AIM: To find the way to improve the eradication rate of first-line therapy in Japanese patients.

METHODS: We prospectively compared the effectiveness of 7-d quadruple therapy to standard 7 d triple therapy in Japanese patients infected with Helicobacter pylori (H. pylori). One hundred and nineteen patients were randomly assigned to receive 7-d non-bismuth quadruple therapy with lansoprazole, amoxicillin, clarithromycin and metronidazole (LACM7) or 7-d triple therapy with lansoprazole, amoxicillin and clarithromycin (LAC7). After three months, H. pylori status was analyzed by ¹³C-urea breath test. Incidence rates of adverse events were evaluated by use of questionnaires.

RESULTS: By intention-to-treat (ITT) analysis, the eradication rate in the LACM7 group was 94.9%, which was significantly higher than the LAC7 group (68.3%, P < 0.001). Per protocol analysis also showed a significantly higher eradication rate in the LACM7 group (98.3%) than the LAC7 group (73.2%, P < 0.001). Nevertheless, the incidence of serious adverse events did not differ between the two groups (RR: 1.10, 95% CI: 0.70-1.73, P = 0.67).

CONCLUSION: Seven day non-bismuth quadruple therapy (LACM7) was superior to standard 7-d triple therapy (LAC7) for first-line eradication.

Helicobacter pylori (H. pylori) infection plays a crucial role in the pathogenesis of chronic atrophic gastritis and peptic ulcer. Moreover, it has been identified as one of the most important causes of gastric cancer and contributes to cancer initiation and progression[1]. H. pylori is associated strongly with the development of intestinal-type gastric cancer and metachronous cancer after endoscopic resection therapy[2,3] and eradication should reduce the risk of developing gastric cancer[4,5].

The recommended treatment for H. pylori is a proton pump inhibitor (PPI)-based triple therapy using PPI, amoxicillin and clarithromycin or metronidazole given twice daily and considerable data support the use of this treatment[5]. However, the eradication rate for standard triple therapy has declined in recent years despite being > 80% before 2000[6,7]. At present, patients who fail first-line therapy usually receive second-line therapy in Japan. However, a second course of eradication therapy increases the financial burden and is time-consuming[8].

Many attempts have been made recently to improve the initial eradication rates of H. pylori. Some studies have suggested prolonging the eradication period or taking drugs four or more times daily, but that might reduce compliance[9,10]. In this study, to find a more effective regimen to complete H. pylori eradication in first-line therapy, we compared the effectiveness of 7 d quadruple therapy of lansoprazole, amoxicillin, clarithromycin and metronidazole (LACM7) to 7 d standard triple therapy with lansoprazole, amoxicillin and clarithromycin (LAC7) for H. pylori eradication.

This study was designed as a randomized prospective study to find the effectiveness of LACM7 quadruple eradication therapy and clearly showed that first-line 7-d quadruple therapy using lansoprazole, amoxicillin, clarithromycin and metronidazole significantly improved the eradication rate of H. pylori compared to standard 7-d triple therapy. Furthermore, LACM7 quadruple therapy showed no significant increases in the risk of adverse events.

In the Asia-Pacific consensus guidelines for H. pylori infection, the currently recommended first-line eradication therapy is PPI-based triple therapy with clarithromycin and either amoxicillin or metronidazole for 7 d[11]. PPI-based triple therapy is also recommended in the Maastricht III consensus report, whereas bismuth-containing quadruple therapy is presented as option[5].

Recently, some non-bismuth quadruple therapies were reported to obtain higher eradication rates[12]. Neville reported that the eradication rate of quadruple therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 250 mg and metronidazole 400 mg, twice daily for 5 d) was 88%[13]. Garcia reported that seven day quadruple therapy of PPI, amoxicillin, trinidazole and bismuth showed a high eradication rate of 84%[14]. In randomized control studies, Kateralis compared quadruple therapy (PPI, bismuth, tetracycline and metronidazole for 7 d) with triple therapy (PPI, amoxicillin, clarithromycin) and eradication rates were 82% and 78%, respectively[15]. There were some reports of higher eradication rates in quadruple therapies than in triple therapies[16-18]. On the other hand, some reports showed better eradication rates in triple therapies than in quadruple therapies. Mantzaris showed that the eradication rate of quadruple therapy (64.8%) was significantly lower than that of triple therapy (78.2%)[19]. Some other studies also showed higher eradication rate in triple therapies than in quadruple therapies[20,21]. Thus, the effectiveness of first-line quadruple therapy is controversial. In this study, we have demonstrated that the eradication rates were 94.9%/98.3% by ITT/per protocol analyses using LACM7 therapy, which showed a higher eradication rate compared to previous treatment regimens. It seems that LACM7 therapy is superior to other first-line eradication therapies.

However, quadruple therapies have not been prevalent in Japan. The concern is that quadruple therapies may induce more severe adverse events than standard triple therapies. In this study, the overall incidence rate of adverse effects in patients receiving LACM7 therapy was 42.9%, which is higher than that in patients receiving LAC7 therapy (38.9%, Table 5). Diarrhea was the most frequent adverse event which was reported in 30.1% of LACM7 compared with 24.1% of LAC7. Other adverse events that occurred with a frequency of more than 10% were taste disturbance (12.5%) and abdominal pain/distention (12.5%) in the LACM7 group. Nevertheless, the rate of adverse events did not differ significantly between two groups (P = 0.06-1.00, Table 6). Whereas some previous reports reported that metronidazole induces acute pancreatitis or brain tumors, these effects are extremely rare and are related to high doses or long-term administration[22,23]. Metronidazole use in the short-term may be favorable to achieve eradication therapy efficiently.

The serology test, which is non-invasive, is widely available to diagnose H. pylori infection[5]. However, as the serology test does not always indicate current infection of H. pylori, patients whose H. pylori status was checked only by serological test were excluded in subgroup analysis (Tables 2 and 4). In this subgroup analysis, eradication rates of LACM7/LAC7 were 94.2%/68.2%, which were similar to results in Table 3. These results confirmed the efficacy of LACM7 therapy.

Recently, the eradication rates in Japan have been decreasing. In other Asian countries, eradication rates have also been decreasing because of drug resistance. The clarithromycin resistance rate is increasing in many countries. In Japan, clarithromycin resistance currently accounts for approximately 25% compared to around 15% in the 1990s[7]. Hence, it is reasonable to use metronidazole for first-line therapy. In addition, clarithromycin is metabolized by the CYP3A4 family of P-450, which is abundant in the liver, and metronidazole is also metabolized in the liver by oxidation. Several drug interactions may occur due to inhibition of oxidative drug metabolism. It was also reported that the combination of metronidazole and clarithromycin induced long-term and concentration-dependent effects[24]. On account of these pharmacological effects, combination use of clarithromycin and metronidazole is more effective than using either drug alone.

There is concern that using LACM7 could cause metronidazole resistance. Actually, metronidazole resistance has also increasing and the resistance rate in other Asian countries is 50%-70%, which is higher than in Japan (4.5%)[25]. In these countries, metronidazole is frequently used for gynecological infections such as Trichomonas vaginalis, which has a high resistance rate. In contrast, metronidazole resistance rate in Japan is lower than in other Asian countries because of the restriction on its use. For these reasons, the influence of short-term use of metronidazole on its resistance might be slight.

Previously, we evaluated 7 d first-line triple therapy with metronidazole (lansoprazole 30 mg, amoxicillin 750 mg, metronidazole 200 mg twice daily for 7 d: LAM) in expectation of a higher eradication rate than other eradication therapies. Eradication of H. pylori was achieved in 91.0%, 91.2% and 86.5% of atrophic gastritis, gastric ulcer and duodenal ulcer patients by ITT analyses (data not shown), which were lower than LACM7 (94.9%). These results suggest that metronidazole-containing quadruple therapy is superior to metronidazole-containing triple therapy as first-line eradication.

LACM7 therapy may be useful when confident H. pylori eradication is needed; for example, gastric mucosa-associated lymphoid tissue (MALT) lymphoma and idiopathic thrombocytopenic purpura (ITP) that is linked closely to H. pylori infection[26,27]. As for MALT lymphoma, immediate H. pylori eradication is recognized as an effective primary treatment[5]. Rapid induction of eradication therapy may reduce tumor size and is expected to prevent undergoing surgical therapy or tumor metastasis if no API2-MALT1 gene translocations exist. As for ITP, when the platelet count is < 3000-5000/μL, immediate H. pylori eradication is strongly recommended to prevent cerebral hemorrhage. Immediate H. pylori eradication improves quality of life and decreases the mortality rate. In these cases, to achieve eradication in the first treatment is so important that the LACM7 regimen should be considered for first-line therapy.

We sincerely thank Dr. Yoshihiro Hirata and Dr. Yutaka Yamaji from University of Tokyo for some valuable suggestions to the study. We sincerely thank Mr. Tachibana and Ms. Iigaya for the management of the clinical database.