Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression.

BACKGROUND: Little is known regarding patient characteristics that influence the speed of reflux oesophagitis (RO) healing. AIM: To investigate patient characteristics that may influence RO healing rates. METHODS: A post hoc analysis of clinical trial data for potent acid suppression treatment of RO (esomeprazole or AZD0865) was conducted. Group A underwent endoscopy at baseline, week 2 and 4, and group B at baseline, week 4 and 8. Group A patients were sub-grouped as 'rapid' (healed at 2 weeks) or unhealed at 2 weeks. Group B patients were sub-grouped as 'slow' (healed at 8 weeks, not at 4 weeks) or 'refractory' (not healed at 8 weeks). Logistic regression analysis was performed only for comparisons within group A. RESULTS: At 2, 4 and 8 weeks, RO had healed in 68%, 65% and 61% of patients unhealed at previous endoscopy, respectively. Low-grade [vs. high-grade (C or D)] RO was the only independent predictor of rapid healing in group A after logistic regression analysis. Significantly more rapid healers had low grade RO (A or B) at baseline than patients with refractory RO (84% vs. 49%; P < 0.001), and significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63%; P = 0.039). CONCLUSIONS: Low- (vs. high-) grade RO determines the most rapid benefit from acid suppression. Roughly two-thirds of patients healed with each time increment of potent acid suppression therapy. This suggests that some unhealed patients may still heal with continued therapy and that truly refractory RO is rare. (ClinicalTrials.gov: NCT00206245).

Impact of persistent, frequent regurgitation on quality of life in heartburn responders treated with acid suppression: a multinational primary care study.

BACKGROUND: In gastro-oesophageal reflux disease (GERD), heartburn responds well to acid suppression, but regurgitation is a common cause of incomplete treatment response. AIM: To assess the prevalence and burden of persistent, frequent regurgitation in primary care patients with GERD treated with acid suppression. METHODS: We analysed observational data from 134 sites across six European countries in patients diagnosed with GERD. Within 3 months of the index visit, symptoms were assessed using the Reflux Disease Questionnaire, and their impact on sleep and work productivity with the Quality of Life in Reflux and Dyspepsia questionnaire and the Work Productivity and Activity Impairment Questionnaire, respectively. Patients provided information on concomitant over-the-counter (OTC) GERD medication use. RESULTS: Persistent, frequent (3-7 days/week) regurgitation was reported by 13.2% (153/1156) of GERD patients with no heartburn on acid suppression; the prevalence was very similar for patients with up to 2 days/week of ongoing mild heartburn. Among patients without heartburn, sleep disturbance of any type was reported by 50.7-60.1% with persistent, frequent regurgitation, compared with 38.1-51.1% and 14.4-19.2% of those with less frequent or no regurgitation respectively. Persistent, frequent regurgitation was associated with increased use of OTC medication and more hours of work missed, whether mild, infrequent heartburn was present or not. CONCLUSIONS: Frequent regurgitation, which persisted in 12-13% of patients with no or infrequent, mild heartburn on acid suppression, negatively affected sleep and work productivity, and increased use of OTC medication. Persistent, frequent regurgitation is problematic for primary care patients with GERD.

Review article: current treatment options and management of functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD), a common functional gastrointestinal disorder, is defined by the Rome III criteria as symptoms of epigastric pain or discomfort (prevalence in FD of 89-90%), postprandial fullness (75-88%), and early satiety (50-82%) within the last 3 months with symptom onset at least 6 months earlier. Patients cannot have any evidence of structural disease to explain symptoms and predominant symptoms of gastroesophageal reflux are exclusionary. Symptoms of FD are non-specific and the pathophysiology is diverse, which explains in part why a universally effective treatment for FD remains elusive. AIM: To present current management options for the treatment of FD (therapeutic gain/response rate noted when available). RESULTS: The utility of Helicobacter pylori eradication for the treatment of FD is modest (6-14% therapeutic gain), while the therapeutic efficacy of proton pump inhibitors (PPI) (7-10% therapeutic gain), histamine-type-2-receptor antagonists (8-35% therapeutic gain), prokinetic agents (18-45%), tricyclic antidepressants (TCA) (response rates of 64-70%), serotonin reuptake inhibitors (no better than placebo) is limited and hampered by inadequate data. This review discusses dietary interventions and analyses studies involving complementary and alternative medications, and psychological therapies. CONCLUSIONS: A reasonable treatment approach based on current evidence is to initiate therapy with a daily PPI in H. pylori-negative FD patients. If symptoms persist, a therapeutic trial with a tricyclic antidepressant may be initiated. If symptoms continue, the clinician can possibly initiate therapy with an anti-nociceptive agent, a prokinetic agent, or some form of complementary and alternative medications, although evidence from prospective studies to support this approach is limited.

Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis - maintenance of healing and symptom relief.

BACKGROUND: Dexlansoprazole MR, a modified-release formulation of dexlansoprazole, an enantiomer of lansoprazole, effectively heals erosive oesophagitis. AIM: To assess dexlansoprazole MR in maintaining healed erosive oesophagitis. METHODS: Patients (n = 451) with erosive oesophagitis healed in either of two dexlansoprazole MR healing trials randomly received dexlansoprazole MR 60 or 90 mg or placebo once daily in this double-blind trial. The percentage of patients who maintained healing at month 6 was analysed using life table and crude rate methods. Secondary endpoints were percentages of nights and of 24-h days without heartburn based on daily diaries. RESULTS: Dexlansoprazole MR 60 and 90 mg were superior to placebo for maintaining healing (P < 0.0025). Maintenance rates were 87% and 82% for the 60 and 90 mg doses, respectively, vs. 26% for placebo (life table), and 66% and 65% vs. 14%, respectively (crude rate). Both doses were superior to placebo for the percentage of 24-h heartburn-free days (60 mg, 96%; 90 mg, 94%; placebo, 19%) and nights (98%, 97%, and 50%, respectively). Diarrhoea, flatulence, gastritis (symptoms) and abdominal pain occurred more frequently with dexlansoprazole MR than placebo, but were not dose-related. CONCLUSION: Dexlansoprazole MR effectively maintained healed erosive oesophagitis and symptom relief compared with placebo, and was well tolerated.

Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis.

BACKGROUND: Dexlansoprazole MR heals all grades of erosive oesophagitis (EO). AIM: To assess efficacy and safety of dexlansoprazole MR in maintaining healed EO and heartburn relief. METHODS: In this randomized, double-blind trial, 445 patients with healed EO received dexlansoprazole MR 30 mg or 60 mg or placebo once daily for 6 months. This trial assessed maintenance of endoscopic healing (primary endpoint) and continued symptom relief based on daily diaries (secondary endpoints). RESULTS: Dexlansoprazole MR 30 mg and 60 mg were superior to placebo for maintaining healed EO (P < 0.0025; Hochberg's). By life-table analysis, maintenance rates were 75%, 83% and 27% for dexlansoprazole MR 30 mg, 60 mg and placebo respectively. Crude maintenance rates were 66% for both dexlansoprazole MR doses and 14% for placebo. Dexlansoprazole MR controlled heartburn (medians of 91-96% for 24-h heartburn-free days, 96-99% for heartburn-free nights). The only more common adverse event occurring at a significantly higher rate in dexlansoprazole MR groups than placebo when analysed per patient-months of exposure was upper respiratory tract infection. CONCLUSIONS: Dexlansoprazole MR effectively maintained EO healing and symptom relief; most patients were heartburn-free for >90% of days. Both doses were well tolerated.

Adherence to best practice guidelines in dyspepsia: a survey comparing dyspepsia experts, community gastroenterologists and primary-care providers.

BACKGROUND: Although 'best practice' guidelines for dyspepsia management have been disseminated, it remains unclear whether providers adhere to these guidelines. AIM: To compare adherence to 'best practice' guidelines among dyspepsia experts, community gastroenterologists and primary-care providers (PCPs). METHODS: We administered a vignette survey to elicit knowledge and beliefs about dyspepsia including a set of 16 best practices, to three groups: (i) dyspepsia experts; (ii) community gastroenterologists and (iii) PCPs. RESULTS: The expert, community gastroenterologist and PCP groups endorsed 75%, 73% and 57% of best practices respectively. Gastroenterologists were more likely to adhere with guidelines than PCPs (P < 0.0001). PCPs were more likely to define dyspepsia incorrectly, overuse radiographic testing, delay endoscopy, treat empirically for Helciobacter pylori without confirmatory testing and avoid first-line proton pump inhibitors (PPIs). PCPs had more concerns about adverse events with PPIs [e.g. osteoporosis (P = 0.04), community-acquired pneumonia (P = 0.01)] and higher level of concern predicted lower guideline adherence (P = 0.04). CONCLUSIONS: Gastroenterologists are more likely than PCPs to comply with best practices in dyspepsia, although compliance remains incomplete in both groups. PCPs harbour more concerns regarding long-term PPI use and these concerns may affect therapeutic decision making. This suggests that best practices have not been uniformly adopted and persistent guideline-practice disconnects should be addressed.

Changing perceptions and practices regarding aspirin, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs among US primary care providers.

BACKGROUND: Our understanding of the benefits and risks of aspirin non steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) selective NSAIDs and gastro-protective agents (GPAs) continues to expand. AIM: To assess the perceptions and practices of US primary care physicians (PCPs) regarding the use of aspirin, NSAIDs, COX-2 selective NSAIDs and GPA. METHODS: A 34-question survey was administered to 1000 US PCPs via the internet. Questions addressed issues involving aspirin, NSAIDs, COX-2 selective NSAIDs, and GPAs. Around 491 of 1000 PCPs had participated in a similar survey conducted in 2003. RESULTS: Eighty-five per cent of PCPs reported that >25% of their patients were taking aspirin for preventive reasons. Nineteen per cent performed a risk calculation when deciding whether to start aspirin for cardioprotection. Fifty-four per cent recommended a proton pump inhibitor (PPI) for a patient with a recently healed ulcer who required ongoing aspirin. Thirty-one per cent reported prescribing NSAIDs more often and 52% were more likely to recommend a GPA with an NSAID than in 2003. Although PCPs were less likely to recommend a COX-2 selective NSAID compared to 2003, only 41% felt that rofecoxib increased cardiovascular risk. One-third felt that celecoxib and traditional NSAIDs were associated with increased cardiac risk. CONCLUSION: This survey identified several areas of ongoing confusion regarding aspirin, NSAIDs, COX-2 selective NSAIDs and GPAs, which should help direct future educational efforts regarding the benefits, risks and appropriate use of these agents.

Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of proton pump inhibitors (PPIs) in the prevention and treatment of acute upper gastrointestinal (UGI) haemorrhage, as well as to compare this with H2-receptor antagonist (H2RA), Helicobacter pylori eradication (in infected patients) or no therapy, for the prevention of first and/or subsequent bleeds among patients who continue to use non-steroidal anti-inflammatory drugs (NSAIDs). Also to evaluate the clinical effectiveness of PPI therapy, compared with other treatments, for the prevention of subsequent bleeds in patients who had previously experienced peptic ulcer (PU) bleeding. DATA SOURCES: Electronic databases and major conference proceedings were searched up to February 2006. REVIEW METHODS: Data were collected from the systematic reviews addressing each research objective. These were then entered into an economic model to compare the costs and quality-adjusted life-days of alternative management strategies over a 28-day period for patients who have had UGI bleeding. A Markov model with a Monte Carlo simulation used data from the systematic reviews to identify the most cost-effective treatment strategy for the prevention of UGI bleeding (first and subsequent) among NSAID users using an outcome of costs per quality-adjusted life-years (QALYs) over a lifetime from age 50 years. RESULTS: PPI treatment initiated after endoscopic diagnosis of PU bleeding significantly reduced re-bleeding and surgery compared with placebo or H2RA. Although there was no evidence of an overall effect of PPI treatment on all-cause mortality, PPIs significantly reduced mortality in subgroups when studies conducted in Asia were examined in isolation or when the analysis was confined to patients with high-risk endoscopic findings. PPI treatment initiated prior to endoscopy in UGI bleeding significantly reduced the proportion of patients with stigmata of recent haemorrhage (SRH) at index endoscopy compared with placebo or H2RA, but there was no evidence that PPI treatment affected clinically important outcomes. Giving oral PPI both before and after endoscopy, with endoscopic haemostatic therapy (EHT) for those with major SRH, is preferred to all others on cost-effectiveness grounds at any threshold over 25,000 pounds per QALY, even if only short-term effects are taken into account, and at any threshold over 200 pounds per life-year gained if long-term effects are included. The risk of NSAID-induced endoscopic gastric and duodenal ulcers was reduced by standard doses of PPI and misoprostol, and double doses of H2RAs. Standard doses of H2RAs reduced the risk of endoscopic duodenal ulcers. PPIs reduced NSAID-induced dyspepsia. PPIs were superior to misoprostol in preventing recurrence of NSAID-induced endoscopic duodenal ulcers, but PPIs were comparable to misoprostol in preventing the recurrence of NSAID-induced endoscopic gastric ulcers. Full-dose misoprostol reduced bleeding, perforation or gastric outlet obstruction due to NSAID-induced ulcers, but misoprostol was poorly tolerated and associated with frequent adverse effects. H. pylori eradication treatment was equally effective with PPI treatment for the primary or secondary prevention of endoscopic ulcers in NSAID users. H. pylori eradication treatment was more effective than placebo for the primary prevention of endoscopic PU and for the prevention of re-bleeding from PU in NSAID users. With regard to primary and secondary prevention of bleeding PU in NSAID users, the two most cost-effective strategies are H. pylori eradication alone, and H. pylori eradication followed by misoprostol (substituted by a PPI, if misoprostol is not tolerated) at an additional 4810 pounds per QALY. In patients who had previously experienced a bleed from a PU, re-bleeding was less frequent after H. pylori eradication therapy than after non-eradication antisecretory therapy, whether or not the latter was combined with long-term maintenance antisecretory therapy. CONCLUSIONS: PPI treatment compared with placebo or H2RA reduces mortality following PU bleeding among patients with high-risk endoscopic findings, and reduces re-bleeding rates and surgical intervention. PPI treatment initiated prior to endoscopy in UGI bleeding significantly reduces the proportion of patients with SRH at index endoscopy but does not reduce mortality, re-bleeding or the need for surgery. The strategy of giving oral PPI before and after endoscopy, with EHT for those with major SRH, is likely to be the most cost-effective. Treatment of H. pylori infection was found to be more effective than antisecretory therapy in preventing recurrent bleeding from PU. H. pylori eradication alone or eradication followed by misoprostol (with switch to PPI, if misoprostol is not tolerated) are the two most cost-effective strategies for preventing bleeding ulcers among H. pylori-infected NSAID users, although the data cannot exclude PPIs also being cost-effective. Further large randomised controlled trials are needed to address areas such as PPI administration prior to endoscopic diagnosis, different doses and administration of PPIs, as well as the primary and secondary prevention of UGI bleeding.

Programme of stepping down from twice daily proton pump inhibitor therapy for symptomatic gastro-oesophageal reflux disease associated with a formulary change at a VA medical center.

BACKGROUND: In July 2001, our Veterans' Affairs hospital changed its formulary proton pump inhibitor (PPI) from lansoprazole to rabeprazole. All patients previously receiving lansoprazole 30 mg twice daily were switched to rabeprazole 20 mg once daily. AIM: To determine if patients with gastro-oesophageal reflux disease (GERD), who were previously managed on lansoprazole 30 mg twice daily, could be maintained on rabeprazole 20 mg once daily. PATIENTS AND METHODS: Four hundred and thirty-five patients had received lansoprazole 30 mg twice daily for at least 12 months before the formulary change. Medical records were reviewed for 12 months before and after the formulary change. RESULTS: There were 432 men and three women with a mean age of 66.7 years (range: 38-91). Two hundred and twelve patients were excluded. Of the remaining 223, 111 (50%) were maintained successfully on rabeprazole 20 mg once daily. Twenty-three (10%) stayed off all acid suppression during follow-up. The number of endoscopies and clinic visits did not significantly change during the follow-up. Fifty-six percent who had erosive oesophagitis failed a dose taper compared with 31% of those with endoscopy-negative GERD (P<0.025). CONCLUSIONS: Most patients receiving twice daily PPI therapy for GERD could be maintained on once daily PPI or no acid suppression for 12 months of follow-up. Dose reduction was more successful in those without erosive oesophagitis.

Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.

BACKGROUND: There is conflicting evidence regarding the clinical efficacy of proton pump inhibitors (PPI) initiated prior to endoscopy in patients with upper gastrointestinal bleeding. OBJECTIVES: We aimed to systematically review evidence from randomised controlled trials (RCTs) that studied PPI treatment initiated before endoscopy in patients with upper gastrointestinal bleeding. SEARCH STRATEGY: A search was undertaken according to the Cochrane Upper Gastrointestinal and Pancreatic Diseases model using CENTRAL, (The Cochrane Library), MEDLINE, EMBASE and CINAHL databases and major conference proceedings up to September 2005. The literature search was re-run in February 2006. SELECTION CRITERIA: Types of studies: Randomised controlled trials (RCTs). TYPES OF PARTICIPANTS: Hospitalised patients with unselected upper gastrointestinal bleeding. Types of interventions: Active treatment with a PPI (oral or intravenous) and control treatment with either placebo or an histamine-(2) receptor antagonist (H(2)RA). Types of outcome measures: Assessed at 30 days: mortality, rebleeding and surgery. Also assessed were stigmata of recent haemorrhage at index endoscopy, length of hospital stay and blood transfusion requirements. DATA COLLECTION AND ANALYSIS: At least two reviewers assessed the eligibility criteria of each study and extracted data regarding outcomes and factors affecting methodological quality. MAIN RESULTS: Five RCTs were included for review. No further RCTS were identified in an updated literature search. Four trials comprising a total of 1512 patients in total reported data for all randomised patients. There was no statistical heterogeneity among trials for the outcomes of mortality, rebleeding and surgery. There were no statistically significant differences in rates of mortality, rebleeding or surgery between PPI and control treatment. Pooled mortality rates were 6.1% and 5.5% respectively (odds ratio (OR)1.12; 95% CI 0.72 to 1.73). Pooled rebleeding rates were 13.9% and 16.6% respectively (OR 0.81; 95%CI 0.61 to 1.09). Pooled rates for surgery were 9.9% and 10.2% respectively (OR 0.96 95% CI 0.68 to 1.35). PPI treatment compared to control significantly reduced the proportion of patients with stigmata of recent haemorrhage at index endoscopy; pooled rates were 37.2% and 46.5% respectively (OR 0.67; 95% CI 0.54 to 0.84). For the continuous outcomes, namely length of hospital stay and blood transfusion requirements, quantitative analysis could not be performed. AUTHORS' CONCLUSIONS: PPI treatment initiated prior to endoscopy in patients with upper gastrointestinal bleeding significantly reduces the proportion of patients with stigmata of recent haemorrhage at index endoscopy. However, there is no evidence that PPI treatment affects clinically important outcomes, namely mortality, rebleeding or need for surgery.

Review article: the clinical pharmacology of proton pump inhibitors.

Proton pump inhibitors inhibit the gastric H+/K+-ATPase via covalent binding to cysteine residues of the proton pump. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell. The relative ease with which these steps occur with different proton pump inhibitors underlies differences in their rates of activation, which in turn influence the location of covalent binding and the stability of inhibition. Slow activation is associated with binding to a cysteine residue involved in proton transport that is located deep in the membrane. However, this is inaccessible to the endogenous reducing agents responsible for restoring H+/K+-ATPase activity, favouring a longer duration of gastric acid inhibition. Pantoprazole and tenatoprazole, a novel proton pump inhibitor which has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, are activated more slowly than other proton pump inhibitors but their inhibition is resistant to reversal. In addition, tenatoprazole has a greatly extended plasma half-life in comparison with all other proton pump inhibitors. The chemical and pharmacological characteristics of tenatoprazole give it theoretical advantages over benzimidazole-based proton pump inhibitors that should translate into improved acid control, particularly during the night.

Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h.

BACKGROUND: Attainment of intragastric pH < 6.0 may require high-dose continuously infused proton pump therapy. AIM: To assess the pharmacokinetic and pharmacodynamic dose-responses of continuous infusion regimens of lansoprazole. METHODS: Healthy adult subjects were assigned to lansoprazole 60-mg intravenous bolus, followed by 6-mg/h continuous infusion; a 90-mg intravenous bolus followed by 6-, 7.5-, or 9-mg/h continuous infusion; or placebo. RESULTS: Mean intragastric pH values for lansoprazole regimens ranged from 4.8 to 5.2 (0-24 h), 5.5 to 6.0 (>24 to 48 h) and 5.2 to 5.6 (0-48 h). Within these three intervals, the percentages of time intragastric pH exceeded 4, 5 and 6 ranged from 65% to 96%, 54% to 88% and 30% to 61% respectively. Pharmacokinetic parameters were dose-independent with steady-state plasma concentrations achieved within 6-12 h postdose and maintained over 48 h. The mean systemic clearance of lansoprazole was lower in CYP2C19 heterozygous metabolizers than in homozygous extensive metabolizers (9.2 vs. 16.5 L/h), with substantial variability resulting in overlapping ranges of clearance values for both subpopulations. All lansoprazole regimens were well-tolerated. CONCLUSIONS: Lansoprazole administered as a 60-mg intravenous bolus followed by 6-mg/h continuous infusion produced intragastric pH effects comparable with those of higher dosage regimens.