Henrik Ahlbom

Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors

OBJECTIVES:Proton pump inhibitors reduce ulcer recurrence in non-steroidal anti-inflammatory drug (NSAID) users, but their impact in at-risk ulcer-free patients using the current spectrum of prescribed agents has not been clearly defined. We assessed esomeprazole for ulcer prevention in at-risk patients (≥60 yr and/or ulcer history) taking NSAIDs, including COX-2 inhibitors. Such studies are particularly relevant, given that concerns regarding adverse cardiovascular outcomes among COX-2 inhibitor users may prompt re-evaluation of their use.METHODS:We conducted two similar double-blind, placebo-controlled, randomized, multicenter studies; VENUS (United States) and PLUTO (multinational). A total of 844 and 585 patients requiring daily NSAIDs, including COX-2 inhibitors were randomized to receive esomeprazole (20 or 40 mg) or placebo, daily for 6 months.RESULTS:In the VENUS study, the life table estimated proportion of patients who developed ulcers over 6 months (primary variable, intent-to-treat population) was 20.4% on placebo, 5.3% on esomeprazole 20 mg (p < 0.001), and 4.7% on esomeprazole 40 mg (p < 0.0001). In the PLUTO study, the values were 12.3% on placebo, 5.2% with esomeprazole 20 mg (p= 0.018), and 4.4% with esomeprazole 40 mg (p= 0.007). Significant reductions were observed for users of both non-selective NSAIDs and COX-2 inhibitors. Pooled ulcer rates for patients using COX-2 inhibitors (n = 400) were 16.5% on placebo, 0.9% on esomeprazole 20 mg (p < 0.001) and 4.1% on esomeprazole 40 mg (p= 0.002). Esomeprazole was well tolerated and associated with better symptom control than placebo.CONCLUSIONS:For at-risk patients, esomeprazole was effective in preventing ulcers in long-term users of NSAIDs, including COX-2 inhibitors.

Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized Trial

BACKGROUND Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because discrepant results have been reported in different ethnic groups. OBJECTIVE To determine whether intravenous esomeprazole prevents recurrent peptic ulcer bleeding better than placebo in a multiethnic patient sample. DESIGN Randomized trial conducted between October 2005 and December 2007; patients, providers, and researchers were blinded to group assignment. SETTING 91 hospital emergency departments in 16 countries. PATIENTS Patients 18 years or older with peptic ulcer bleeding from a single gastric or duodenal ulcer showing high-risk stigmata. INTERVENTION Intravenous esomeprazole bolus, 80 mg, followed by 8-mg/h infusion, over 72 hours or matching placebo, each given after successful endoscopic hemostasis. Intervention was allocated by computer-generated randomization. After infusion, both groups received oral esomeprazole, 40 mg/d, for 27 days. MEASUREMENTS The primary end point was rate of clinically significant recurrent bleeding within 72 hours. Recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety were also assessed. RESULTS Of 767 patients randomly assigned, 764 provided data for an intention-to-treat analysis (375 esomeprazole recipients and 389 placebo recipients). Fewer patients receiving intravenous esomeprazole (22 of 375) had recurrent bleeding within 72 hours than those receiving placebo (40 of 389) (5.9% vs. 10.3%; difference, 4.4 percentage points [95% CI, 0.6% to 8.3%]; P = 0.026). The difference in bleeding recurrence remained significant at 7 days and 30 days (P = 0.010). Esomeprazole also reduced endoscopic re-treatment (6.4% vs. 11.6%; difference, 5.2 percentage points [95% CI of difference, 1.1 percentage points to 9.2 percentage points]; P = 0.012), surgery (2.7% vs. 5.4%), and all-cause mortality rates (0.8% vs. 2.1%) more than placebo, although differences for the latter 2 comparisons were not significant. About 10% and 40% of patients in both groups reported serious and nonserious adverse events, respectively. LIMITATION Endoscopic therapy was not completely standardized; some patients received epinephrine injection, thermal coagulation, or hemoclips alone, whereas others received combination therapy, but there were similar proportions with single therapy in each group. CONCLUSION High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days. PRIMARY FUNDING SOURCE AstraZeneca Research and Development.

Esomeprazole 40 mg i.v. provides faster and more effective intragastric acid control than pantoprazole 40 mg i.v.: results of a randomized study

Background : Oral esomeprazole 40 mg provides greater acid control than oral pantoprazole 40 mg.

Efficacy of esomeprazole for resolution of symptoms of heartburn and acid regurgitation in continuous users of non‐steroidal anti‐inflammatory drugs

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is often associated with upper gastrointestinal symptoms such as heartburn and acid regurgitation.

Intravenous esomeprazole (40 mg and 20 mg) inhibits gastric acid secretion as effectively as oral esomeprazole: results of two randomized clinical studies

Objectives Two studies compared the effects of intravenous (i.v.) and oral esomeprazole (40 mg and 20 mg) on gastric acid suppression and pharmacokinetics after both single (day 1) and repeated (day 5) dosing. Methods Two randomized, two-way, cross–over, comparative studies of similar design were performed in healthy male and female volunteers. In both studies, subjects received esomeprazole as a 30-min i.v. infusion or orally once-daily for 5 days, separated by a wash-out period of at least 13 days. In one study, which was double-blind (double dummy), subjects received 40 mg esomeprazole. In the other open study, subjects were given 20 mg esomeprazole. Results In total, 40 and 24 subjects were randomized for treatment with 40 mg and 20 mg esomeprazole, respectively. No significant differences were found between i.v or oral administration of esomeprazole with respect to the amount of time with mean intragastric pH>4 throughout day 1 or day 5 of treatment in the 40 mg study (day 1, 10.1 h and 8.8 h versus day 5, 15.9 h and 15.3 h, respectively) and the 20 mg study (day 1, 7.3 h and 6.6 h versus day 5, 11.9 h and 12.3 h, respectively). The area under the plasma concentration–time curve values were higher following i.v. relative to oral administration on day 1 of dosing, with less pronounced differences after repeated (day 5) dosing. Both administration routes were similarly well tolerated. Conclusions Esomeprazole, 40 mg and 20 mg i.v., provides similar levels of intragastric acid control on both day 1 and day 5 of treatment compared with oral administration.

Safety and tolerability of high-dose intravenous esomeprazole for prevention of peptic ulcer rebleeding

IntroductionEfficacy of a continuous high-dose intravenous infusion of esomeprazole, followed by an oral regimen after successful endoscopic therapy for peptic ulcer bleeding (PUB) was established in the PUB study (ClinicalTrials. gov identifier: NCT00251979). Mortality rates and detailed safety and tolerability results from this study are reported here.MethodsThis was a double-blind, randomized study in patients ≥18 years with overt signs of upper gastrointestinal bleeding, following endoscopic diagnosis of a single gastric or duodenal ulcer (≥5 mm) with stigmata indicating current/ recent bleeding (Forrest class Ia, Ib, IIa, or IIb). Postendoscopic hemostasis, patients received intravenous esomeprazole (80 mg/30 minutes, then 8 mg/hour for 71.5 hours) or placebo. Postinfusion, all patients received open-label oral esomeprazole 40 mg once daily for 27 days. Mortality rates were analyzed using Fisher’s exact test; other safety variables were analyzed descriptively.ResultsA total of 767 patients were randomized; 764 comprised the safety analysis set (375 patients received esomeprazole, 389 placebo). Baseline characteristics were similar across the two treatment groups. Three deaths from the esomeprazole treatment group and eight from the placebo group occurred during the trial (0.8% versus 2.1%; P=0.22). From these 11 all-cause deaths, one (esomeprazole group; rebleeding from duodenal ulcer) occurred during the 72-hour intravenous treatment phase. Adverse event (AE) frequency was similar for the two groups over the intravenous treatment phase (esomeprazole, 39.2%; placebo, 41.9%), with gastrointestinal disorders being most commonly reported (12.3% and 19.8%, respectively). Serious AEs were mostly related to bleeding events. Infusion-site reactions (mild, transient) were reported in 4.3% of esomeprazole-treated patients versus 0.5% of placebo patients. These did not lead to treatment discontinuation.ConclusionEsomeprazole, given as a continuous high-dose intravenous infusion followed by an oral regimen after successful endoscopic therapy for PUB, was well tolerated, with no apparent safety concerns from either the high-dose intravenous treatment or oral phases.

Intravenous Esomeprazole 40mg is Effective for the Control of Intragastric Acid Levels Whether Given as a 3-Minute Injection or a 30-Minute Infusion.

AbstractBackground: An intravenous (IV) formulation of esomeprazole has been developed as an alternative to oral administration. To meet the needs of different clinical situations it would be preferable if an IV dose could be administered as either an injection or an infusion, while producing similar effects. Aim: To compare the effects of IV esomeprazole 40mg given as a 3-minute injection or a 30-minute infusion on intragastric pH during single and repeated once-daily dosing in healthy subjects. Methods: In this single-centre, double-blind, double-dummy, randomised, two-way crossover study, subjects were randomised to receive either a 3-minute IV injection or a 30-minute IV infusion of esomeprazole 40mg. Both regimens were given once daily for 10 days. After a washout period of at least 13 days, subjects were crossed over to the other treatment. Intragastric pH monitoring was performed on days 1 and 10. Blood samples were also taken throughout days 1 and 10. Results: Data were available from 41 subjects. Time with intragastric pH >4 was 3.1h/24h at baseline, increasing to almost 8h in association with IV esomeprazole injection or infusion on day 1, and to >13h on day 10. Geometric mean time with pH >4/24h ratios (injection/infusion) were 0.99 on day 1 and 1.03 on day 10. Mean esomeprazole AUC values were approximately 15% higher with the injection than the infusion, but 90% CI limits for geometric mean AUC ratios ranged from 1.07 to 1.23, indicating bioequivalence. Conclusions: IV esomeprazole 40mg provides similarly potent acid control whether administered by injection or infusion.

Reassessment of Rebleeding Risk of Forrest IB (Oozing) Peptic Ulcer Bleeding in a Large International Randomized Trial

OBJECTIVES:Our aims were to assess risks of early rebleeding after successful endoscopic hemostasis for Forrest oozing (FIB) peptic ulcer bleeding (PUBs) compared with other stigmata of recent hemorrhage (SRH).METHODS:These were post hoc multivariable analyses of a large, international, double-blind study (NCT00251979) of patients randomized to high-dose intravenous (IV) esomeprazole (PPI) or placebo for 72 h. Rebleeding rates of patients with PUB SRH treated with either PPI or placebo after successful endoscopic hemostasis were also compared.RESULTS:For patients treated with placebo for 72 h after successful endoscopic hemostasis, rebleed rates by SRH were spurting arterial bleeding (FIA) 22.5%, adherent clot (FIIB) 17.6%, non-bleeding visible vessel (FIIA) 11.3%, and oozing bleeding (FIB) 4.9%. Compared with FIB patients, FIA, FIIB, and FIIA had significantly greater risks of rebleeding with odds ratios (95% CI’s) from 2.61 (1.05, 6.52) for FIIA to 6.66 (2.19, 20.26) for FIA. After hemostasis, PUB rebleeding rates for FIB patients at 72 h were similar with esomeprazole (5.4%) and placebo (4.9%), whereas rebleed rates for all other major SRH (FIA, FIIA, FIIB) were lower for PPI than placebo, but the treatment by SRH interaction test was not statistically significant.CONCLUSIONS:After successful endoscopic hemostasis, FIB patients had very low PUB rebleeding rates irrespective of PPI or placebo treatment. This implies that after successful endoscopic hemostasis the prognostic classification of FIB ulcers as a high-risk SRH and the recommendation to treat these with high-dose IV PPI’s should be re-evaluated.

225 Intravenous Esomeprazole for Prevention of Peptic Ulcer Re-Bleeding in a Predominantly Caucasian Population: Results On Clinical Benefits and Hospital Resource Use

and quantified CagA translocation by Western blot using anti-phosphotyrosine and antiCagA antibodies. Significantly higher levels of CagA were translocated by the 7.13 0310mutant compared to wild-type H. pylori strain 7.13. By utilizing proteomics technology to contrast two closely related H. pylori strains that induce distinct phenotypes, we have shown that HP0310 may function to alter levels of peptidoglycan, thereby affecting the composition of substrates translocated by the cag secretion system. These studies also provide an important foundation for investigating the role of bacterial virulence factors in H. pylori-induced pathologic sequelae, as such results would ultimately allow for generation of a profile of H. pylori proteins to use for screening persons infected with strains most likely to induce severe disease.