Healing and relapse rates in gastroesophageal reflux disease treated with the newer proton-pump inhibitors lansoprazole, rabeprazole, and pantoprazole compared with omeprazole, ranitidine, and placebo: evidence from randomized clinical trials

BACKGROUND: The older proton pump inhibitor (PPI) omeprazole and the newer PPIs lansoprazole, rabeprazole, and pantoprazole are approved for the acute and maintenance treatment of gastroesophageal reflux disease (GERD). OBJECTIVE: On the basis of the results of randomized clinical trials, this study sought to estimate healing and relapse rates in acute and maintenance treatment of GERD with the newer PPIs compared with omeprazole, the histamine2-receptor antagonist ranitidine (the most frequent non-PPI comparator in studies of PPIs), and placebo. METHODS: A search of MEDLINE was conducted to identify randomized, controlled clinical trials that included a PPI in > or =1 treatment arm and assessed the healing of erosive esophagitis endoscopically. The primary outcome for studies of acute therapy was healing rate, and the primary outcome for studies of maintenance therapy was relapse rate. RESULTS: Fifty-three studies were identified, of which 38 involved acute therapy (12 excluded) and 15 maintenance therapy. None of the studies of pantoprazole met the inclusion criteria for maintenance therapy. The 8-week overall healing rate ratios in the comparison of newer PPIs with omeprazole 20 mg/d were as follows: lansoprazole 30 mg/d, 1.02 (95% CI, 0.98-1.06): rabeprazole 20 mg/d, 0.93 (95% CI, 0.87-1.00); and pantoprazole 40 mg/d, 0.98 (95% CI, 0.90-1.07). In the comparison of any PPI with ranitidine 300 mg/d, the ratios were as follows: lansoprazole, 1.62 (95% CI, 1.46-1.76); rabeprazole, 1.36 (95% CI, 1.20-1.54); pantoprazole, 1.60 (95% CI, 1.33-1.96); and omeprazole, 1.58 (95% CI, 1.41-1.78). Relapse rates over 1 year of treatment were similar between lansoprazole and rabeprazole. Compared with ranitidine, there were statistically significant differences in the rates of resolution of heartburn symptoms (P < 0.002), ulcer healing (P < 0.05), and relapse (P < 0.01). Similar results were seen in the comparison of PPIs with placebo in terms of rates of resolution of heartburn symptoms (P < 0.01), ulcer healing (P < 0.001), and relapse (P < 0.006). CONCLUSIONS: In this study, the newer PPIs were of similar efficacy to omeprazole in terms of heartburn control, healing rates, and relapse rates. All the PPIs were superior to ranitidine and placebo in healing erosive esophagitis and decreasing relapse rates.     

Combination drug therapy for gastroesophageal reflux disease

OBJECTIVE: To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD). DATA SOURCES: Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug. DATA SYNTHESIS: Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.     

Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious complications such as haemorrhage or perforation. NSAID-induced gastrointestinal toxicity is a significant medical problem worldwide. Misoprostol is effective in reducing NSAID-induced mucosal damage, but patient compliance is limited by poor tolerance. Histamine receptor antagonists are relatively effective against duodenal ulcers but offer no significant protection against gastric ulcers. Proton pump inhibitors (PPIs), such as pantoprazole, omeprazole and lansoprazole, have been shown to be effective in preventing the development of gastric and duodenal ulcers in high-risk patients taking NSAIDs. PPI therapy is also beneficial in healing NSAID-induced ulcers and preventing their recurrence in patients requiring ongoing NSAID therapy. PPIs have an excellent safety profile, and pantoprazole--with its low potential for drug-drug interactions--is particularly suitable for administration to elderly patients who often require concomitant treatment with other medications.     

An overview of proton pump inhibitors.

SUMMARY: Proton pump inhibitors are the standard of treatment for acid-related disorders. These disorders include gastroesophageal reflux disease and its complications (i.e., erosive esophagitis and Barrett's esophagus), peptic ulcer disease, Zollinger-Ellison syndrome, and idiopathic hypersecretion. Proton pump inhibitors are also successfully used for the treatment of Helicobacter pylori infection and upper gastrointestinal bleeding.There are currently five proton pump inhibitors approved by the Food and Drug Administration and available in the United States. These are omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), and esomeprazole (Nexium). This review discusses the history of proton pump inhibitors and compares and evaluates the pharmacology including mechanism of action, pharmacokinetics, pharmacodynamics, administration, dosage, and drug interactions. Information regarding therapeutic indications, clinical efficacy, short- and long-term side effects, and cost is also presented. A case presentation offers an analysis of the use of proton pump inhibitors in individualized patient care.     

Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H2 receptor antagonists, H2RAs) or inhibit gastric H+,K+-ATPase (e.g., proton pump inhibitors, PPIs). Of the 2 approaches, the inhibition of the final step in acid production by PPIs provides more effective relief of symptoms and healing. Despite the documented efficacy of the PPIs, therapeutic doses have a gradual onset of effect and do not provide complete symptom relief in all patients. There is scope for further improvements in acid suppressive therapy to maximize healing and offer more complete symptom relief. It is unlikely that cholecystokinin2 (CCK2, gastrin) receptor antagonists, a class in clinical trials, will be superior to H2RAs or PPIs. However, a new class of acid suppressant, the potassium-competitive acid blockers (P-CABs), is undergoing clinical trials in GERD and other acid-related diseases. These drugs block gastric H+,K+-ATPase by reversible and K+-competitive ionic binding. After oral doses, P-CABs rapidly achieve high plasma concentrations and have linear, dose-dependent pharmacokinetics. The pharmacodynamic properties reflect the pharmacokinetics of this group (i.e., the effect on acid secretion is correlated with plasma concentrations). These agents dose dependently inhibit gastric acid secretion with a fast onset of action and have similar effects after single and repeated doses (i.e., full effect from the first dose). Animal studies comparing P-CABs with PPIs suggest some important pharmacodynamic differences (e.g., faster and better control of 24-hr intragastric acidity). Studies in humans comparing PPIs with P-CABs will help to define the place of this new class in the management of acid-related diseases.     

泮托拉唑与兰索拉唑治疗胃溃疡的药物经济学分析

目的评价泮托拉唑与兰索拉唑治疗胃溃疡的药物经济学效果。方法选取本院2010年7月—2012年7月消化内科收治的胃溃疡患者83例,采用随机数字表法分为观察组(n=43)和对照组(n=40),分别给予泮托拉唑和兰索拉唑治疗。比较2组患者临床改善总有效率、不良反应发生率、总治疗费用、成本-效果等指标。结果观察组与对照组临床改善总有效率分别为93.03%和95.00%,不良反应发生率分别为27.91%和27.50%,2组患者临床改善总有效率及不良反应发生率比较差异均无统计学意义(P>0.05);观察组与对照组成本-效果指标分别为4.99和5.57;与观察组相比,对照组治疗成本更高。结论在胃溃疡治疗中,泮托拉唑方案的药物经济学价值高于兰索拉唑方案。     

Dyspepsia: challenges in diagnosis and selection of treatment

BACKGROUND: Despite considerable study, the pathophysiology of dyspepsia remains obscure. This and other factors have impeded development of precise and effective treatment strategies. OBJECTIVE: This paper provides a brief review of the clinical syndrome of dyspepsia and its pathophysiology, symptoms, diagnosis, and treatment. METHODS: To identify articles for inclusion in this review, a search of MEDLINE was conducted using the key word dyspepsia. Because the literature on this topic is voluminous and duplicative, the search was limited primarily to literature from the last decade and to articles concerning dyspepsia in adults. RESULTS: The symptoms of dyspepsia, which may include epigastric pain, heartburn. bloating, and early satiety, defy diagnosis in as many as 50% of patients, even after endoscopy and other appropriate studies. In the other half of patients, such causative disorders as gastroesophageal reflux disease (GERD), peptic ulcer disease, cholecystitis, pancreatitis, and gastric cancer may be diagnosed. Despite controversy regarding the selection of therapy, empiric treatment is common for apparent idiopathic dyspepsia. Histamine2-receptor antagonists, proton pump inhibitors (PPIs), promotility agents, and coating agents have all been used as empiric therapy for dyspeptic symptoms. With empiric treatment, subsequent management is directed by the therapeutic response. In the absence of a definitive diagnosis, treatment is usually selected on the basis of the type and severity of symptoms, a thorough history and physical examination, and factors such as age and the presence of Helicobacter pylori infection. Five PPIs are currently available--lansoprazole, omeprazole, rabeprazole, pantoprazole, and esomeprazole--all with established efficacy in GERD and other acid-mediated disorders. The PPIs can be expected to be useful in certain patients with dyspepsia, and may be prescribed for patients who are found to re- spond to potent antisecretory therapy. Patients' concern about their symptoms, practical considerations, and restrictions imposed by managed care organizations may all affect the choice between empiric therapy and early endoscopy in patients with dyspepsia. CONCLUSIONS: Despite the variety of therapeutic options available for the symptoms of dyspepsia, the many presentations of this condition and the uncertainty of the response to the currently available therapeutic options continue to pose a substantial clinical challenge.     

A review of the clinical and economic impact of using esomeprazole or lansoprazole for the treatment of erosive esophagitis

BACKGROUND: The use of proton pump inhibitors (PPIs) for the treatment of erosive esophagitis has had a major impact on the prescribing budgets of primary care organizations in the United Kingdom. Assessments of the clinical and economic effectiveness of PPIs would provide useful tools for decision-making. OBJECTIVE: The goal of this study was to review the available preclinical and clinical studies comparing esomeprazole with lansoprazole in the healing and maintenance of erosive esophagitis, and to compare the budgeting impact of the 2 strategies. Comparative tolerability was also reviewed. METHODS: MEDLINE (1966-September 2002) and EMBASE (1980-September 2002) were searched for abstracts and articles reporting comparative studies of esomeprazole and lansoprazole. The search terms used were gastroesophageal reflux disease, reflux esophagitis, and proton pump inhibitor; all comparisons of esomeprazole and lansoprazole at any dose were considered. The database search was supplemented based on the authors' familiarity with the literature. RESULTS: The comparative studies that were identified fell into 4 categories: (1) intragastric acid suppression studies; (2) randomized controlled trials in the healing of erosive esophagitis; (3) randomized controlled trials in the maintenance of erosive esophagitis; and (4) health economic analyses. Based on these studies, when healing doses (esomeprazole 40 mg once daily, lansoprazole 30 mg once daily) and low doses (20 and 15 mg once daily, respectively) were compared, esomeprazole was more efficacious than lansoprazole in suppressing acid in the intragastric compartment (both comparisons, P < 0.05). More patients with erosive esophagitis experienced healing at 4 and 8 weeks with esomeprazole 40 mg once daily than with lansoprazole 30 mg once daily (P < 0.001 at 4 and 8 weeks). At 6 months, remission was maintained in more patients receiving esomeprazole 20 mg once daily than in those receiving lansoprazole 15 mg once daily (P < 0.001). No significant differences in tolerability were noted in clinical trials that directly compared the 2 PPIs. When the cost-effectiveness of esomeprazole treatment was compared with that of lansoprazole treatment in the healing and maintenance of erosive esophagitis, the greater efficacy of esomeprazole translated into potential cost savings and better outcomes. CONCLUSION: The currently available comparative data for esomeprazole and lansoprazole indicate clinical and cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole.     

Influence of antisecretory treatment with proton pump inhibitors on serum pepsinogen I levels

It has been reported in literature that serum pepsinogen levels rise during omeprazole and lansoprazole administration. However, the influence of pantoprazole and esomeprazole on serum pepsinogens levels is still to be assessed. The aim of this study was to evaluate the influence of proton pump inhibitor (PPI) therapy on pepsinogen I (PGI) levels. PGI and gastrin (G17) levels (EIA; Biohit, Helsinki, Finland) in 126 consecutive patients (M 57; F 69, mean age 53, range 15-91), with upper gastrointestinal symptoms at baseline condition and after 2 months of PPI treatment, were evaluated. Patients underwent a therapy schedule based on: omeprazole 20 mg b.i.d. (20 patients), pantoprazole 40 mg b.i.d. (27 patients), esomeprazole 40 mg b.i.d. (29 patients), lansoprazole 30 mg b.i.d. (21 patients) and rabeprazole 20 mg b.i.d. (26 patients) for 2 months. A significant increase in serum PGI (sPGI) levels was found after a 2-month treatment for all five different PPIs: omeprazole, pantoprazole, esomeprazole, lansoprazole and rabeprazole (P < 0.05). The effect of rabeprazole on sPGI was less pronounced as compared with other PPIs, whereas esomeprazole achieved superior sPGI levels, with no overall statistically significant difference among the five groups (P > 0.05). However, a comparison within a single group of PPIs showed a statistical significance when the esomeprazole group was compared with the rabeprazole group (P = 0.007). sPGI levels are significantly influenced by antisecretory therapy, rising under PPI treatment. Moreover, a statistically significant difference in sPGI levels between the rabeprazole and esomeprazole groups has been demonstrated.     

A review of omeprazole use in the treatment of acid-related disorders in children

BACKGROUND: Acid peptic disease is a common problem, with a similar prevalence of gastroesophageal reflux disease (GERD) in adults and children. The presentation of GERD in infants and children varies from crying, irritability, or sleep disturbance to feeding difficulties, vomiting, or rumination. Helicobacter pylori (HP)-related diseases and gastric and duodenal ulcers are much more common in adults than in children, who are more likely to have gastritis or duodenitis. However, because HP infection is most likely acquired in childhood, treatment of children with endoscopically documented active HP disease may minimize the potential risk for peptic ulcer or gastric cancer in adulthood, although this is yet to be proved. OBJECTIVE: Omeprazole has been shown to be effective in the treatment of acid-related diseases. This paper reviews the literature on the use and administration of omeprazole for the treatment of GERD, peptic ulcer disease, HP infection, and other acid-related conditions in children. METHODS: Studies were identified through searches of MEDLINE and Science Citation Index for the period 1986 to November 2000, and from the reference lists of identified articles. The search terms used included omeprazole, proton pump inhibitor (PPI), children, pediatrics, routes of administration, GERD, HP infection, esophagitis, and administration. In addition, the manufacturer of omeprazole was asked for relevant unpublished information. RESULTS: Marketed and extemporaneous formulations of omeprazole have been administered to children aged 2 months to 18 years for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, HP infection, and related conditions at dosages of 5 to 80 mg/d (0.2-3.5 mg/kg/d) for periods ranging from 14 days to 36 months with a low incidence of adverse effects. The initial dose most consistently reported to heal esophagitis and provide relief of symptoms of GERD appears to be 1 mg/kg per day. CONCLUSIONS: In uncontrolled clinical trials and case reports to date, omeprazole has been effective and well tolerated for the acute and chronic treatment of esophageal and peptic ulcer disease in children, particularly those who had failed to respond to previous treatment with histamine2-receptor antagonists. Should future long-term, controlled clinical trials in children demonstrate safety and efficacy, this PPI is likely to find a place in the armamentarium of pediatric pharmacotherapy.     

消化性溃疡合并上消化道出血应用潘妥拉唑钠注射液治疗临床分析

目的探讨潘妥拉唑钠治疗消化性溃疡合并上消化道出血的临床效果。方法将收治的68例消化性溃疡合并上消化道出血患者,随机分为对照组和观察组。两组均给予常规补液、维持水电解质平衡、积极治疗原发病等综合治疗。对照组在综合治疗的基础上加用奥美拉唑治疗,观察组在综合治疗的基础上加用潘妥拉唑钠治疗。分析两组治疗效果及不良反应发生情况。结果观察组总有效率显著高于对照组,差异有统计学意义(P<0.05)。对照组与治疗组治疗前胃液pH值差异无统计学意义,对照组治疗前后胃液pH值差异有统计学意义(P<0.01)。观察组治疗前后胃液pH值差异有统计学意义(P<0.01)。观察组治疗后胃液pH值显著高于对照组,差异具有显著性(P<0.01)。结论使用潘托拉唑治疗消化性溃疡伴上消化道出血,止血效果优于奥美拉唑,不良反应少,使用方便,值得临床推广应用。     

Proton pump inhibitors in the treatment of peptic ulcers resistant to H2-receptor antagonists]

The aim of this study is to evaluate the therapeutic effect of proton pump inhibitors on peptic ulcers resistant to H2-receptor antagonists. Patients with ulcers resistant to at least 3 months treatment with standard or greater doses of H2-receptor antagonists were treated with 20 mg of omeprazole or 30 mg of lansoprazole, once daily, for 2 to 8 weeks. Endoscopy was performed every 2 weeks to confirm ulcer healing. Eleven of 28 (39%) gastric ulcers healed within 4 weeks and 20 (71%) within 8 weeks with omeprazole. Eight of 19 (42%) gastric ulcers healed within 4 weeks and 14 (74%) within 8 weeks with lansoprazole. All of the duodenal ulcer healed within 6 weeks with omeprazole or lansoprazole. No adverse effects were observed in this study. These results suggest that proton pump inhibitors are highly effective in the treatment of peptic ulcer resistant to H2-receptor antagonists.     

Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole

BACKGROUND AND OBJECTIVES: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD. METHODS: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients. RESULTS: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups. CONCLUSIONS: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.     

Double-blind controlled-clinical trials of lansoprazole in the treatment of peptic ulcer]

Two multicentre clinical trials of lansoprazole, a new proton pump inhibitor, were completed in patients with gastric and duodenal ulcer. Double-blind comparative studies with a beta-blocker, famotidine, in gastric ulcer (study 1) and in duodenal ulcer (study 2) were conducted. Study 1. A total of 316 cases of gastric ulcer, 158 for lansoprazole, 158 for famotidine were treated for eight weeks and the bollowing observed. Healing rates by endoscopic findings were 90% for lansoprazole and 72% for famotidine respectively, with a significant difference (p less than 0.01). Adverse events were observed in five cases in lansoprazole group, six cases in the famotidine group. Study 2. A total of 291 cases of duodenal ulcer, 148 for lansoprazole, 143 for famotidine, were treated for six weeks. Healing rates by endoscopic fendings were 92% for lansoprazole and 85% for famotidine respectively. Adverse effects were observed in 5.3% in the lansoprazole group, and 5.5% in the famotidine group.     

长期使用质子泵抑制剂对肠道菌群的影响

目的观察胃食管反流病和消化性溃疡患者长期使用质子泵抑制剂治疗后肠道菌群变化。方法选取胃食管反流病及消化性溃疡患者60例（观察组）,口服奥美拉唑,20mg,每日2次,疗程8周;选取健康志愿者20例（对照组）;利用实时荧光定量聚合酶链反应（PCR）检测观察组患者服药前、服药后4周、8周及对照组健康者清晨粪便中大肠杆菌、肠球菌属、双歧杆菌属及乳酸杆菌属数量,并对各目标菌群数量进行比较分析。结果与对照组相比,观察组患者服药前及服药后4周粪便中4种目标菌群无明显变化（P〉0.05）,服药后8周,粪便中大肠杆菌（4.81±0.77）lonN/g及肠球菌属（5.24±0.63）lonN/g仍无显著变化（P〉0.05）,但双歧杆菌属（8.82±0.91）lonN/g及乳酸杆菌属（6.99±0.69）lonN/g明显减少（P〈0.05）。结论长期服用质子泵抑制剂后可致肠道双歧杆菌属及乳酸杆菌属数量明显下降,使肠道生物屏障受损,增加了肠源性感染风险。     

Effects of pantoprazole 20 mg in mildgastroesophageal reflux disease: Once-daily treatment in the acute phase, and comparison of on-demand versus continuous treatment in the long term

Background:

Gastroesophageal reflux disease (GERD) is a chronic disorder,and although effective short-term treatment strategies are known, the rate of relapse within 1 year is as high as 90% despite successful acute treatment. Consequently, most patients with GERD require an effective long-term management strategy to achieve adequate symptom control and maintain mucosal healing.

Objective:

The present study was undertaken to compare the control ofGERD symptoms during long-term (24-week) treatment with pantoprazole 20 mg used on-demand or continuously in patients with mild GERD after complete relief of acute GERD symptoms.

Methods:

Patients with endoscopically confirmed Savary/Miller grade 0(normal mucosa) or I (patchy red lesions without white coating or with central white coating) GERD were enrolled in this multinational, multicenter study comprising 2 phases. In the first phase, which was open label, patients were treated with pantoprazole 20 mg QD for 4 weeks. The presence and intensity of the symptoms of heartburn, acid regurgitation, and pain on swallowing were assessed. In the second phase, which was an open-label, 24-week, randomized design, only patients completely free of GERD symptoms after acute treatment were included. During this phase, on-demand treatment with pantoprazole 20 mg was directly compared with continuous treatment. The rate of failure to control GERD symptoms after 24 weeks of treatment was estimated using the Kaplan-Meier method. Subsequently, the difference between treatments (on-demand minus continuous) and its 95% CI were calculated, and the on-demand treatment was tested for noninferiority using a predefined noninferiority margin of 20%. The mean daily symptom loads were compared between the treatment groups using the 1-sided Wilcoxon rank sum test on a 5% α level. The point estimate of the difference was determined using the Hodges-Lehman estimator and the 1-sided 95% CI according to Moses. The number of patients unwilling to continue due to insufficient control of heartburn, acid regurgitation, and pain on swallowing was analyzed using the Kaplan-Meier (time-to-event) analysis. Analysis was performed in the same manner as for the rate of failure to control GERD symptoms, but the 95% CI was interpreted for statistical superiority.

Results:

A total of 558 patients were enrolled in this study. At the end of theacute phase, 82.1% of patients in the per-protocol (PP) population and 79.1% in the intent-to-treat (ITT) population were relieved of all GERD symptoms, and subsequently entered the long-term phase. After 24 weeks of treatment, analysis of the failure rates revealed that on-demand treatment was noninferior to continuous treatment because the 95% CI was completely below 20% (ITT, 12.1% difference [95% CI, −∞ to 18.9%]; PP, 10.1% difference [95% CI, −∞ to 17.7%]). The higher perceived mean (SD) daily symptom load in the on-demand group (ITT, 1.26 [1.491 vs 0.82 [1.341) was balanced by the reduced tablet intake in that group (PP, 0.51 [0.31 ] vs 0.97 [0.11 ] tablets/d; P < 0.001). With respect to the rate of patients unwilling to continue treatment, no statistically significant difference was observed between the on-demand and continuous groups (ITT/PP, 0.95/1.13 vs 0.95/1.26).

Conclusions:

In this study of pantoprazole 20 mg tablets in patients withmild GERD, patients receiving on-demand treatment benefited despite their higher symptom load. The similar rates of unwillingness to continue treatment in both groups might suggest that patients were satisfied with the on-demand treatment strategy. On-demand treatment with pantoprazole 20 mg was found to be noninferior compared with continuous therapy with regard to symptom control. Both on-demand and continuous treatments were well tolerated.     

Proton pump inhibitor-induced hypomagnesemia complicated with serious cardiac arrhythmias

Introduction: Magnesium is the third most common intracellular ion after potassium and calcium and is an important element in the functions of the body, since it participates in more than 300 enzyme systems. It also, plays a significant role in the transport of calcium and potassium across the cell membranes and protects against cardiac arrhythmias and is useful for their treatment due to hypomagnesemia induced from the proton pump inhibitors (PPIs).

Areas covered: PPIs are used for the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD), but have been associated with hypomagnesemia with serious cardiac arrhythmias including torsades de pointes (TdP). To better understand the magnitude of this problem, a Medline search of the English language literature was conducted from 2010 to 2018 and 35 papers with pertinent information were selected.

Expert commentary: The review of these papers suggests that PPIs cause hypomagnesemia, which could be associated with serious cardiac arrhythmias including TdP. However, its incidence is not very common considering the millions of people taking PPIs, but the FDA has advised the physicians to be watchful about this serious adverse effect of PPIs and check the magnesium levels before initiation of PPI treatment.