Indexed In : Science Citation Index Expanded(SCIE), MEDLINE,
Pubmed/Pubmed Central, Elsevier Bibliographic, Google Scholar,
Databases(Scopus & Embase), KCI, KoreaMed, DOAJ
Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.
The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.
Seong tae Lee, Dong Ho Lee, Ji Hyun Lim, Nayoung Kim, Young Soo Park, Cheol Min Shin, Hyun Jin Jo, and In sung Song
Correspondence to: Dong Ho Lee, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 463-707, Korea Tel: +82-31-787-7006, Fax: +82-31-787-4051, E-mail: dhljohn@yahoo.co.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2015;9(4):478-485. https://doi.org/10.5009/gnl14020
Published online July 25, 2014, Published date July 31, 2015
Copyright © Gut and Liver.
Bismuth-containing quadruple and moxifloxacin-based triple regimens are recommended as second-line therapy for From August 2004 to October 2012, a total of 949 patients (mean age, 54.32±12.08 years; male, 49.4%) who failed The eradication rates by 7-BMT, 14-BMT, 7-MA, and 14-MA were 66.4% (290/437), 71.1% (113/159), 53.1% (51/96), and 73.5% (189/257), respectively, by intention-to-treat analysis (ITT) and 76.5% (284/371), 83.8% (109/130), 55.6% (50/90), and 80.6% (187/232), respectively, by per-protocol analysis (PP). The eradication rates were higher in 14-BMT than 7-BMT by the ITT and PP analyses (p=0.277 and p=0.082, respectively). The 14-BMT and 14-MA treatments showed similar efficacies by ITT and PP (p=0.583 and p=0.443, respectively). The 7-BMT, 14-BMT, and 14-MA treatments showed similar and suboptimal efficacies. In both regimens, extending the duration of treatment may be reasonable considering the high level of antibiotic resistance in Korea.Background/Aims
Methods
Results
Conclusions
Keywords:
In Korea, the standard first-line therapy consisting of proton pump inhibitor (PPI), amoxicillin and clarithromycin has been generally used for 7 days.2,3,5,6 However, during the last few years, this PPI-based triple therapy regimen failed to achieve eradication rate ≥80% in several large clinical trials and meta-analyses.7,8 Moreover, in the clinical setting the failure rate of standard first-line therapy can in fact be higher and several studies have reported the decreasing efficacy of this regimen to lower than 75% and even to lower than 50% on an intention-to-treat (ITT) basis.9–12 These unsatisfactory results are increasing the needs for second-line treatment options.
At present, the internationally recommended salvage eradication therapy for
However, resistance to fluoroquinolones among
It is known that the Korean population has a high risk for
The aim of this study was to compare the efficacy, compliance and adverse events of bismuth-containing quadruple therapy with moxifloxacin-based triple therapy according to the duration of treatment as second-line treatment for a Korean study population of the recent 9 years.
This was a retrospective study in which consecutive patients who fulfilled the following inclusion criteria were recruited using a computer-generated table during the period from August 2004 to October 2012 at Seoul National University Bundang Hospital in Korea. We reviewed all the patients who were at least 18 years of age and initially failed to eradicate
Failure to eradicate
The exclusion criteria were (1) the use of H2-receptor antagonists, PPIs, NSAIDs, or antibiotics during the previous 4 weeks; (2) advanced gastric cancer or previous gastric surgery; (3) the presence of systemic illness such as liver cirrhosis or chronic renal failure; (4) pregnant or breast-feeding women; (5) age <18 years; or (6) any condition possibly correlated with poor compliance such as alcoholics or drug abusers.
Four groups of patients treated with second-line eradication therapy were named using acronyms. Bismuth-containing quadruple therapy consisting of tripotassium dicitrato bismuthate (DENOL®; Greencross Co., Seoul, Korea) 300 mg 4 times a day (three tabs 30 minutes before meals and one tab 2 hours after dinner), tetracycline 500 mg 4 times a day, metronidazole 500 mg 3 times a day and usual dose of PPI twice a day for 7 days was named as 7-BMT and that for 14 days as 14-BMT, respectively. Moxifloxacin-based triple therapy consisting of moxifloxacin 400 mg every day, amoxicillin 1,000 mg twice a day and usual dose of PPI twice a day for 7 days was named as 7-MA and that for 14 days as 14-MA, respectively.
The 949 patients were assigned to one of the following four treatment regimens as second-line eradication: 7-BMT (n=437); 14-BMT (n=159); 7-MA (n=96); and 14-MA (n=257).
Additionally, compliance with therapy was assessed by direct questions by a physician and pill count 1 week or 2 weeks after completion of therapy. Good compliance was considered when patient intake the drug more than 85%. At the same time, adverse events of the patients were reviewed.
No PPI, bismuth, H2-blocker, and antibiotics were allowed within 4 weeks before the urea breath test and before the test patient was fasted for 4 hours. Test meal was not given, and a predose breath sample was obtained. Then patient administered 75 mg of 13C-urea powder (HelikitTM; Isotechnika, Edmonton, Canada) dissolved in 50 mL of water, orally. Thirty minutes later, a second breath sample was collected. The cutoff value used was 4‰.31 The collected samples were analyzed by means of an isotope ratio mass spectrometer (Heliview®; Medichems, Seoul, Korea).
Two biopsy specimens, one each from the antrum and the body, were used for the rapid urease test (CLO test). Antral and body biopsy specimens were evaluated separately, and color change of all urease tests were monitored for up to 24 hours.
Two biopsy specimens obtained from the antrum and the body were fixed in formalin and submitted to two experienced pathologists for histological examination. They assessed the presence of
The analysis was conducted using SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA).
Finally, 949 eligible patients were reviewed in this study group from August 2004 to October 2012. The schematic diagram of the study population is shown in Fig. 1, and baseline characteristics of the study population are summarized in Table 1. Baseline characteristics of age, comorbidities (hypertension, diabetes mellitus), and alcohol intake were similar, but male gender, current smoking, and endoscopic diagnosis were different among the four treatment groups; male gender (49.2% vs 61.6% vs 50.0% vs 42.0%, p=0.002), current smoking (12.4% vs 13.8% vs 8.3% vs 5.4%, p=0.011) and endoscopic diagnosis (p<0.001).
The ITT eradication rates were 66.4% (95% confidence interval [CI], 61.8 to 70.5; 290/437) and 71.1% (95% CI, 63.5 to 77.4; 113/159) between 7-BMT and 14-BMT (p=0.277), 53.1% (95% CI, 42.7 to 63.5; 51/96) and 73.5% (95% CI, 68.5 to 79.0; 189/257) between 7-MA and 14-MA (p<0.001), respectively. Additionally, the ITT eradication rates were 66.4% and 53.1% between 7-BMT and 7-MA (p=0.014), 66.4% and 73.5% between 7-BMT and 14-MA (p=0.048), 71.1% and 73.5% between 14-BMT and 14-MA (p=0.583).
The PP eradication rates were 76.5% (95% CI, 72.1 to 80.9; 284/371) and 83.8% (95% CI, 77.1 to 90.1; 109/130) between 7-BMT and 14-BMT (p=0.082), 55.6% (95% CI, 45.5 to 65.5; 50/90) and 80.6% (95% CI, 75.5 to 85.6; 187/232) between 7-MA and 14-MA (p<0.001), respectively. Additionally, the PP eradication rates were 76.5% and 55.6% between 7-BMT and 7-MA (p<0.001), 76.5% and 80.6% between 7-BMT and 14-MA (p=0.242), 83.8% and 80.6% between 14-BMT and 14-MA (p=0.443).
Fig. 3 shows that the overall eradication rate of bismuth-containing quadruple therapy has been decreasing as time elapsed (p for linear trend=0.006). However, moxifloxacin-based triple therapy showed no statistical significance in the changes of eradication rate according to time (p for linear trend=0.225).
The compliance of the BMT group (represents 7-BMT plus 14-BMT) was inferior compared to that of MA group (represents 7-MA plus 14-MA); 84.1% vs 91.2%, p=0.002. However, no significant differences were reported according to the duration of therapy within same therapeutic regimen.
The adverse events were recorded in 42 of 7-BMT (9.6%) and 29 of 14-BMT (18.2%) (p=0.011) and in 7 of 7-MA (7.3%) and 87 of 14-MA (33.9%) (p<0.001), respectively. Details about adverse events that occurred during the period of study are listed in Table 2. Generally, adverse events were reported in 71 of the bismuth-containing quadruple therapy group (11.9%) and 94 of the moxifloxacin-based triple therapy group (26.6%) (p<0.001).
The number of patients who discontinued therapy due to adverse events were 7 of 7-BMT (1.6%), 5 of 14-BMT (3.1%) (p=0.236), 1 of 7-MA (1.0%) and 6 of 14-MA (2.3%) (p=0.438), respectively. Generally, the number of patients who discontinued therapy due to adverse events were 12 in the bismuth-containing quadruple therapy group (2.0%) and 7 in the moxi-floxacin-based triple therapy group (2.0%) (p=0.974).
The prevalence of adverse events increased as the duration of therapy increased. The most frequent adverse events were nausea/vomiting in the 7-BMT and 14-BMT, while diarrhea was more frequent than nausea/vomiting in the 7-MA and 14-MA.
It is uncertain what is the best second-line therapy for
These results can be explained by antibiotic resistance. Pre-treatment resistance to antibiotics may be the most important factor in patients who do not respond to eradication therapy.32 This indicates that the choice of regimen for second-line eradication depends on what kind of regimen was used initially, as retreatment with the same regimen cannot be recommended.33 Resistance to antibiotics has been increasing in many countries as a major cause of eradication failure,7,34 but we have not investigated antibiotic resistance due to the retrospective nature of this study. Thus, this study referred to previous reports about antibiotic susceptibility of
Similarly, resistance of
In addition, poor compliance is also another important factor in treatment failure.36,45 Moxifloxacin-based triple therapy is more simpler than bismuth-containing quadruple therapy in the method of taking medicine, while bismuth-containing quadruple therapy entails a complex scheme in relation to the number of tablets and the method of administration, causing poor patient compliance.36,45 This study also showed that the MA group had better compliance than the BMT group, and revealed no significant difference according to treatment duration within the same regimen.
In our study, we found a higher rate of adverse events with 14 days compared to 7 days of treatment duration in each therapeutic regimen. Adverse events were increased as the duration of therapy was prolonged, but the rates of discontinued medication according to the duration of therapy were not significantly different. These phenomena may be due to the fact that most side effects causing discontinue eradication therapy appear in the early phase of treatment.
The limitation of our study is its retrospective design. There were 77/596 (12.9%) follow-up losses in the BMT group and 22/353 (6.2%) in the MA group (p<0.001). The overall adverse events were 71/596 (11.9%) in the BMT group compared with 94/353 (26.6%) in the MA group (p<0.001). Adverse events could be lower in BMT group because the patients who experienced adverse events might be exist in follow-up loss patients. Furthermore, limitation of the retrospective nature of this study hindered collecting interviews for adverse events. The adverse events may also be undervalued because no record about adverse events was regarded as none of them. For these reasons, 14-MA may show more adverse events than 14-BMT, which is a somewhat different finding from other studies.21,22,24 Therefore, assessment regarding adverse events through our study cannot be considered appropriate.
In conclusion, treatment duration of 14 days may show better results in high metronidazole resistant areas although the optimal treatment duration of bismuth-containing quadruple therapy as second-line is controversial. If moxifloxacin-based triple therapy is decided as second-line therapy, the treatment duration should be 14 days considering high fluoroquinolone-resistance in Korea. According to the European
7-BMT, 7-day bismuth-containing quadruple therapy; 14-BMT, 14-day bismuth-containing quadruple therapy; 7-MA, 7-day moxifloxacin-based triple therapy; 14-MA, 14-day moxifloxacin-based triple therapy; ITT, intention-to-treat; PP, per-protocol.
7-BMT, 7-day bismuth-containing quadruple therapy; 14-BMT, 14-day bismuth-containing quadruple therapy; 7-MA, 7-day moxifloxacin-based triple therapy; 14-MA, 14-day moxifloxacin-based triple therapy.
Baseline Characteristics of the Study Population
Characteristic | 7-BMT | 14-BMT | 7-MA | 14-MA |
---|---|---|---|---|
No. of patients | 437 | 159 | 96 | 257 |
Age, yr | 54.0±11.7 | 53.7±12.2 | 54.2±12.2 | 55.4±12.5 |
Gender, male/female | 215/222 | 98/61 | 48/48 | 108/149 |
Comorbidity | ||||
Hypertension | 94 (21.5) | 33 (20.8) | 13 (13.5) | 58 (22.6) |
Diabetes | 37 (8.5) | 21 (13.2) | 6 (6.3) | 20 (7.8) |
Current smoking | 54 (12.4) | 22 (13.8) | 8 (8.3) | 14 (5.4) |
Alcohol intake | 98 (22.4) | 34 (21.4) | 19 (19.8) | 39 (15.2) |
Endoscopic diagnosis | ||||
HPAG | 196 (44.9) | 79 (49.7) | 62 (64.6) | 153 (59.5) |
Gastric ulcer | 68 (15.6) | 10 (6.3) | 12 (12.5) | 29 (11.3) |
Duodenal ulcer | 147 (33.6) | 52 (32.7) | 19 (19.8) | 53 (20.6) |
GU+DU | 17 (3.9) | 8 (5.0) | 2 (2.1) | 7 (2.7) |
Early gastric cancer | 6 (1.4) | 5 (3.1) | 1 (1.0) | 14 (5.4) |
MALToma | 3 (0.7) | 5 (3.1) | 0 | 0 |
Carcinoid tumor | 0 | 0 | 0 | 1 (0.4) |
Outcomes in the 7- and 14-Day Bismuth-Containing Quadruple and Moxifloxacin-Based Triple Therapies
7-BMT | 14-BMT | 7-MA | 14-MA | p-value | |
---|---|---|---|---|---|
Eradication rate | |||||
ITT analysis | 290/437 (66.4) | 113/159 (71.1) | 51/96 (53.1) | 189/257 (73.5) | 0.002 |
95% CI, % | 61.8–70.5 | 63.5–77.4 | 42.7–63.5 | 68.5–79.0 | |
PP analysis | 284/371 (76.5) | 109/130 (83.8) | 50/90 (55.6) | 187/232 (80.6) | <0.001 |
95% CI, % | 72.1–80.9 | 77.1–90.1 | 45.5–65.5 | 75.5–85.6 | |
Compliance | 371/437 (84.9) | 130/159 (81.8) | 90/96 (93.8) | 232/257 (90.3) | 0.009 |
Adverse events | <0.001 | ||||
Nausea/vomiting | 12 (2.7) | 10 (6.3) | 2 (2.1) | 19 (7.4) | |
Diarrhea | 6 (1.4) | 4 (2.5) | 2 (2.1) | 31(12.1) | |
Taste disturbance | 3 (0.7) | 1 (0.6) | 0 | 11 (4.3) | |
Epigastric soreness | 12 (2.7) | 6 (3.8) | 1 (1.0) | 17 (6.6) | |
Bloating | 0 | 1 (0.6) | 0 | 3 (1.2) | |
Headache | 0 | 1 (0.6) | 1 (1.0) | 1 (0.4) | |
Urticaria | 3 (0.7) | 3 (1.9) | 0 | 2 (0.8) | |
Dizziness/weakness | 6 (1.4) | 3 (1.9) | 1 (1.0) | 3 (1.2) | |
Total | 42 (9.6) | 29 (18.2) | 7 (7.3) | 87 (33.9) |
Gut and Liver 2015; 9(4): 478-485
Published online July 31, 2015 https://doi.org/10.5009/gnl14020
Copyright © Gut and Liver.
Seong tae Lee, Dong Ho Lee, Ji Hyun Lim, Nayoung Kim, Young Soo Park, Cheol Min Shin, Hyun Jin Jo, and In sung Song
Division of Gastroenterology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
Correspondence to: Dong Ho Lee, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 463-707, Korea Tel: +82-31-787-7006, Fax: +82-31-787-4051, E-mail: dhljohn@yahoo.co.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bismuth-containing quadruple and moxifloxacin-based triple regimens are recommended as second-line therapy for From August 2004 to October 2012, a total of 949 patients (mean age, 54.32±12.08 years; male, 49.4%) who failed The eradication rates by 7-BMT, 14-BMT, 7-MA, and 14-MA were 66.4% (290/437), 71.1% (113/159), 53.1% (51/96), and 73.5% (189/257), respectively, by intention-to-treat analysis (ITT) and 76.5% (284/371), 83.8% (109/130), 55.6% (50/90), and 80.6% (187/232), respectively, by per-protocol analysis (PP). The eradication rates were higher in 14-BMT than 7-BMT by the ITT and PP analyses (p=0.277 and p=0.082, respectively). The 14-BMT and 14-MA treatments showed similar efficacies by ITT and PP (p=0.583 and p=0.443, respectively). The 7-BMT, 14-BMT, and 14-MA treatments showed similar and suboptimal efficacies. In both regimens, extending the duration of treatment may be reasonable considering the high level of antibiotic resistance in Korea.Background/Aims
Methods
Results
Conclusions
Keywords:
In Korea, the standard first-line therapy consisting of proton pump inhibitor (PPI), amoxicillin and clarithromycin has been generally used for 7 days.2,3,5,6 However, during the last few years, this PPI-based triple therapy regimen failed to achieve eradication rate ≥80% in several large clinical trials and meta-analyses.7,8 Moreover, in the clinical setting the failure rate of standard first-line therapy can in fact be higher and several studies have reported the decreasing efficacy of this regimen to lower than 75% and even to lower than 50% on an intention-to-treat (ITT) basis.9–12 These unsatisfactory results are increasing the needs for second-line treatment options.
At present, the internationally recommended salvage eradication therapy for
However, resistance to fluoroquinolones among
It is known that the Korean population has a high risk for
The aim of this study was to compare the efficacy, compliance and adverse events of bismuth-containing quadruple therapy with moxifloxacin-based triple therapy according to the duration of treatment as second-line treatment for a Korean study population of the recent 9 years.
This was a retrospective study in which consecutive patients who fulfilled the following inclusion criteria were recruited using a computer-generated table during the period from August 2004 to October 2012 at Seoul National University Bundang Hospital in Korea. We reviewed all the patients who were at least 18 years of age and initially failed to eradicate
Failure to eradicate
The exclusion criteria were (1) the use of H2-receptor antagonists, PPIs, NSAIDs, or antibiotics during the previous 4 weeks; (2) advanced gastric cancer or previous gastric surgery; (3) the presence of systemic illness such as liver cirrhosis or chronic renal failure; (4) pregnant or breast-feeding women; (5) age <18 years; or (6) any condition possibly correlated with poor compliance such as alcoholics or drug abusers.
Four groups of patients treated with second-line eradication therapy were named using acronyms. Bismuth-containing quadruple therapy consisting of tripotassium dicitrato bismuthate (DENOL®; Greencross Co., Seoul, Korea) 300 mg 4 times a day (three tabs 30 minutes before meals and one tab 2 hours after dinner), tetracycline 500 mg 4 times a day, metronidazole 500 mg 3 times a day and usual dose of PPI twice a day for 7 days was named as 7-BMT and that for 14 days as 14-BMT, respectively. Moxifloxacin-based triple therapy consisting of moxifloxacin 400 mg every day, amoxicillin 1,000 mg twice a day and usual dose of PPI twice a day for 7 days was named as 7-MA and that for 14 days as 14-MA, respectively.
The 949 patients were assigned to one of the following four treatment regimens as second-line eradication: 7-BMT (n=437); 14-BMT (n=159); 7-MA (n=96); and 14-MA (n=257).
Additionally, compliance with therapy was assessed by direct questions by a physician and pill count 1 week or 2 weeks after completion of therapy. Good compliance was considered when patient intake the drug more than 85%. At the same time, adverse events of the patients were reviewed.
No PPI, bismuth, H2-blocker, and antibiotics were allowed within 4 weeks before the urea breath test and before the test patient was fasted for 4 hours. Test meal was not given, and a predose breath sample was obtained. Then patient administered 75 mg of 13C-urea powder (HelikitTM; Isotechnika, Edmonton, Canada) dissolved in 50 mL of water, orally. Thirty minutes later, a second breath sample was collected. The cutoff value used was 4‰.31 The collected samples were analyzed by means of an isotope ratio mass spectrometer (Heliview®; Medichems, Seoul, Korea).
Two biopsy specimens, one each from the antrum and the body, were used for the rapid urease test (CLO test). Antral and body biopsy specimens were evaluated separately, and color change of all urease tests were monitored for up to 24 hours.
Two biopsy specimens obtained from the antrum and the body were fixed in formalin and submitted to two experienced pathologists for histological examination. They assessed the presence of
The analysis was conducted using SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA).
Finally, 949 eligible patients were reviewed in this study group from August 2004 to October 2012. The schematic diagram of the study population is shown in Fig. 1, and baseline characteristics of the study population are summarized in Table 1. Baseline characteristics of age, comorbidities (hypertension, diabetes mellitus), and alcohol intake were similar, but male gender, current smoking, and endoscopic diagnosis were different among the four treatment groups; male gender (49.2% vs 61.6% vs 50.0% vs 42.0%, p=0.002), current smoking (12.4% vs 13.8% vs 8.3% vs 5.4%, p=0.011) and endoscopic diagnosis (p<0.001).
The ITT eradication rates were 66.4% (95% confidence interval [CI], 61.8 to 70.5; 290/437) and 71.1% (95% CI, 63.5 to 77.4; 113/159) between 7-BMT and 14-BMT (p=0.277), 53.1% (95% CI, 42.7 to 63.5; 51/96) and 73.5% (95% CI, 68.5 to 79.0; 189/257) between 7-MA and 14-MA (p<0.001), respectively. Additionally, the ITT eradication rates were 66.4% and 53.1% between 7-BMT and 7-MA (p=0.014), 66.4% and 73.5% between 7-BMT and 14-MA (p=0.048), 71.1% and 73.5% between 14-BMT and 14-MA (p=0.583).
The PP eradication rates were 76.5% (95% CI, 72.1 to 80.9; 284/371) and 83.8% (95% CI, 77.1 to 90.1; 109/130) between 7-BMT and 14-BMT (p=0.082), 55.6% (95% CI, 45.5 to 65.5; 50/90) and 80.6% (95% CI, 75.5 to 85.6; 187/232) between 7-MA and 14-MA (p<0.001), respectively. Additionally, the PP eradication rates were 76.5% and 55.6% between 7-BMT and 7-MA (p<0.001), 76.5% and 80.6% between 7-BMT and 14-MA (p=0.242), 83.8% and 80.6% between 14-BMT and 14-MA (p=0.443).
Fig. 3 shows that the overall eradication rate of bismuth-containing quadruple therapy has been decreasing as time elapsed (p for linear trend=0.006). However, moxifloxacin-based triple therapy showed no statistical significance in the changes of eradication rate according to time (p for linear trend=0.225).
The compliance of the BMT group (represents 7-BMT plus 14-BMT) was inferior compared to that of MA group (represents 7-MA plus 14-MA); 84.1% vs 91.2%, p=0.002. However, no significant differences were reported according to the duration of therapy within same therapeutic regimen.
The adverse events were recorded in 42 of 7-BMT (9.6%) and 29 of 14-BMT (18.2%) (p=0.011) and in 7 of 7-MA (7.3%) and 87 of 14-MA (33.9%) (p<0.001), respectively. Details about adverse events that occurred during the period of study are listed in Table 2. Generally, adverse events were reported in 71 of the bismuth-containing quadruple therapy group (11.9%) and 94 of the moxifloxacin-based triple therapy group (26.6%) (p<0.001).
The number of patients who discontinued therapy due to adverse events were 7 of 7-BMT (1.6%), 5 of 14-BMT (3.1%) (p=0.236), 1 of 7-MA (1.0%) and 6 of 14-MA (2.3%) (p=0.438), respectively. Generally, the number of patients who discontinued therapy due to adverse events were 12 in the bismuth-containing quadruple therapy group (2.0%) and 7 in the moxi-floxacin-based triple therapy group (2.0%) (p=0.974).
The prevalence of adverse events increased as the duration of therapy increased. The most frequent adverse events were nausea/vomiting in the 7-BMT and 14-BMT, while diarrhea was more frequent than nausea/vomiting in the 7-MA and 14-MA.
It is uncertain what is the best second-line therapy for
These results can be explained by antibiotic resistance. Pre-treatment resistance to antibiotics may be the most important factor in patients who do not respond to eradication therapy.32 This indicates that the choice of regimen for second-line eradication depends on what kind of regimen was used initially, as retreatment with the same regimen cannot be recommended.33 Resistance to antibiotics has been increasing in many countries as a major cause of eradication failure,7,34 but we have not investigated antibiotic resistance due to the retrospective nature of this study. Thus, this study referred to previous reports about antibiotic susceptibility of
Similarly, resistance of
In addition, poor compliance is also another important factor in treatment failure.36,45 Moxifloxacin-based triple therapy is more simpler than bismuth-containing quadruple therapy in the method of taking medicine, while bismuth-containing quadruple therapy entails a complex scheme in relation to the number of tablets and the method of administration, causing poor patient compliance.36,45 This study also showed that the MA group had better compliance than the BMT group, and revealed no significant difference according to treatment duration within the same regimen.
In our study, we found a higher rate of adverse events with 14 days compared to 7 days of treatment duration in each therapeutic regimen. Adverse events were increased as the duration of therapy was prolonged, but the rates of discontinued medication according to the duration of therapy were not significantly different. These phenomena may be due to the fact that most side effects causing discontinue eradication therapy appear in the early phase of treatment.
The limitation of our study is its retrospective design. There were 77/596 (12.9%) follow-up losses in the BMT group and 22/353 (6.2%) in the MA group (p<0.001). The overall adverse events were 71/596 (11.9%) in the BMT group compared with 94/353 (26.6%) in the MA group (p<0.001). Adverse events could be lower in BMT group because the patients who experienced adverse events might be exist in follow-up loss patients. Furthermore, limitation of the retrospective nature of this study hindered collecting interviews for adverse events. The adverse events may also be undervalued because no record about adverse events was regarded as none of them. For these reasons, 14-MA may show more adverse events than 14-BMT, which is a somewhat different finding from other studies.21,22,24 Therefore, assessment regarding adverse events through our study cannot be considered appropriate.
In conclusion, treatment duration of 14 days may show better results in high metronidazole resistant areas although the optimal treatment duration of bismuth-containing quadruple therapy as second-line is controversial. If moxifloxacin-based triple therapy is decided as second-line therapy, the treatment duration should be 14 days considering high fluoroquinolone-resistance in Korea. According to the European
7-BMT, 7-day bismuth-containing quadruple therapy; 14-BMT, 14-day bismuth-containing quadruple therapy; 7-MA, 7-day moxifloxacin-based triple therapy; 14-MA, 14-day moxifloxacin-based triple therapy; ITT, intention-to-treat; PP, per-protocol.
7-BMT, 7-day bismuth-containing quadruple therapy; 14-BMT, 14-day bismuth-containing quadruple therapy; 7-MA, 7-day moxifloxacin-based triple therapy; 14-MA, 14-day moxifloxacin-based triple therapy.
Table 1 Baseline Characteristics of the Study Population
Characteristic | 7-BMT | 14-BMT | 7-MA | 14-MA |
---|---|---|---|---|
No. of patients | 437 | 159 | 96 | 257 |
Age, yr | 54.0±11.7 | 53.7±12.2 | 54.2±12.2 | 55.4±12.5 |
Gender, male/female | 215/222 | 98/61 | 48/48 | 108/149 |
Comorbidity | ||||
Hypertension | 94 (21.5) | 33 (20.8) | 13 (13.5) | 58 (22.6) |
Diabetes | 37 (8.5) | 21 (13.2) | 6 (6.3) | 20 (7.8) |
Current smoking | 54 (12.4) | 22 (13.8) | 8 (8.3) | 14 (5.4) |
Alcohol intake | 98 (22.4) | 34 (21.4) | 19 (19.8) | 39 (15.2) |
Endoscopic diagnosis | ||||
HPAG | 196 (44.9) | 79 (49.7) | 62 (64.6) | 153 (59.5) |
Gastric ulcer | 68 (15.6) | 10 (6.3) | 12 (12.5) | 29 (11.3) |
Duodenal ulcer | 147 (33.6) | 52 (32.7) | 19 (19.8) | 53 (20.6) |
GU+DU | 17 (3.9) | 8 (5.0) | 2 (2.1) | 7 (2.7) |
Early gastric cancer | 6 (1.4) | 5 (3.1) | 1 (1.0) | 14 (5.4) |
MALToma | 3 (0.7) | 5 (3.1) | 0 | 0 |
Carcinoid tumor | 0 | 0 | 0 | 1 (0.4) |
Data are presented as mean±SD or number (%).
7-BMT, 7-day bismuth-containing quadruple therapy; 14-BMT, 14-day bismuth-containing quadruple therapy; 7-MA, 7-day moxifloxacin-based triple therapy; 14-MA, 14-day moxifloxacin-based triple therapy; HPAG,
Table 2 Outcomes in the 7- and 14-Day Bismuth-Containing Quadruple and Moxifloxacin-Based Triple Therapies
7-BMT | 14-BMT | 7-MA | 14-MA | p-value | |
---|---|---|---|---|---|
Eradication rate | |||||
ITT analysis | 290/437 (66.4) | 113/159 (71.1) | 51/96 (53.1) | 189/257 (73.5) | 0.002 |
95% CI, % | 61.8–70.5 | 63.5–77.4 | 42.7–63.5 | 68.5–79.0 | |
PP analysis | 284/371 (76.5) | 109/130 (83.8) | 50/90 (55.6) | 187/232 (80.6) | <0.001 |
95% CI, % | 72.1–80.9 | 77.1–90.1 | 45.5–65.5 | 75.5–85.6 | |
Compliance | 371/437 (84.9) | 130/159 (81.8) | 90/96 (93.8) | 232/257 (90.3) | 0.009 |
Adverse events | <0.001 | ||||
Nausea/vomiting | 12 (2.7) | 10 (6.3) | 2 (2.1) | 19 (7.4) | |
Diarrhea | 6 (1.4) | 4 (2.5) | 2 (2.1) | 31(12.1) | |
Taste disturbance | 3 (0.7) | 1 (0.6) | 0 | 11 (4.3) | |
Epigastric soreness | 12 (2.7) | 6 (3.8) | 1 (1.0) | 17 (6.6) | |
Bloating | 0 | 1 (0.6) | 0 | 3 (1.2) | |
Headache | 0 | 1 (0.6) | 1 (1.0) | 1 (0.4) | |
Urticaria | 3 (0.7) | 3 (1.9) | 0 | 2 (0.8) | |
Dizziness/weakness | 6 (1.4) | 3 (1.9) | 1 (1.0) | 3 (1.2) | |
Total | 42 (9.6) | 29 (18.2) | 7 (7.3) | 87 (33.9) |
Data are presented as number (%).
7-BMT, 7-day bismuth-containing quadruple therapy; 14-BMT, 14-day bismuth-containing quadruple therapy; 7-MA, 7-day moxifloxacin-based triple therapy; 14-MA, 14-day moxifloxacin-based triple therapy; ITT, intention-to-treat; CI, confidence interval; PP, per-protocol.