed and had symptom control during the last week were randomized to maintenance therapy for 6 months with esomeprazole 20 mg, taken either once daily or on-demand. RESULTS: Of 539 enrolled patients, 494 (91%) were healed at 8 weeks and 477 were randomized to maintenance therapy with esomeprazole 20 mg, 243 once daily and 234 on-demand. After once daily treatment, 81% of patients were still in remission at 6 months, compared with only 58% who took on-demand treatment (P < 0.0001). A difference in remission was found irrespective of baseline grade of oesophagitis, but it was more pronounced for the more severe grades. There was no difference in overall symptomatic remission between the two treatments, although heartburn was significantly more prevalent in the on-demand group. CONCLUSIONS: Once daily esomeprazole 20 mg was better than that taken on-demand for maintaining healed erosive oesophagitis, regardless of baseline Los Angeles grade.     

A comparison of lansoprazole and ranitidine in the treatment of erosive oesophagitis

Background: Lansoprazole is a new proton pump inhibitor which produces prolonged decrease of gastric acidity. The aim of this study was to compare lansoprazole to a standard dose of ranitidine in the treatment of patients with reflux oesophagitis. Methods: Two hundred and forty-seven patients with erosive oesophagitis were randomly assigned to 8 weeks of treatment with either 30 mg lansoprazole once daily or 150 mg ranitidine twice daily. Results: Two hundred and forty-two patients were included in the analysis. Lansoprazole (30 mg) daily, healed oesophagitis in 92.1% of patients after 8 weeks of treatment. This was significantly superior to 150 mg ranitidine b.d.s. which healed oesophagitis in 69.9% of patients (P < 0.001). Relief of reflux symptoms was superior with lansoprazole to that with ranitidine. Both lansoprazole and ranitidine were well tolerated with no serious drug-related adverse events noted. Conclusion: Lansoprazole, 30 mg once daily, is highly effective and safe in the short-term treatment of erosive oesophagitis.     

Safety and efficacy of long term esomeprazole therapy in patients with healed erosive oesophagitis.

OBJECTIVE: To evaluate the safety and tolerability of long term treatment with esomeprazole in patients with healed erosive oesophagitis, and to describe its efficacy in the maintenance of healing. DESIGN AND SETTING: US multicentre, noncomparative, nonblind study. PATIENTS AND PARTICIPANTS: 807 patients with endoscopically confirmed healed erosive oesophagitis. METHODS: Patients received esomeprazole 40 mg once daily for up to 12 months. Adverse events and clinical laboratory tests were assessed over the study period. Endoscopy was performed at the final visit of the antecedent healing trials and at months 6 and 12 of the current safety trial; gastric biopsies were obtained at the initial visit of the healing trials and at the end of the safety trial. RESULTS: 80.9% of patients completed 6 months of treatment; 76.6% completed 12 months of treatment. There were no serious drug-related adverse events. Diarrhoea, abdominal pain, flatulence, and headache were the only treatment-related adverse events reported by >3% of patients. Mean changes in laboratory measures were generally small and not clinically meaningful. Plasma gastrin levels increased, as expected, and reached a plateau after 3 months. No changes in gastric histological scores were noted in the majority of patients. Evaluation of gastric biopsies revealed an overall decline in chronic inflammation and atrophy. Intestinal metaplasia findings remained essentially unchanged. Life table estimates of maintenance of healing were 93.7% [95% confidence interval (CI) 92.0 to 95.5%] at 6 months and 89.4% (95% CI 87.0 to 91.7%) at 12 months. CONCLUSIONS: Daily treatment with esomeprazole 40 mg for up to 1 year in patients with healed erosive oesophagitis was generally well tolerated and effective. No safety concerns arose.     

Lansoprazole 15 and 30 mg daily in maintaining healing and symptom relief in patients with reflux oesophagitis

Background: In patients with reflux oesophagitis, endoscopic healing and symptom relief are considered important treatment goals in long-term care.
Aim: To compare the effect of lansoprazole 15 and 30 mg daily on maintaining endoscopic healing and symptom relief in patients with moderate reflux oesophagitis.
Patients and methods: In a single-centre, double-blind randomized clinical trial, 103 patients with grade 1 or 2 reflux oesophagitis who were endoscopically healed and asymptomatic after lansoprazole 30 mg daily for 12 weeks, were randomized to maintenance therapy with either lansoprazole 15 mg or 30 mg o.m. Endoscopy was repeated after 3, 6 and 12 months, and symptom relief assessed after 3, 6, 9 and 12 months. Relapse of oesophagitis or symptoms were considered end-points.
Results: After 12 months, 14/50 patients (28%) receiving lansoprazole 15 mg daily had suffered an endoscopic relapse compared to 8/53 patients (15%) treated with lansoprazole 30 mg daily. A life table analysis showed no statistically significant difference between the two groups ( P =0.086). Significantly more patients were kept in complete symptomatic remission in the 30 mg group ( P <0.01). In the 15 mg group, 23/50 (46%) had suffered either an endoscopic or symptomatic relapse on completion of the study, compared to 12/53 (23%) in the 30 mg group. A life table analysis showed this difference to be statistically significant ( P =0.010). Lansoprazole 15 and 30 mg daily were equally well tolerated.
Conclusion: No statistically significant differences were found in endoscopic relapse rate or occurrence of adverse events, while lansoprazole 30 mg proved superior to 15 mg in maintaining patients in symptomatic relief and combined endoscopic and symptomatic remission.