Rabeprazole is a new proton pump inhibitor with more potent acid suppressive and anti-Helicobacter effects.
Rabeprazole is a new proton pump inhibitor with more potent acid suppressive and anti-Helicobacter effects.
To compare two different regimens of rabeprazole-based triple therapy vs. 7-day omeprazole-based triple therapy for the eradication of Helicobacter pylori infection.
Patients with proven H. pylori infection were randomized to receive: (i) 7-day rabeprazole, 10 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily; (ii) 3-day rabeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily; or (iii) 7-day omeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, all twice daily. Endoscopy (CLO test, histology) was performed before randomization and 6 weeks after drug treatment.
One hundred and seventy-three patients were randomized. H. pylori eradication rates (intention-to-treat, n=173/per protocol, n=167) were 88%/91% for 7-day rabeprazole-based therapy, 72%/72% for 3-day rabeprazole-based therapy and 82%/89% for 7-day omeprazole-based therapy, respectively. The per protocol eradication rate was significantly better in the 7-day rabeprazole-based therapy and 7-day omeprazole-based therapy groups when compared to the 3-day rabeprazole-based therapy group (P=0.01 and P=0.04, respectively). Compliance was excellent and all three regimens were well tolerated.
The efficacy of seven-day rabeprazole-based triple therapy is similar to 7-day omeprazole-based triple therapy for the eradication of H. pylori infection.
In the Asia-Pacific consensus conference on the management of Helicobacter pylori infection, the recommended regimens included the use of a proton pump inhibitor at a standard dose, plus two antibiotics (clarithromycin, amoxicillin or metronidazole), each given twice daily for 7 days. This regimen should attain a per protocol eradication rate of at least 90%, or an intention-to-treat eradication rate of at least 80%.1 The high eradication rates of these combinations have been confirmed in Western countries.2, 3 In the MACH 1 study, the regimen using omeprazole plus amoxicillin, 1000 mg, and clarithromycin, 500 mg (OAC), all given twice daily, was one of the most effective regimens, with an intention-to-treat eradication rate of 91%.2 The high efficacy of this low-dose clarithromycin regimen was confirmed by the MACH 2 study, which showed an intention-to-treat eradication rate of 94% in a cohort with 27% metronidazole resistance.3 Furthermore, the eradication rate of the OAC group was unaffected by metronidazole resistance, making it the therapy of choice for the treatment of H. pylori infection in areas with high prevalence of metronidazole resistance, such as Hong Kong.4
Rabeprazole is a newly developed benzimidazole proton pump inhibitor, which is a more potent inhibitor of H+,K+-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole and pantoprazole.5, 6In vitro studies have demonstrated that it has a more potent antibacterial activity against H. pylori when compared with either omeprazole or lansoprazole.7, 8 One-week rabeprazole-based triple therapy has been shown to be highly efficacious for the treatment of H. pylori infection with an intention-to-treat eradication rate of 86–95%.9–13 Few data are available on the direct comparison of the efficacy of rabeprazole–amoxicillin–clarithromycin (RAC) triple therapy with OAC triple therapy in regions with high prevalence of metronidazole resistance. As rabeprazole is a potent and fast-acting proton pump inhibitor, there exists a theoretical possibility of shortening the duration of therapy to 3 days with a comparable eradication rate to that of the 7-day regimen.
The aims of this study were: (i) to perform a head-to-head comparison of 7-day OAC triple therapy with two different regimens of RAC triple therapy (3-day and 7-day) for the eradication of H. pylori infection in an area with a high prevalence of metronidazole resistance; and (ii) to determine the side-effect profiles of the three regimens.
Consecutive patients referred to the endoscopy units of the Department of Medicine, Queen Mary Hospital, Department of Medicine, Tuen Mun Hospital and Department of Surgery, Kwong Wah Hospital for the investigation of dyspepsia were assessed for recruitment. Dyspepsia was defined as persistent or recurrent upper abdominal pain or discomfort over the preceding 3-month period in accordance with the Rome criteria of dyspepsia. Informed written consent was obtained from all patients participating in the study. Inclusion criteria included all patients between 18 and 80 years of age, with proven H. pylori infection. Exclusion criteria included patients who had severe concomitant illness, active gastrointestinal bleeding or histology-proven gastric cancer, patients who had been taking aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, H2-receptor blockers, bismuth or proton pump inhibitors in the preceding 4 weeks, and patients with a history of H. pylori eradication or previous gastric surgery. The study was approved by the local ethics committees.
During the first endoscopy, two antral biopsies and one corpus biopsy were taken. One antral biopsy was used for CLO test and the rest were sent for histological examination of H. pylori status by haematoxylin and eosin stains and Giemsa stain if necessary. Additional ulcer site biopsies from four quadrants were obtained from all gastric ulcer patients. Specimens were read by experienced pathologists who were blind to all clinical information, including the CLO test results. The definition of H. pylori infection in this study required both tests to be positive. Equivocal cases were excluded from the study. This approach has been validated previously in our centre with an accuracy of 100%, and less than 0.3% of cases cannot be diagnosed by this approach.14
The patients were randomized to receive one of the following treatments: 7-day RAC (rabeprazole, 10 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, each given twice daily for 7 days); 3-day RAC (rabeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, each given twice daily for 3 days); 7-day OAC (omeprazole, 20 mg, amoxicillin, 1000 mg, and clarithromycin, 500 mg, each given twice daily for 7 days). Randomization was performed by drawing a sealed envelope that contained a preassigned randomized treatment generated by computer on entry to the study. All gastric ulcer patients received an additional 4-week course of famotidine, 20 mg twice daily. Other patients were given antacids whenever necessary. The patients were given a diary in which they recorded the side-effects and symptoms during therapy. Endoscopy (CLO test, histology) was repeated 6 weeks after initiation of drug treatment. At all follow-up endoscopies, the endoscopists were blind to the treatment type and any clinical information related to the patients. Successful eradication was indicated if urease test and histological examination were negative.
Symptoms of daytime epigastric pain, nocturnal abdominal pain, bloating or postprandial fullness, belching, acid reflux and heartburn were assessed. All symptoms were rated as absent, mild (transient and easily tolerated), moderate (discomfort and disrupted normal activities) or severe (incapacitating symptoms with an inability to perform daily activities). The clinical response of each subject was assessed at the follow-up visit. A pre-treatment symptom was considered to be resolved if the severity changed from mild, moderate or severe to absent. A symptom was considered to be improved if it changed from severe to moderate or mild, or moderate to mild. A symptom was considered to be unresolved if it stayed the same or worsened. If all symptoms were resolved, the patient was classified as ‘cured’. Symptom ‘improvement’ was assigned when some pre-treatment symptoms were improved, whilst ‘failure’ was assigned when there was no improvement. The condition was indeterminate if the patient was asymptomatic before treatment or if the patients were not assessed.
The statistics used included chi-squared test, Fisher’s exact test and Student’s t-test, and Mann–Whitney U-test (non-parametric) for data with a skewed distribution. A P value of 0.05 or less was considered to be statistically significant. The intention-to-treat analysis included all patients who had taken at least one drug tablet. In the per protocol analysis, patients with poor drug compliance (< 75% intake of any study drug) and defaulters were excluded.
Fifty-eight patients were randomized to receive 7-day RAC, 58 to receive 3-day RAC and 57 to receive 7-day OAC triple therapy. Six patients were excluded from the per protocol analysis (one patient was non-compliant with the protocol and five patients refused or were lost to follow-up). The baseline characteristics of the patients and their respective diagnoses are listed in Table 1. The mean age of the patients was 49.4 years (range, 19–80 years). There were 83 males (mean age, 50.5 years) and 90 females (mean age, 48.4 years).
According to the intention-to-treat analysis at week six, H. pylori eradication was achieved in 51 patients (88%; 95% CI, 77–95%) in the 7-day RAC group, 42 patients (72%; 95% CI, 59–83%) in the 3-day RAC group and 47 patients (82%; 95% CI, 70–91%) in the 7-day OAC group. For per protocol analysis, H. pylori eradication was achieved in 91% (95% CI, 80–97%) of the 7-day RAC group, 72% (95% CI, 59–83%) of the 3-day RAC group and 89% (95% CI, 77–96%) of the 7-day OAC group. The per protocol eradication rate was significantly better in both the 7-day RAC and 7-day OAC groups when compared to the 3-day RAC group (P=0.01 and P=0.04, respectively). There was a trend for the intention-to-treat eradication rate to be higher in the 7-day RAC group when compared to the 3-day RAC group (P=0.06). The mean age of patients who failed H. pylori eradication was the same as that of patients with successful eradication (49.3 years vs. 49.3 years, P=0.99). Sex, smoking and drinking had no effect on the outcome of eradication. The healing rate of gastric and duodenal ulcers was similar between the three treatment groups (P=N.S. by intention-to-treat and per protocol analysis), although the numerical results were higher in the 7-day RAC and 7-day OAC groups. One patient with duodenal ulcer in the 3-day RAC group developed upper gastrointestinal bleeding 4 weeks after the first endoscopy. Therapeutic endoscopy with adrenaline (epinephrine) injection and heater probe application was required for the treatment of bleeding duodenal ulcer. H. pylori eradication failed in this patient. He had an uneventful recovery after a course of H2 antagonist.
The most common symptoms reported at the baseline visit were daytime epigastric pain (71%), bloating or postprandial fullness (67%), nocturnal abdominal pain (57%) and acid regurgitation (50%). There was no difference in the proportion of patients with cure, improvement or failure in the three treatment groups (Table 2).
Drug compliance was excellent. Ninety eight per cent of patients in the 7-day RAC group, 100% of patients in the 3-day RAC group and 96% of patients (two patients defaulted follow-up) in the 7-day OAC group completed the study medications. Intolerable side-effects were documented in one patient only in the 7-day RAC group, leading to early discontinuation of treatment. The most common side-effects included bitter taste, loose stool/diarrhoea, dizziness and malaise. There were no differences in the number of patients having side-effects between the three groups, but the mean duration of all side-effects was significantly shorter in the 3-day RAC group when compared to the 7-day RAC group (2.8 days vs. 6.0 days, P < 0.001) and the 7-day OAC group (2.8 days vs. 5.3 days, P < 0.001).
We have reported a randomized study with head-to-head comparison of 7-day and 3-day rabeprazole-based triple therapy regimen vs. standard 7-day omeprazole-based triple therapy using clarithromycin plus amoxicillin for the eradication of H. pylori infection in an area with a high prevalence of metronidazole resistance. The H. pylori eradication rates using intention-to-treat/per protocol analysis were 88%/91% in the 7-day RAC group, 72%/72% in the 3-day RAC group and 82%/89% in the 7-day OAC group. Several interesting points were noted in our study.
We have shown previously that metronidazole susceptibility is a significant factor for successful H. pylori eradication by omeprazole plus clarithromycin and metronidazole triple therapy and lansoprazole plus amoxicillin and metronidazole triple therapy in the local population which has a high prevalence of metronidazole resistance.4, 15, 16 Thus, a combination of omeprazole plus amoxicillin and high-dose clarithromycin, which avoided the use of metronidazole, was used in the current study. The efficacy of this combination was confirmed by a recent meta-analysis.17 The intention-to-treat eradication rate of the OAC regimen was 82%, which was inferior to that of the MACH 1 (91%) and MACH 2 (94%) studies, but comparable to that of the DU-MACH (78%),18 GU-MACH (79%)19 and a recent multicentre study from Asia and Africa.20 The inferior rate of the OAC regimen in this study may be related to the relatively high prevalence of clarithromycin resistance of 10.8% in the local population when compared to that of the population in the MACH 2 study, with a clarithromycin resistance rate of 3% only.21 Unfortunately, no culture of H. pylori was available in the current study.
In the earlier H. pylori eradication trials using rabeprazole, the dosage employed was 20 mg twice daily plus clarithromycin and amoxicillin for 7 days.9, 10 However, low-dose rabeprazole (10 mg twice daily) was found to be as effective as high-dose rabeprazole and the standard dose of omeprazole and lansoprazole for H. pylori eradication.11 Although low-dose clarithromycin was shown to be as effective as high-dose clarithromycin, we still prefer high-dose regimens as suggested by a recent meta-analysis.16 We found that the 7-day RAC regimen had a satisfactory H. pylori eradication rate of 88% (intention-to-treat), comparable with that of the 7-day OAC regimen (intention-to-treat, 83%) and correlated well with previous studies.9–13 A report from Germany studied the efficacy of 4 days of rabeprazole, 20 mg, amoxicillin, 1 g and clarithromycin, 500 mg, all given twice daily for the treatment of H. pylori-related peptic ulcer disease; the results were very promising with an eradication rate of 90%, but this study involved 20 patients only.22 We employed the same dosage as the German regimen but attempted to decrease the duration of therapy to 3 days. However, the results of the 3-day RAC regimen were less promising in our study (72%). We used standard doses of amoxicillin and clarithromycin and a higher dose of rabeprazole for the 3-day arm. However, the shorter duration of therapy cannot be compensated for by using a higher dose of rabeprazole. The reason for the less favourable response for the 3-day regimen may be the different antibiotic resistance rate as well as the genetic heterogeneity of H. pylori.23 Moreover, the failure of the clarithromycin-based regimen may lead to the development of secondary clarithromycin resistance. In a large multinational, multicentre, randomized clinical trial to assess the efficacy of proton pump inhibitor-based triple therapy for the treatment of H. pylori infection,3 secondary resistance to clarithromycin occurred in strains from 12 of 105 patients (11.4%) after the failure of a clarithromycin-based regimen.24 Others have reported a secondary clarithromycin resistance rate after OAC triple therapy for 1 week of around 23%.25 Although the duration of side-effects was significantly shorter and the compliance was 100% in the 3-day RAC group, the lower eradication rate is still a concern. Furthermore, one patient with duodenal ulcer in the 3-day group developed gastrointestinal bleeding requiring hospitalization. Thus, further studies need to be performed to confirm the utility of the 3-day (or short-term) RAC regimen. Isomoto et al. studied the efficacy of a 5-day rabeprazole triple therapy regimen for H. pylori eradication with essentially similar results, although the doses of amoxicillin and clarithromycin used were lower than those recommended by the Asia Pacific Consensus Conference.1, 13
The reported side-effects in all treatment arms were high in this study, but intolerable side-effects were documented in one patient only, leading to early discontinuation of treatment. We employed a direct question approach to enquire of patients about possible side-effects during or after treatment. The high reported prevalence of side-effects in this study was probably a consequence of this approach. In general, all three regimens were well tolerated with excellent compliance. The proportion of patients having side-effects was similar between all treatment groups, but the mean duration of all side-effects was significantly shorter in the 3-day RAC group when compared to the 7-day RAC group and the 7-day OAC group, indicating better tolerability of the 3-day regimen. This is in agreement with a previous study showing a significantly shorter duration of side-effects in patients receiving 3-day regimens than 7-day regimens.26 The most common adverse events were taste disturbance, which is a frequently reported occurrence with clarithromycin, followed by diarrhoea, dizziness and malaise.
In conclusion, 7-day RAC triple therapy had a similar efficacy to the standard omeprazole-based triple therapy for the eradication of H. pylori infection and was well tolerated and effective. The 3-day rabeprazole-based triple therapy had a lower H. pylori eradication rate than the 7-day regimen.
The authors would like to thank participating endoscopists Drs C. K. Lee, K. F. Chang, Grace S. W. Wong and S. F. Lau of the Department of Medicine, Tuen Mun Hospital, and Drs Maket W. C. Wong, J. Hui and T. W. Chow of the Department of Surgery, Kwong Wah Hospital. They would also like to thank the endoscopy nurses of the three participating centres for nursing assistance. This study was supported by an unrestricted grant from Eisai Hong Kong Ltd, the Simon K. Y. Lee Gastroenterology Research Fund and the Peptic Ulcer Research Fund, University of Hong Kong.
*Contributed equally to this work.