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- Materials and methods
Background : Several studies in Western countries showed that proton-pump inhibitors are superior to histamine2-receptor antagonists or placebo in the treatment of non-erosive gastro-oesophageal reflux disease. The efficacy of acid-suppressive drugs for non-erosive gastro-oesophageal reflux disease in Japan, in which the prevalence of Helicobacter pylori infection is higher compared with Western countries, is unknown.
Aim : To compare the efficacy of famotidine and omeprazole in Japanese patients with non-erosive gastro-oesophageal reflux disease by a prospective randomized multicentre trial.
Methods : A total of 98 patients received either famotidine 20 mg b.d. (n = 48) or omeprazole once daily (n = 50). Frequency of gastro-oesophageal reflux disease symptoms and health-related quality of life were evaluated at baseline and after 4 weeks of treatment. Complete relief was defined as no gastro-oesophageal reflux disease symptoms during the 7-day interval in week 4.
Results : Complete relief was achieved in 23 (48%) of patients receiving famotidine and 28 (56%) of patients treated with omeprazole. In the famotidine group, complete relief rate in H. pylori-negative patients was significantly lower than H. pylori-positive patients (35% vs. 64%). Both famotidine and omeprazole improved most scales of health-related quality of life. Omeprazole significantly improved reflux score irrespective of H. pylori infection while famotidine significantly improved reflux score in H. pylori-positive patients but not in H. pylori-negative patients.
Conclusions : Omeprazole is more effective than famotidine for the control of gastro-oesophageal reflux disease symptoms in H. pylori-negative patients, while similar efficacy is observed in H. pylori-positive patients with non-erosive gastro-oesophageal reflux disease.
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- Materials and methods
Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal (GI) disorder. Epidemiological studies in Western countries showed that the prevalence of GERD symptoms such as heartburn and acid regurgitation ranges from 10 to 48%.1 The prevalence of GERD in the Japanese population is low but not uncommon, accounting for approximately 6.6–9.8% of Japanese adults.2, 3 GERD includes erosive oesophagitis and non-erosive GERD. Only one-third to half of GERD patients have endoscopically positive findings such as erosions and ulcers, while others have no obvious mucosal breaks during endoscopic examination although GERD symptoms are present.4 Because the presence of GERD symptoms has a significant negative impact on health-related quality of life (QoL),5, 6 and patients reported more frequent interruptions during sleep, work and social events5 as well as worse emotional well-being than those with diabetes or hypertension,6 sufficient control of GERD symptoms is the goal of GERD treatment, in patients with especially non-erosive GERD.
Meta-analysis showed that proton-pump inhibitors (PPIs) are more effective than histamine2-receptor antagonists (H2RAs) in the healing of oesophageal mucosal injury and relieving GERD symptoms in patients with erosive oesophagitis.7 Several clinical studies8–15 demonstrated that PPIs are superior to H2RAs or placebo in controlling GERD symptoms in patients with non-erosive GERD. Because these studies were performed in Western countries where the prevalence of Helicobacter pylori infection is lower than in Japan,16 the efficacy of acid-suppressive drugs in Japanese patients with non-erosive GERD is unknown. In addition, as H. pylori infection is more common in Japanese patients with non-erosive GERD than those with erosive oesophagitis,17H. pylori infection might affect the outcome of non-erosive GERD treatment. The aim of the study was to examine and evaluate the effectiveness of a PPI (omeprazole) vs. an H2RA (famotidine) in Japanese patients with non-erosive GERD, by assessment of GERD symptoms and health-related QoL.
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- Materials and methods
A total of 106 patients with non-erosive GERD were randomized into famotidine (n = 53) and omeprazole (n = 53) groups. Five patients in the famotidine group and three patients in the omeprazole group did not visit after 4 weeks of treatment. Ultimately, we analysed 98 subjects (48, famotidine group; 50, omeprazole group). Table 1 shows baseline characteristics of the study subjects. There were no significant differences in age, gender, BMI, cigarette smokers, alcoholic beverage drinkers, frequency of GERD symptoms, endoscopic appearance, hiatal hernia, abnormal flap valve, H. pylori infection and QoL score (PCS and MCS) between famotidine and omeprazole groups. No serious adverse effects or complications were encountered during the treatment.
Table 1. Baseline characteristics of the study subjects
| ||Famotidine (N = 48)||Omeprazole (N = 50)||P-value|
|Age (years)||56.6 ± 15.5||55.0 ± 16.7||0.624|
|BMI (kg/m2)||22.2 ± 3.0||22.8 ± 4.2||0.408|
|Frequency of GERD symptoms (per week)||4.1 ± 2.2||4.3 ± 2.3||0.282|
|Endoscopic appearance (N/M)||28/20||30/20||0.867|
|Hiatal hernia (%)||22.9||28.0||0.564|
|Abnormal flap valve (%)||25.0||32.0||0.443|
|Helicobacter pylori infection (%)||45.8||44.0||0.855|
|Quality of life|
| SF-36 physical component summary score||49.7 ± 7.3||47.5 ± 12.1||0.380|
| SF-36 mental component summary score||43.1 ± 9.7||43.8 ± 11.5||0.855|
Efficacy of treatment
Table 2 summarizes the efficacy of treatments in this study. In the famotidine group, 23 patients showed CR, 13 PR and 12 NR, while 28 patients in the omeprazole group showed CR, 15 PR and seven NR. There were no differences in efficacy between famotidine and omeprazole groups (P = 0.385 by chi-square test). Omeprazole treatment had a higher CR rate (56.0%) compared with famotidine treatment (47.9%) but statistically no significant differences were observed (P = 0.423 by chi-square test). In H. pylori-positive patients, CR rate was similar between famotidine and omeprazole (63.6 and 59.1%) while famotidine had a lower CR rate compared with the omeprazole group in H. pylori-negative patients (34.5 and 53.6%, P = 0.069 by chi-square test). In the famotidine group, a significantly lower CR rate in H. pylori-negative patients than those in H. pylori-positive patients was observed (P = 0.045 by chi-square test). There was no significant difference in NR rate between famotidine and omeprazole groups (P = 0.552 by chi-square test).
Table 2. Efficacy of famotidine and omeprazole on control of GERD symptoms after 4 weeks of treatment
| ||N||Efficacy of treatment (%)|
| Helicobacter pylori-positive||22||14 (63.6)||3 (13.6)||5 (22.7)|
| H. pylori-negative||26||9 (34.5)||10 (38.5)||7 (26.9)|
| Total||48||23 (47.9)||13 (27.1)||12 (25.0)|
| H. pylori-positive||22||13 (59.1)||5 (22.7)||4 (18.2)|
| H. pylori-negative||28||15 (53.6)||10 (35.7)||3 (10.7)|
| Total||50||28 (56.0)||15 (30.0)||7 (14.0)|
Efficacy of treatment on GSRS scores
Baseline values and changes of GSRS scores between baseline and after 4 weeks of treatment are shown in Table 3. There were no significant differences in baseline GSRS scores including total and each dimensions between famotidine and omeprazole groups. Both famotidine and omeprazole significantly decreased GSRS scores in total dimensions and category for reflux, abdominal pain and indigestion. Famotidine also decreased in category score for diarrhoea and constipation. Figure 1 shows the mean change in GSRS score after 4 weeks of treatment. Changes in reflux score were highest among GSRS category, and there were no significant differences in total and each dimensions of GSRS between famotidine and omeprazole groups. Changes in GSRS reflux scores according to the H. pylori infection status is shown in Figure 2. Both famotidine and omeprazole significantly decreased GSRS reflux scores after 4 weeks of treatment, and this observation was found in H. pylori-positive patients. In H. pylori-negative patients, omeprazole significantly decreased reflux scores, however, no significant change was observed in the famotidine group.
Table 3. Baseline values of Gastrointestinal Symptom Rating Scale (GSRS) scores and changes between baseline and after 4 weeks of treatment
|GSRS||Baseline||Visit week 4||P-value|
Figure 1. Mean changes in Gastrointestinal Symptom Rating Scale (GSRS) scores after 4 weeks of treatment. Data are expressed as a mean with 95% confidence interval (CI). There were no significant differences in GSRS score changes including total score and all dimensions between famotidine and omeprazole.
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Figure 2. Efficacy of famotidine and omeprazole on Gastrointestinal Symptom Rating Scale (GSRS) reflux score according to Helicobacter pylori infection status. Omeprazole significantly improved reflux symptom score in both H. pylori-positive and -negative patients while famotidine significantly improved reflux symptom in H. pylori-positive patients, but not in H. pylori-negative patients. Data are expressed as a mean with 95% confidence interval (CI). *P < 0.01 by the Wilcoxon pairs matched single ranks test.
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Efficacy of treatment on SF-36 scores
There were no significant differences in each scale of SF-36 between famotidine and omeprazole groups at baseline. Both famotidine and omeprazole treatments significantly improved most SF-36 scales (Table 4). There were no significant differences in changes of each scale of SF-36 from baseline to visit week 4 between famotidine and omeprazole groups, irrespective of H. pylori infection status (data not shown). Figure 3 demonstrates deviation score of each SF-36 scale compared with each score among the general Japanese population. Scores of all scales before treatment were lower compared with the standard Japanese subjects, whose scores averaged as 50. Improvement of most of each SF-36 scale in both famotidine and omeprazole treatment was observed.
Table 4. Baseline and visit week 4 values of Short Form (SF)-36 scores
|SF-36||Baseline||Visit week 4||P-value*|
Figure 3. Changes in deviation scores of each Short Form (SF)-36 scales. Scores in all scales were lower in comparison with general Japanese subjects, which showed a score of 50. Both famotidine and omeprazole improved most SF-36 scales. Data are expressed as the mean score of each scale. Mean score and standard deviation of general Japanese is 50 and 10, respectively. PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health.
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- Materials and methods
The present study demonstrated that both famotidine and omeprazole were effective in relieving GERD symptoms in approximately half of patients with non-erosive GERD. CR rate in the omeprazole group was increased (56.0%) but not significantly when compared with the famotidine group (47.9%). Health-related QoL in patients with non-erosive GERD scored lower than the general Japanese adult population, and both treatments significantly improved most scales of health-related QoL as previous studies have reported.22, 23 Omeprazole significantly improved reflux symptoms by GSRS irrespective of H. pylori infection, while famotidine significantly improved reflux symptoms in H. pylori-positive patients, but not in H. pylori-negative patients, suggesting that H. pylori infection affects the efficacy of acid-suppressive drugs, especially H2RA, for non-erosive GERD in Japanese patients.
Several studies showed the significant efficacy of PPIs including omeprazole,8–10 lansoprazole11 and rabeprazole12 compared with placebo in non-erosive GERD. A recent review by Dean et al.24 demonstrated that therapeutic gain of PPI therapy over placebo ranged from 30 to 35% for sufficient heartburn control and from 25 to 30% for complete heartburn control in patients with non-erosive GERD; also, PPIs provide a more modest therapeutic gain in patients with non-erosive GERD when compared to those with erosive oesophagitis. As our study did not include a placebo group, exact therapeutic gain of treatment is unknown. Several studies concerning the efficacy of H2RA in non-erosive GERD have been reported. Bate et al.14 showed that omeprazole is superior to standard dosages of cimetidine for the relief of heartburn. Richter et al.15 showed that lansoprazole is more effective than ranitidine in relieving GERD symptoms. In the present study, the overall CR rate was similar for both treatment methods. Differences of the outcome of non-erosive GERD treatment between our study and previous ones may be due to differences in genetic factors as well as in the prevalence of H. pylori infection among Japanese and Western patients.
Prevalence of H. pylori infection in patients with GERD was significantly lower than those without GERD, with geographical variation being a strong contributor to the heterogeneity among studies.25 Patients with GERD from the Far East including Japan had a lower prevalence of H. pylori than patients from Western countries, despite a higher prevalence of H. pylori infection in the general population.25–28 However, our previous study showed that H. pylori infection is significantly more common in patients with non-erosive GERD compared with erosive oesophagitis among Japanese patients.17 In this study, about half of non-erosive GERD patients had H. pylori infection while the prevalence of H. pylori infection in the study by Richter et al.15 was reported to be about 20%. Higher prevalence of H. pylori infection in our study subjects might affect the present outcome, especially the overall CR rate, because famotidine was significantly more effective in the treatment of H. pylori-positive patients.
Interestingly, our study showed a significant difference in efficacy of treatment between H. pylori infection status. The exact reasons why H. pylori infection affects efficacy of treatment in non-erosive GERD are unknown. Several studies have shown associations between H. pylori infection and efficacy of GERD treatment but are controversial. Holtmann et al.29 demonstrated a slight but significantly better healing rate of erosive oesophagitis in H. pylori-positive than H. pylori-negative patients at 4 weeks of treatment with PPI. Hatlebakk et al.30 showed that GERD symptom control was achieved significantly more often in H. pylori-positive patients, but other studies showed no differences between H. pylori infection status and the effectiveness of rabeprazole31 or the dose of omeprazole needed for maintained relief of symptoms.32 In our study, omeprazole improved GERD symptoms irrespective of H. pylori, while famotidine improved GERD symptoms in H. pylori-positive patients but not in H. pylori-negative patients. Although omeprazole has been reported to increase gastric acidity in H. pylori-positive patients compared with H. pylori-negative patients.33 Recently, Fujisawa et al.34 reported that H. pylori infection has a decisive effect on occurrence of the tolerance phenomenon, defined as the attenuation of the H2RA antisecretary effect during continuous administration. They found that 2 weeks of famotidine treatment did not cause the tolerance phenomenon, and remarkably raised the daytime intragastric pH in H. pylori-positive patients.34 In addition, the CagA-positive strain, which is considered more pathogenic for atrophic gastritis,35 has been found mostly in Japanese patients,36 and severity of gastric atrophy is related to decrease in gastric acid secretion.37 Taken together, a lack of tolerance phenomenon and hyposecretion of gastric acid because of gastric atrophy from H. pylori infection may explain the higher efficacy of famotidine for non-erosive GERD in H. pylori-positive patients.
This study acknowledges some potential limitations. First, the number of study samples was relatively low. Sample size might affect the present results. Especially, higher but not significantly better efficacy of omeprazole compared with famotidine in overall CR rate might be due to the small number of study subjects. Secondly, we measured the frequency of GERD symptoms and health-related QoL at baseline and after 4 weeks of treatment to compare the efficacy of famotidine and omeprazole for non-erosive GERD and evaluate CR of GERD symptoms as a primary end-point. There is no gold standard to evaluate the outcome of treatment with non-erosive GERD at the present time. Review by Junghard et al.38 showed that patients with initially mild symptoms considered their treatment to be adequate if the frequency did not exceed once a week during the treatment. Satisfaction of non-erosive GERD treatment might be dependent on each patient. Furthermore, we did not include factors associated with the efficacy of acid-suppressive drugs, especially omeprazole. Future studies should include these factors, such as CYP2C19 gene polymorphism. Finally, recent studies suggest that patients with non-erosive GERD are a heterogeneous group with different aetiologies for their heartburn:39, 40 however, definite diagnosis criteria of each subtype of non-erosive GERD have not yet been established. Further studies are necessary to examine the efficacy of treatment in each subgroup of non-erosive GERD patients.
In conclusion, the present multicentre prospective randomized study shows that both omeprazole and famotidine significantly improved QoL scores in patients with non-erosive GERD. Omeprazole is more effective than famotidine for control of GERD symptoms in H. pylori-negative patients, while similar efficacy between famotidine and omeprazole is observed in H. pylori-positive patients with non-erosive GERD. However, acid-suppressive drugs are effective in only half of the patients with non-erosive GERD. Other treatments or combined therapy should be considered for non-erosive GERD patients for whom acid-suppressive drugs are ineffective.