To determine whether a 5-day regimen with rabeprazole, clarithromycin and amoxicillin (RCA) was as effective as a 7-day regimen.
To determine whether a 5-day regimen with rabeprazole, clarithromycin and amoxicillin (RCA) was as effective as a 7-day regimen.
A total of 139 H. pylori-infected patients were randomized to receive either a 5-day or 7-day course of rabeprazole 10 mg b.d., clarithromycin 400 mg b.d. and amoxicillin 750 mg b.d. Eradication was assessed by CLO test, histology and 13C-urea breath test.
On the intention-to-treat basis, eradication rates were 66% (46 out of 70) and 84% (58 out of 69) for the 5- and 7-day regimens, respectively (P < 0.05). Using per protocol analysis, eradication rates were 70% (46 out of 66) and 91% (58 out of 64) for the 5- and 7-day regimens, respectively (P < 0.01). Adverse events, which were observed in 14 patients from each group, caused discontinuation of treatment in only two patients, resulting in excellent compliance.
Our 5-day regimen of RCA yielded inferior results, whereas the 7-day regimen achieved an eradication rate exceeding 90% on the per protocol basis. Therefore, treatment regimens of less than 7 days for proton pump inhibitor–clarithromycin–amoxicillin therapies cannot be recommended.
Helicobacter pylori causes type B chronic gastritis and plays a critical role in the pathogenesis of peptic ulceration.1, 2 Eradication of H. pylori infection facilitates ulcer healing and prevents recurrence.3–5 Currently, the treatment of choice for H. pylori infection is a 7-day course of proton pump inhibitor-based triple therapy, comprising a proton pump inhibitor and two antimicrobials, capable of curing the infection in over 90% of patients.6, 7
The accepted benchmark for duration of triple therapy is 7 days, but there is no theoretical reason why the duration of treatment could not be decreased.8 If a shorter regimen proved effective, it would result in reduced costs and improved patient acceptability and compliance. At present, the efficacy of proton pump inhibitor triple therapies for 5 days is still controversial, whereas a 3-day regimen appears to be too short.9–12
More recently, a new substituted proton pump inhibitor, rabeprazole, was demonstrated to yield similar or even higher eradication rates, when combined with two antibiotics from the choice of clarithromycin, amoxicillin or metronidazole.13–15 Moreover, this proton pump inhibitor drug is a more potent inhibitor of acid secretion than omeprazole, and has a faster onset of antisecretory action than omeprazole, lansoprazole or pantoprazole, in equivalent doses.16, 17In vitro studies have demonstrated that rabeprazole itself has antibacterial activity against H. pylori that is greater than the activity of either omeprazole or lansoprazole.17–19 These findings suggested that rabeprazole had potential advantages over the other available proton pump inhibitors in the shorter regimens for eradicating the infection.
In the Japanese population, 7-day low-dose triple therapy with clarithromycin plus amoxicillin in combination with rabeprazole 10 mg b.d., which is the standardized daily dosage in Japan, has proved as efficacious as incorporating lansoprazole at the officially recommended double dosage (60 mg per day).15 Therefore, we sought to investigate whether a 5-day course of low-dose triple therapy with clarithromycin plus amoxicillin in combination with rabeprazole (10 mg b.d.) would be as effective as a 7-day course.
The present study was designed as a prospective, open and randomized trial, which was performed between April 1998 and March 2000. The study was conducted according to Good Clinical Practice and the Declaration of Helsinki, and was approved by the local ethics committees. All patients gave written informed consent prior to their inclusion in the study.
The patient population comprised 142 consecutive H. pylori-infected out-patients. Exclusion criteria were: age < 18 years; pregnancy or lactation; severe concomitant disease; previous intake of medications effective against H. pylori such as bismuth compounds, proton pump inhibitors, or antibiotics during the last 3 months; alcoholic abuse; drug addiction; chronic corticosteroid or nonsteroidal anti-inflammatory drug use; and prior gastroduodenal surgery. Information on alcohol intake and smoking habits was obtained at entry into the study. Ex-smokers and social drinkers were considered as non-smokers and non-drinkers, respectively.
The presence of H. pylori was confirmed by serology (anti-H. pylori IgG antibody, HEL-p TEST, AMRAD Co., Melbourne, Australia), rapid urease test (CLO test, Delta West Co., Bentley, Australia) and histology (haematoxylin and eosin or Giemsa staining) using biopsy specimens obtained during endoscopy from the antrum, within 2 cm of the pyloric ring and corpus along the greater curvature. Patients were considered to be infected with H. pylori if at least two of these examinations yielded positive results. If all test results were negative, patients were classified as H. pylori-negative.
The enrolled patients were randomized by drawing a sealed envelope which contained pre-assigned treatment instructions, and were allocated to receive either a 5-day (5-day group) or 7-day course (7-day group) of rabeprazole at a standard dosage of 10 mg b.d., clarithromycin 400 mg b.d. and amoxicillin 750 mg b.d. If an active ulcer (defined as a circumscribed break in the mucosa measuring at least 5 mm in diameter with apparent depth and covered with an exudate) was found at baseline endoscopy, it was treated with a H2-receptor antagonist (famotidine 20 mg b.d.) for 4 weeks after the eradication therapy. In cases of peptic ulcer scar or non-ulcer dyspepsia, no other ulcer healing drugs were allowed throughout the study. Participants returned at the conclusion of therapy for interview regarding adverse events. Compliance with medication was checked immediately after stopping treatment by counting the returned pills. Four weeks after cessation of eradication therapy, repeat endoscopy was performed to assess H. pylori status by CLO test and histology, as before treatment. In 75 patients with peptic ulcer in the active phase, ulcer healing (defined as complete re-epithelialization) was also assessed at the time of endoscopy. Furthermore, we adapted the 13C-urea breath test for the evaluation of H. pylori cure 4 weeks or longer after completion of treatment. The urea breath test was performed as described previously by Miwa et al.20 Briefly, the procedure involved fasting overnight, dosing with 100 mg 13C-urea, mouthwash before and after dosing, maintaining a sitting position, and breath sampling before and 20 min after dosing, with measurement by an automatic 13C analyser (ABCA, European Scientific, Cheshire, UK). The cut-off value was set at 5.0‰; eradication of H. pylori was considered successful if all test results were negative.
H. pylori cure rate was evaluated by intention-to-treat and per protocol analyses. Intention-to-treat analysis included all enrolled patients, and patients who dropped out were regarded as treatment failures; per protocol analysis included all patients who took at least 80% of each study medication as prescribed and returned for assessment of H. pylori cure. The cure rate was calculated together with 95% confidence intervals (CI). Statistical analyses were performed using the chi-squared, Fisher’s exact and Student’s t-tests, as appropriate. A P-value of less than 0.05 was accepted as statistically significant.
Of the 142 patients, three (two with gastric ulcer; one with duodenal ulcer) proved to be positive by histology only, and were therefore excluded from this study. The remaining 139 patients were enrolled in this study. They included 102 with peptic ulcer (or ulcer scar) and 37 with non-ulcer dyspepsia, diagnosed at endoscopy. They comprised 99 men and 40 women, and their mean age was 48 years (range 21–72 years). Baseline characteristics of the study population are listed in Table 1. There were no significant differences in gender, age, alcohol intake, smoking habits and baseline diagnosis between the two treatment groups. Of the 139 patients eligible for this study, five patients, (two from the 5-day group and three from the 7-day group), were lost to follow-up. A further four patients (two in each group), were excluded from per protocol analysis as their compliance was less than 80%, leaving 130 patients for per protocol analysis.
In the intention-to-treat analysis, H. pylori cure rates were 66% (46 out of 70) in the 5-day group and 84% (58 out of 69) in the 7-day group (Table 2). There was a significant difference between the two groups (P < 0.05). In the per protocol analysis, the eradication rate in the 7-day group was also significantly higher than that in the 5-day group (70% vs. 91%, respectively, P < 0.01). Diagnosis, gender, alcohol intake and smoking habits had no significant impact on these results.
Two of the 75 patients with active peptic ulcers, one in each group, were lost to follow-up. These two patients were regarded as treatment failures. Ulcer healing was observed in 31 out of 33 patients (94%, 95% CI: 80–99%) in the 5-day group and 40 out of 42 patients (95%, 95% CI: 84–100%) in the 7-day group, which was not a significant difference.
Adverse events were noted in 14 patients from each group. These included diarrhoea or loose stools, nausea, taste disturbance, skin rash and pharyngeal oedema (Table 3) and resulted in discontinuation of treatment in one patient from the 5-day group (frequent diarrhoea) and one from the 7-day group (severe skin rash). Mild reflux oesophagitis with Los Angeles classification A or B, which was not apparent at the initial endoscopy, was observed in two patients in the 5-day group and three in the 7-day group at repeat endoscopy, although these patients had no reflux symptoms. There were no differences in the incidence and proportion of adverse events between the two groups.
The goal of this study was to determine whether the duration of proton pump inhibitor triple therapy could be reduced below the current well-established 7-day protocol without compromising efficacy. Compared with other available proton pump inhibitors, rabeprazole is more potent, has a faster antisecretory action and a greater antibacterial activity against H. pylori, with a minimum inhibitory concentration of 1.57–3.13 mg/mL.17–19 In addition, the action of rabeprazole is known to be less affected by genetic polymorphisms of cytochrome p450 2C19.21 By incorporating this novel proton pump inhibitor drug into the 5-day regimen, we expected a comparable eradication rate to that achieved with 7 days of triple therapy, however, this was not the case. The 5-day regimen cured H. pylori infection in only 70% of patients. This eradication rate is well below the widely recommended level of 80–90%.6–8, 22 In contrast, the 7-day regimen achieved significantly higher eradication rates of 84% and 91% on intention-to-treat and per protocol analyses, respectively, comparable to previous results with rabeprazole-based triple therapies.13–15 Thus, we consider the shorter regimen to be unacceptable for the treatment of H. pylori infection.
Several studies have examined the impact of therapy duration of proton pump inhibitor-based regimens on eradication efficacy.9–12, 23–26 Adamek et al. found that dual therapy with omeprazole and amoxicillin was completely ineffective when given for 5 days or less.23 The proton pump inhibitor dual therapies, administered for 7 or 14 days, have been tried with generally unsatisfactory rates of eradication and are no longer recommended.24 Several groups have shown that quadruple therapies containing proton pump inhibitor for shorter periods yielded satisfactory results.25, 26 De Boer et al. reported that a 4-day proton pump inhibitor quadruple therapy resulted in a cure rate of over 90%, but even at 4 days, it was a cumbersome regimen due to the consumption of more than 16 pills per day, and side-effects which interfered with daily activities in 79% of the patients.26 With respect to proton pump inhibitor triple therapies, studies evaluating eradication efficacy of the shorter regimens reported discordant results.9–11 The regimen of 5 days of lansoprazole in combination with clarithromycin and metronidazole provided comparable efficacy with a 7-day protocol.9, 11 Even a 4-day course of lansoprazole, azithromycin and tinidazole has been reported to be as effective as standard 7-day triple therapy with omeprazole, clarithromycin plus metronidazole.10 In contrast, Moayyedi et al. reported that lansoprazole combined with clarithromycin and amoxicillin administered for 5 days resulted in an unacceptably low cure rate of 62%, consistent with the results of our study.11 Higher drug doses may boost H. pylori cure rates in the shorter regimens, but this will be accompanied by reduced advantages over the standard 7-day regimens. With the proton pump inhibitor–clarithromycin–amoxicillin therapies, it is unlikely that the search for effective regimens shorter than 7 days will be helpful, although large double-blind studies evaluating regimens of different durations should be performed.
In this study, susceptibility of H. pylori to antibiotics was not assessed, although we did endeavour to minimize the risk of antibiotic resistance by excluding patients who had taken medications effective against the organism. However, Hoshiya et al. reported that 12.5% of Japanese patients with H. pylori infection showed primary resistance to clarithromycin, and the secondary acquisition of resistance may be increasing due to its current wide use in Japan.27 Antibiotic resistance and compliance with medications have been considered key factors in determining the outcome of H. pylori therapy.28, 29 In particular, recent evidence indicates that clarithromycin resistance influences treatment results of proton pump inhibitor triple therapies incorporating this drug, with a reported decrease in efficacy from 92% in susceptible H. pylori strains to 50% in resistant strains.27, 29 The shorter regimens will more than likely suffer the same fate.
The incidence of adverse events was comparable between the two groups, affecting approximately 20% of patients, which is similar to previous data.13–15 These adverse events, however, were generally mild, causing discontinuation of the therapies in only two patients (one from each group). Even the 7-day regimen was well-tolerated, with excellent compliance.
In conclusion, our results showed that a 5-day course of rabeprazole, clarithromycin and amoxicillin yielded unsatisfactory results for the eradication of H. pylori infection. In contrast, a 7-day regimen with the same drug combination and dose attained a cure rate exceeding 90%, with similar good acceptability and compliance to that for the 5 day course. We therefore suggest that if proton pump inhibitor-based triple therapies with clarithromycin plus amoxicillin are used to eradicate H. pylori, treatment courses shorter than 7 days cannot be recommended.
The authors did not receive any financial benefits before, during, or after the study from any commercial source, which directly or indirectly affected the reported results.