Randomized controlled trial of effectiveness of lafutidine versus pantoprazole in uninvestigated dyspepsia

Abstract

Objectives:

Lafutidine is a new H₂-blocker in India claimed to be more potent and effective than existing H₂-blockers. Proton pump inhibitors (PPIs), by virtue of their mechanism of action, have greater efficacy than H₂-blockers in gastric acid suppression. However, clinical trials comparing H₂-blockers directly with PPIs are limited. We carried out a head-to-head comparison of the effectiveness of lafutidine versus the PPI pantoprazole in uninvestigated dyspepsia [CTRI/2013/12/004261].

Materials and Methods:

A prospective, open label, randomized, controlled trial was conducted in a tertiary care hospital. Ambulatory adult patients with dyspepsia, not yet subjected to endoscopy, were recruited if they had at least moderately severe symptoms, defined as a score of ≥ 4 on a 7-point Global Overall Symptom (GOS) Scale. Those with alarm features or significant comorbidity were excluded. Subjects received either once daily lafutidine 10 mg or pantoprazole 40 mg, orally, for 8 weeks. Reflux, dysmotility and pain scores were assessed by Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSGERD), and quality of life (QoL) by SF-8 scale. The latter had physical and mental components summarized by physical component summary score (PCS) and a mental component summary score (MCS).

Results:

Of 122 patients enrolled, data of 57 on lafutidine and 60 on pantoprazole were analyzed. At 4 weeks, proportion of subjects responding (GOS score ≤ 2) in the two arms (lafutidine 45.61% vs. pantoprazole 48.33%, P = 0.854) or showing symptom resolution (GOS score ≤ 1) (lafutidine 12.28% vs. pantoprazole 5.00%; P = 0.197) were comparable. Similarly at 8 weeks, both responder (lafutidine 52.63% vs. pantoprazole 56.67%; P = 0.712) and symptom resolution proportions (lafutidine 33.33% vs. pantoprazole 30%; P = 0.843) were comparable. Total score on mFSSGERD scale, as well as all its three component scores, and PCS and MCS scores on QoL SF-8 scale showed improvement but no statistically significant difference between the two arms. Tolerability of both drugs was excellent.

Conclusions:

Lafutidine is well-tolerated and there is no clinically worthwhile difference between the two drugs in the empirical treatment of uninvestigated dyspepsia.

Introduction

Dyspepsia is a common problem. The term refers to symptoms arising from the upper gastrointestinal tract and represents a symptom cluster rather than a diagnosis. The first influential definition was the 1988 Working Party classification[1] that stated that dyspepsia includes any symptom referable to the upper gastrointestinal tract; symptoms need to be present for at least 4 weeks and include upper abdominal pain or discomfort, heartburn, acid reflux, nausea and vomiting. It subdivided dyspepsia patients, on the basis of symptom patterns, into ‘ulcer-like’ (epigastric pain), ‘reflux-like’ (heartburn and acid regurgitation), ‘dysmotility-like’ (bloating and nausea) and ‘unclassifiable’ categories. In India, dyspepsia is more prevalent in metropolitan cities where it is reported by almost one-third of the population.[2] Uninvestigated dyspepsia describes patients matching the 1988 Working Party definition of dyspepsia who have not yet undergone endoscopic investigation.[3] Empirical therapy with antacids, antisecretory and prokinetic agents has long been the approach for most primary care physicians in the initial management of patients with uninvestigated dyspepsia.[4,5]

Lafutidine is the newest H₂ receptor antagonist to be introduced in India. It suppresses both daytime and nighttime acid secretion through reversible H₂ receptor antagonism and can provide effective symptom relief in gastroesophageal reflux disease at single daily doses.[6] It has additional mucoprotective effect that is independent of its acid antisecretory activity. A recent study has reported that improved mucosal host-defense via capsaicin-sensitive afferent nerves may contribute to the therapeutic action of lafutidine.[7] The protective effects may be the result of activation of capsaicin sensitive calcitonin gene related peptide (CGRP)[8,9] which produces nitric oxide (NO) in endothelial cells. NO participates in the regulation of gastric mucosal blood flow through vasodilatation in the gastric microvasculature.[10] CGRP released from afferent neurons in the gastric mucosa stimulates D cells in the antral and fundic glands and increases somatostatin secretion from D cells. Somatostatin inhibits gastric acid secretion, acting directly on somatostatin receptors on parietal cells and indirectly by decreasing gastrin from antral G cells.

Pantoprazole is a proton pump inhibitor (PPI) widely used in India. There are few published reports on head-to-head comparison between pantoprazole and H₂-receptor blockers in general and pantoprazole and lafutidine in particular. We therefore sought to compare the effectiveness of lafutidine versus pantoprazole in uninvestigated dyspepsia.

Materials and Methods

The study was designed as a single center, prospective, parallel group, open label, randomized controlled trial. It has been registered with Clinical Trials Registry India [CTRI/2013/12/004261].

After obtaining institutional ethics committee approval, patients of either sex, aged between 18–55 years, attending the outpatient clinic in General Medicine in a teaching Hospital in Kolkata with a complaint of dyspepsia were screened between June 2011–May 2012. Patients symptomatic for at least 1 month with moderate-to-severe symptoms (score ≥ 4 on the 7-point Global Overall Symptoms [GOS] scale) were included after obtaining written informed consent. Pregnant or lactating women, patients with alarm features (unintentional weight loss, recurrent vomiting, dysphagia, hemetemesis, melena, fever, jaundice, or anemia), history of any serious gastrointestinal disease (including peptic ulcers, malignancy, esophageal dysmotility, a previous endoscopic diagnosis of erosive gastroesophagitis or Barrett's esophagus), gastrointestinal surgery within 30 days, or history of angina pectoris, were excluded. Patients who showed laboratory test abnormalities [hemoglobin < 9.5 g/dL, total leukocyte count < 3000/μL, platelet count < 75000/μL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >120 IU/L, creatinine > 1.5 mg/dL] were also excluded. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs), H₂-receptor blockers, proton pump inhibitors, prokinetic agents, misoprostol, sucralfate or other ulcer healing agents within 15 days prior to enrollment (but not antacids), concomitant use of psychotropic drugs and history of alcohol or substance abuse were other exclusion criteria.

Subjects were randomized (simple balanced randomization by computer generated list) to two groups of 61 subjects each. One group received tablet lafutidine 10 mg (brand used LAFAXID-10, marketed by M/s Zuventus Pharmaceuticals, Mumbai) while the other received tablet pantoprazole 40 mg (brand used PAN-40, marketed by M/s Alkem Laboratories, Mumbai). Both drugs were administered as a single daily morning dose before breakfast for 8 weeks. Each subject underwent one follow-up study visit at 4 weeks following commencement of trial medication and the treatment concluded at 8 weeks.

The primary efficacy variable was GOS Scale score which is obtained by a validated 7-point Likert scale.[11] Subjects were asked to rate the overall severity of their dyspepsia symptoms during the previous one month on following 7 points: (1) no problem, (2) minimal problem (can be easily ignored without effort), (3) mild problem (can be ignored with effort), (4) moderate problem (cannot be ignored but does not influence daily activities), (5) moderately severe problem (cannot be ignored and occasionally limits daily activities), (6) severe problem (cannot be ignored and often limits concentration on daily activities) and (7) very severe problem (cannot be ignored, markedly limits daily activities and often requires rest). Subjects achieving overall severity score ≤ 2 in this scale were considered as responders and those achieving score of ≤ 1 were considered as having attained symptom resolution.

Secondary efficacy measures used were the Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSGERD)[12] and Quality of Life (QOL) as measured by short form-8 (SF-8) questionnaire scores.[13] The mFSSGERD scale provided total score (Q-T), reflux score (Q-R), dyspepsia score (Q-D) and pain score (Q-P). The SF-8 was divisible into a physical component summary score (PCS) and a mental component summary score (MCS). Variation between pre- and post-treatment scores were compared in both the groups.

Safety was evaluated at each visit by thorough history and clinical examination. Complaints of the patient as well as adverse events noted by the investigators were recorded as treatment emergent adverse events. In addition, routine blood counts and tests of hepatorenal function were done at baseline and at study end. Compliance with study medication was assessed by the traditional pill count method.

The sample size was calculated to detect a difference of 25% in the responder rate (assuming the rate to be 50% in the control arm and 75% in the test drug arm) with 80% power and 5% probability of type 1 error. This returned a requirement of 58 subjects per arm. Keeping a margin of 5% for dropouts, the recruitment target was set at 61 subjects per arm. The modified intention to treat approach was used during analysis; data of all patients presenting for at least one post-baseline visit were included. Numerical variables were compared between groups by Student's unpaired t-test, if normally distributed, and by Mann-Whitney U-test, if otherwise. Categorical variables, such as the proportion of responders and proportion attaining symptom resolution, were compared between groups by Fisher's exact test. Median mFSSGERD and QoL scores over time were assessed for statistically significant change by Friedman's analysis of variance (ANOVA) with Dunn's multiple comparison test as post hoc test. All analyses were two-tailed and P < 0.05 was considered statistically significant. Statistica version 6 [Tulsa, Oklahoma: StatSoft Inc., 2001] and GraphPad Prism version 4 [San Diego, California: GraphPad Software Inc., 2005] software were used for analysis.

Results

Of the 61 patients randomized to each of the two groups, 57 on lafutidine and 60 on pantoprazole were considered analyzable. Figure 1 shows the flow of patients during the study. As seen from Table 1, demography and baseline characteristics were comparable in the two groups.

Figure 1.

Flow of patients in the two study arms

Table 1.

Baseline demographic and clinical summary of the study subjects

At the end of both week 4 and week 8 after commencement of treatment [Figure 2], there was no statistically significant difference in the proportion of responders between the two treatment groups (week 4: lafutidine 45.61% vs. pantoprazole 48.33%, P = 0.854; week 8: lafutidine 52.63% vs. pantoprazole 56.67%; P = 0.712). The proportion of subjects showing symptom resolution [Figure 3] were also comparable at both week 4 (lafutidine 12.28% vs. pantoprazole 5.00%; P = 0.197) and week 8 (lafutidine 33.33% vs. pantoprazole 30%; P = 0.843).

Figure 2.

Responder rate at 4 weeks and 8 weeks after starting treatment (White bar = Lafutidine, Grey bar = Pantoprazole)

Figure 3.

Proportion showing symptom resolution at 4 weeks and 8 weeks (White bar = Lafutidine, Grey bar = Pantoprazole)

Patients in both the treatment groups showed significant reduction in symptom scores over 4 and 8 weeks in mFSSGERD scale (reflux symptoms, dysmotility symptoms and pain symptoms) and improvement in both physical and mental component subscores on the QoL SF-8 scale [Table 2 and Figure 4]. In both the arms, symptom relief on all components of the mFSSGERD scale were noted at 4 weeks. There was further reduction at 8 weeks, although the changes from fourth to eight week were mostly not significant statistically. Significant QoL improvement was also seen at 4 weeks and this was sustained at 8 weeks.

Table 2.

Response to treatment in the study groups over time

Figure 4.

Changes in Quality of Life Short Form 8 (SF-8) scores in the study groups (PCS = physical component summary; MCS = mental component summary). *** indicates P< 0.001 in comparison to corresponding pre-treatment score. (White box = Lafutidine, Grey box = Pantoprazole)

Only few adverse events were encountered during the study. Two patients in lafutidine arm complained of transient diarrhea and one in the pantoprazole arm complained of headache. All recorded adverse events were mild and settled spontaneously. Laboratory parameters (data not shown) did not show any statistically significant changes in either group. Hospitalizations or other serious adverse events were not encountered during the study. Adherence was excellent for over 90% subjects in both study arms, as assessed at the final visit.

Discussion

The pathophysiology of uninvestigated dyspepsia is complex and diverse group of diseases present with upper gastrointestinal complaints. The impact on QoL varies with a proportion of subjects showing marked deterioration. In this study we evaluated the overall dyspepsia problem over 8 weeks (by GOS scale) as well as different groups of symptoms (by mFSSGERD). The GOS scale is a validated outcome measure and has been used successfully in the Canadian Adult Dyspepsia Empiric Treatment (CADET) Clinical Trials Program. In the validation of the GOS study, it has been shown that a change in GOS from ≥ 4–≤2 is rated as clinically important by patients.[11] The mFSSGERD scale used in this study is also a validated scale and has been employed successfully to assess different symptom groups in earlier studies.[12] Further, both physical and mental dimensions of QoL were measured and compared between the groups using a standardized instrument.[13]

A meta-analysis evaluating the efficacy of H₂-receptor antagonist in non-ulcer functional dyspepsia has shown that H₂-blockers are superior to placebo.[14] PPIs are more potent inhibitors of gastric acid secretion than the H₂-receptor antagonists and give better results in acid-peptic disorders, including better patient satisfaction.[15,16] Most clinicians acknowledge the advantage of PPIs over H₂-receptor antagonists, because the former exert stronger and longer acid suppression than the latter.[17] Clinical trials comparing a PPI (e.g. omeprazole, lansoprazole) with a H₂-receptor antagonist (e.g. cimetidine, ranitidine) demonstrate superiority of PPI over the latter in dyspepsia. However, in the current study, the results suggest that lafutidine is as effective as pantoprazole in uninvestigated dyspepsia. Both appeared to alleviate all three groups of dyspeptic symptoms (viz. reflux symptoms, pain and dysmotility symptoms) over the 8 weeks treatment period and both drugs had excellent tolerance.

Although pantoprazole inhibits the final common pathway of acid secretion, lafutidine, the new H₂ receptor antagonist was comparable in effectiveness. This can possibly be explained by the potent and long-lasting action of lafutidine on the human histamine H₂ receptor and potential additional mechanisms of action of lafutidine.[8,18] Gastroprotective effect of Lafutidine is independent of its acid antisecretory activity. It activates capsaicin-sensitive afferent neurons and stimulates the release of CGRP which, in turn, inhibits acid secretion and stimulates mucosal blood flow.[9,10] In addition to gastroesophageal reflux disease, clinical trials have reported lafutidine to be effective in Helicobacter pylori eradication[19] and prevention of non-steroidal anti-inflammatory drug (NSAID) induced ulceration.[20] Our experience is in conformity with an earlier study which suggests that both lafutidine and rabeprazole provide symptom relief and are adequate empiric therapy in patients with heartburn-dominant uninvestigated dyspepsia.[21] In our case, the study cohort included patients with heartburn as well as other kinds of dyspeptic symptoms. We did not encounter any published reports of head-to-head comparison of lafutidine and pantoprazole.

This study had its share of limitations. Blinding could not be achieved as we depended on commercially available products and failed to find brands with tablets closely matching. Dyspepsia of different symptom groups (that is predominant ‘ulcer-like’, ‘reflux-like’ and ‘dysmotility-like’) have not been compared in the this study. The observation period was limited to 8 weeks. Further, rebound dyspepsia after withdrawal of study drug was not assessed.

Notwithstanding these limitations, we can conclude that there is no clinically worthwhile difference between the two drugs in the empirical treatment of uninvestigated dyspepsia, at least in the relatively short term. Further studies are needed to assess comparative effectiveness in other kinds of acid-peptic disorders, such as peptic ulcer disease and NSAID gastropathy, as well as effects upon long-term treatment.