Comparison of 10-day sequential therapy with 7-day standard triple therapy for Helicobacter pylori eradication in inactive peptic ulcer disease and the efficiency of sequential therapy in inactive peptic ulcer disease and non-ulcer dyspepsia

Standard triple therapy, when first proposed, was demonstrated to have a high eradication efficacy with a success rate over 85 % [24]. Therefore, most therapeutic guidelines from major academic committees worldwide recommended a proton pump inhibitor based triple therapy plus clarithromycin and amoxicillin or metronidazole as the first-line regimen for eradication of H. pylori [7‐9]. Unfortunately, the eradication rate of this gold standard therapy declined rapidly during the following 10 years toward unacceptable levels [25]. The frustrating outcome of the poor eradication rate led to several new strategies aimed to raise eradication efficacy. Innovative therapeutic approaches included extending therapy duration, the altering of conventionally used antibiotics to novel ones, and the addition of multi-drug regimens.

A two-phase sequential regimen, by adding a fourth drug, has been shown to have promising eradication results in many studies worldwide. However, most of these trials were conducted in patients diagnosed with H. pylori infection and without separately analyzed eradication rates in either ulcer related or non-ulcer related groups. Our current work was a trial to compare the eradication efficacy of sequential therapy and conventional triple therapy exclusively in inactive duodenal ulcer and non-ulcer dyspepsia patients. The results demonstrated that a 10-day sequential regimen was superior to conventional triple therapy for eradication of H. pylori in treatment naïve patients. Overall, the eradication rate of sequential therapy was 88.1 % with PP analysis and 83.5 % with ITT analysis, which were higher than those of triple therapy (85.0 % with PP analysis and 77.3 % with ITT analysis). The result is similar to that shown in other studies in Western and Asian countries [26‐31]. However, in our trial, the eradication rate of sequential therapy did not reach the good category according to the Graham’s report card for grading H. pylori therapy [32] (90–95 % intention-to-treat) as with most other studies [15, 33, 34] and did not demonstrate a significant difference compared to triple therapy. One randomized controlled trial in southern Taiwan reported a high eradication rate (92.9 % with PP and 93.2 % with ITT analysis) of sequential therapy [35]. Patients they enrolled had either gastric ulcers or duodenal ulcers (94.3 % of total patients). We suggest the reason why our results did not yield a higher eradication efficacy may be due to the type of gastroduodenal diseases in our patients. Our patient pool only consisted of either inactive duodenal ulcer or non-ulcer dyspepsia patients.

Previous studies found that the eradication rate of standard triple therapy in non-ulcer dyspepsia tends to be lower than that in peptic-ulcer patients [21, 36]. Contrary results are observed in sequential therapy and the success rates are not significantly affected by pathological findings (peptic-ulcer vs. non-ulcer dyspepsia) [37, 38]. Our study’s result was different, in that the eradication rate of sequential therapy (Table 3) was better in duodenal ulcer scar patients than in non-ulcer dyspepsia with ITT analysis (87.3 % vs. 81.5 %) and with PP analysis (92.4 % vs. 85.8 %), which reached a significant difference. Two large studies (DU-MACH [39] and GU-MACH [40]) have therefore looked at the impact of inflammation on H. pylori eradication. Polymorph infiltration in the antrum of patients with inflammation of grades 2/3 was associated with a significantly higher eradication rate when compared with inflammation of grades 0/1. Previous ulcer diseases may induce inflammation processes that cause degradation of the mucus and epithelial layers and altered epithelial permeability. That may allow better penetration of antibiotics from the gastric lumen and better systemic delivery of drugs. Besides, the subtype of H. Pylori that cause ulcer may be more aggressive which has a better response to the antibiotics. Therefore, we speculate that the low eradication rate of sequential therapy in non-ulcer dyspepsia patients tarnished the overall eradication rate of sequential therapy in our 364 patients with either duodenal ulcer scar or non-ulcer dyspepsia. Although eradication of Helicobacter Pylori is both suggested in patient with duodenal ulcer scar or non-ulcer dyspepsia, the difference in eradication rate could provide us a better outcome predication to discuss with the patient.

Although the difference was not statistically significant, subgroup analysis revealed a superior eradication rate of sequential therapy in duodenal ulcer scar patients (Table 2; ITT, 87.3 % vs. 77.3 %; PP, 92.4 % vs. 85.0 %). Sequential therapy also achieved the acceptable effectiveness category (86–89 %, ITT) and was better than triple therapy (unacceptable category: <80 %, ITT) according to Graham’s category [32]. Since many studies have proved that successful eradication of H. pylori substantially reduces the recurrent rate of duodenal ulcers, it is recommended by a worldwide consensus. We believe that a 10-day sequential regimen could be a valid alternative therapy in initial treatment for the eradication of H. pylori in duodenal ulcer scar patients.

Our data showed that the overall adverse event rate was higher in the sequential group than that in the triple group (Table 4; 36.3 % vs. 22.7 %). The highest incidence of adverse events was mouth bitterness in both groups. The sequential group had an even higher frequency of mouth bitterness. Nonetheless, patient-reported compliance was similar in both the triple and sequential therapy groups (90.9 % vs. 94.8 %).

We also performed the multivariate analysis to investigate the independent factors predicting eradication failure in this study. Table 5 showed the eradication efficiency has no relationship with age and gender. Besides, the successful eradication group has a significantly higher adverse reaction rate then the failure group. It seemed that the eradication rate was associated independently with the different protocol and presence of ulcer scar.

Furthermore, Table 6 shows the cost of each individual regimen. Clarithromycin was the most expensive drug and cost $32.30 in the standard triple therapy regimen, out of a total cost of $51.00. The sequential therapy regimen cost only $47.6. Due to the comparative expense of standard therapy, replacement of it with the less costly sequential regimen would greatly reduce total treatment costs. This economical consideration also favors the use of the latter treatment regimen.

The present study had a couple of limitations. Firstly, that patients were not randomized to receive either standard triple therapy or 10-day sequential therapy. Patients with iDU were assigned into 2 groups according to a physician’s discretion, which may have introduced selection bias. Therefore, the number in the iDU triple group was too small. However, all patients were prospectively followed up with a standard protocol and were well informed about adverse problems and compliance. Secondly, bacterial culture was not performed in our protocol, and therefore the effect of antibiotic resistance was not able to be assessed. However, the resistance rates of Amoxicillin, Clarithromycin, Metronidazole, and Tetracycline in Cathy General Hospital are 13.9, 27.8, 19.4, and 0 % respectively.