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doi:10.1111/jgh.12983
GASTROENTEROLOGY
Concomitant and hybrid therapy for Helicobacter pylori infection: A randomized clinical trial Jun Heo,* Seong Woo Jeon,* Jin Tae Jung,† Joong Goo Kwon,† Dong Wook Lee,† Hyun Soo Kim,‡ Chang Hun Yang,§ Jeong Bae Park,§ Kyung Sik Park,¶ Kwang Bum Cho,¶ Si Hyung Lee,** Byung Ik Jang** and Daegu-Gyeongbuk Gastrointestinal Study Group *Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University Hospital, †Division of Gastroenterology and Hepatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, ‡Division of Gastroenterology and Hepatology, Department of Internal Medicine, Daegu Fatima Hospital, ¶Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, **Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, and §Division of Gastroenterology and Hepatology, Department of Internal Medicine, Dongguk University Gyeongju Hospital, Gyeongju, Korea
Key words Helicobacter pylori, peptic ulcer diseases, stomach, treatment and antimicrobial resistance. Accepted for publication 24 March 2015. Correspondence Dr Seong Woo Jeon, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University Hospital, 474 Hakjeongdong, Buk-gu, Daegu, South Korea. Email: [email protected] Conflict of interest: None. Guarantor of the article: Seong Woo Jeon, MD, PhD. Specific author contributions: Jun Heo was involved in the analysis and interpretation of data, drafting of the manuscript, statistical analysis. Seong Woo Jeon was involved in the study design, analysis and interpretation of data, critical revision of the manuscript, administrative, technical and material support, obtained funding. Jin Tae Jung, Joong Goo Kwon, Dong Wook Lee, Hyun Soo Kim, Chang Hun Yang, Jeong Bae Park, Kyung Sik Park, Kwang Bum Cho, Si Hyung Lee, Byung Ik Jang were involved in the acquisition of data, critical revision of the manuscript, study supervision. All authors read and approved the final manuscript.
Abstract Background and Aims: This study aimed to validate the equivalence of first-line concomitant and hybrid regimens for Helicobacter pylori infection in an era of increasing antibiotic resistance. The study also aimed to assess regimen compliance. Methods: H. pylori-infected patients from six hospitals in Korea were randomly assigned to either concomitant or hybrid regimens. The concomitant regimen consisted of 20 mg of esomeprazole, 1 g of amoxicillin, 500 mg of clarithromycin, and 500 mg metronidazole, twice daily for 10 days. The hybrid regimen consisted of a 5-day dual therapy (20 mg of esomeprazole and 1 g of amoxicillin, twice daily) followed by a 5-day quadruple therapy (20 mg of esomeprazole, 1 g of amoxicillin, 500 mg of clarithromycin, and 500 mg of metronidazole, twice daily). Results: Eradication rates for concomitant and hybrid therapy were 78.6% (187/238) and 78.8% (190/241) in the intention-to-treat analysis, and 89.8% (176/196) and 89.6% (181/ 202) in the per protocol analysis. For both analyses, 95% confidence intervals fell within the ± 8% equivalence margin. Adherence was better in the hybrid group (95.0%) than in the concomitant group (90.1%), a difference that was borderline significant (P = 0.051). Adverse event rates were higher in the concomitant group than in the hybrid group for nausea (15.8% vs 8.8%; P = 0.028) and regurgitation (17.6% vs 10.7%; P = 0.040). Conclusion: As compared with concomitant therapy, hybrid therapy offered similar efficacy, better compliance, and fewer adverse events. Hybrid therapy could be a reasonable first-line treatment option for H. pylori in areas with high antibiotics resistance.
Introduction Helicobacter pylori infection’s relationships with gastritis, gastric ulcer, and gastric cancer have been investigated in many studies.1 Treatment for Helicobacter was developed to decrease the involve-
ment of H. pylori infection in these diseases. However, resistance to antibiotic therapy has increased alongside rapid growth in the use of antibiotics for H. pylori and other infections. Consequently, the conventional triple regimen is no longer recommended for use in regions where the rate of clarithromycin resistance has been
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reported to exceed 20%, such as in Korea, Japan, Italy, and Greece.2–5 To overcome the antibiotic resistance, non-bismuth quadruple regimens, three major options—sequential, concomitant, and hybrid therapies—have been validated as the next generation of treatment through many years of studies. Sequential and concomitant regimens have shown higher eradication rates than that with triple therapy.6,7 However, the efficacy of sequential therapy has declined since 2008.8 On the other hand, hybrid regimen needs to be validated in through additional randomized controlled trials. Concomitant and hybrid therapies have been compared in only one previous study, which was conducted in Italy and Spain.9 No studies comparing both regimens have been conducted in Asia, which has high rates of clarithromycin and metronidazole resistance. Optimal eradication depends on two major factors: the regimen’s eradication ability and patient compliance.10 Each regimen’s eradication ability depends on several external factors, in addition to innate capacity. These external factors include gastric acidity, the density of infection, the patient’s metabolism, and more importantly, the antibiotic resistance of H. pylori. In Korea, rates of H. pylori resistance against clarithromycin and metronidazole have been reported to be as high as ≥ 20% and ≥ 30%, respectively.5 The extent of patient compliance with a regimen is usually a reflection of that regimen’s adverse events. In the present study, we compared concomitant and hybrid therapy in terms of both eradication ability and patient compliance, which were assessed in a multicenter, randomized, prospective trial.
Methods Study design. This prospective, randomized, controlled, open-label trial was conducted at six medical centers in the Daegu and Kyungsang territories, Korea, between March 2013 and April 2014. The study was approved by the institutional international review board of each participating center and was registered as a clinical trial (http://www.cris.nih.go.kr, approved number KCT 0000728). The trial was conducted in accordance with good clinical practices under the principles of the Declaration of Helsinki. Participants. This study enrolled patients who both required and were willing to receive treatment for H. pylori infection. There were eight criteria for inclusion in this study. (i) The patient had been diagnosed with H. pylori infection. The diagnosis of H. pylori infection was defined as the presence of positive results of any two of the following tests: a rapid urease test, a histologic assessment, or a 13 C-urea breath test (UBT). (ii) The patients had an active/inactive peptic ulcer diagnosed through endoscopy. (iii) The patient had dyspepsia without organic disorders, as determined by endoscopy. (iv) The patient underwent endoscopic mucosal resection or submucosal dissection to treat gastric adenoma or early gastric cancer. The exclusion criteria were as follows: (i) younger than 18 years old; (ii) refusal to participate in the study; (iii) previous treatment for Helicobacter infection; (iv) receiving steroids, aspirin, or an antithrombotic; (v) a history of gastric surgery (excluding endoscopic gastric mucosal resection or dissection); (vi) severe comorbidities that influenced his or her 1362
life; (vii) known allergy to antibiotics; and (viii) current pregnancy or the possibility of becoming pregnant. Written informed consent was obtained from all participants. Randomization and intervention. Once the H. pylori infection status was confirmed, participants were randomly assigned to either of the two groups using a computer-generated randomization procedure (SPSS software, version 18.0; Chicago, IL, USA) that was implemented by an external statistician. The patients were randomized in blocks of six without stratification. The randomized list was maintained by the study coordinator, who was involved in the randomization of only one of the participating centers. The study investigator enrolled the patients and ascertained their treatment assignments. The concomitant regimen consisted of esomeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, which were administered twice daily for 10 days. The hybrid regimen consisted of esomeprazole 20 mg and amoxicillin 1 g, which were administered twice daily for 10 days, and clarithromycin 500 mg and metronidazole 500 mg, which were administered twice daily for the last 5 days. Outcomes and follow-up. The study’s primary outcome was the eradication rate of H. pylori infection. Eradication rates were compared for the concomitant and hybrid therapies. The secondary outcomes were treatment adherence rates and the frequencies of adverse events resulting from the two different eradication regimens. Treatment success was determined by a follow-up UBT (UBITIR-300, Photal, Otsuka, Japan). UBTs were performed at least 4 weeks after the end of each treatment. After eradication failure, rescue therapy consisted of bismuth-containing quadruple therapy (20 mg of esomeprazole twice daily, 300 mg of bismuth subcitrate four times daily, 500 mg of metronidazole three times daily, and 500 mg of tetracycline four times daily, as administered for 14 days). Rescue therapy response was assessed by UBTs that were performed at least 4 weeks after treatment. Sample size and statistical analysis. Sample sizes were calculated based on an equivalence test for an 8% difference between 90% for concomitant therapy and 90% for hybrid therapy, with a power of 0.80 and a two-sided α of 0.05. The total number of subjects was 482, requiring 241 patients in each group. The eradication rates were assessed in intention-to-treat (ITT), per protocol (PP), and modified ITT analyses. The ITT analysis included patients who enrolled in the study, regardless of whether they received medication for H. pylori infection. The modified ITT analysis included patients who took at least one medication and could be assessed using a follow-up UBT. The PP population was defined as patients who took each regimen for more than 90% and for whom a follow-up UBT was possible. The primary outcome was assessed in the ITT, modified ITT, and PP analyses. Baseline characteristics and secondary outcomes were validated based on the modified ITT population. All data were analyzed using SPSS software. Chi-square tests, t-tests, and logistic regression analyses were used. Values of P < 0.05 were considered statistically significant.
Journal of Gastroenterology and Hepatology 30 (2015) 1361–1366 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Therapy for Helicobacter pylori infection
Figure 1 Flow chart of participants through study. *3 diarrhea, 1 nausea, 2 regurgitation, and 1 headache.
Results Demographic and clinical characteristics. A total of 485 patients were enrolled in this study. After excluding screening failures, 238 patients were assigned to concomitant therapy and 241 patients were assigned to hybrid therapy (Fig. 1). During the study, 29 patients in the concomitant therapy group and 28 patients in the hybrid therapy group were lost to follow-up, because of low compliance or adverse events. The modified ITT population comprised 209 patients assigned to concomitant therapy and 213 patients assigned to hybrid therapy. Among patients in the modified ITT population, 195 patients assigned to concomitant therapy and 192 patients assigned to hybrid therapy were available for the PP analysis. There were no significant differences between the two groups in terms of baseline or clinical characteristics (Table 1). Outcomes. The H. pylori eradication rate was 78.6% (187/ 238) in the concomitant group and 78.8% (190/241) in the hybrid group, as determined by the ITT analysis (95% confidence interval [CI] for the between-group difference: −7.6, 7.1%). In the modified ITT analysis, the eradication rate was 89.5% (187/209) in the concomitant group and 89.2% (190/213) in the hybrid group (95% CI for the between-group difference: −5.6, 6.2%). The PP analysis was similar to the modified ITT analysis, in that the eradication rate was 89.8% (176/196) in the concomitant group and 89.6% (181/202) in the hybrid group (95% CI for the between-group difference: −5.8, 6.2%). For each of the analyses (ITT, modified ITT, and PP), the 95% confidence interval for the difference fell within the ± 8% margin of equivalence. Univariate analysis showed that clinical factors did not influence the therapeutic outcomes in either regimen (Table 2). In the treatment failure group of each regimen, 9 of 22 patients in the concomitant and 9 of 23 patients in the hybrid group were treated with bismuth quadruple therapy as rescue therapy. The
Table 1 Baseline demographic and clinical characteristics of the patients Characteristic
Concomitant Hybrid therapy therapy (n = 209) (n = 213)
P value
Gender 0.891 Male 125 (59.8%) 126 (59.2%) Female 84 (40.2%) 87 (40.8%) Age (mean ± SD), y 57.0 ± 11.5 57.5 ± 11.6 0.653 Smoking 66 (31.6%) 73 (34.3%) 0.556 Endoscopic findings Gastric ulcer 25 (12.0%) 22 (10.3%) 0.594 Duodenal ulcer 23 (11.0%) 20 (9.4%) 0.583 Gastritis 123 (58.9%) 128 (60.1%) 0.795 0.904 Helicobacter pylori colonization† Mild 74 (44.3%) 93 (53.8%) Moderate 35 (21.0%) 41 (23.7%) Marked 26 (15.6%) 19 (11.0%) †
Data were available for 167 and 173 patients, in the concomitant and hybrid therapy groups, respectively. SD, standard deviation.
eradication rate for rescue therapy was 88.9% (8/9) in the concomitant group and 66.7% (6/9) in the hybrid group. Compliance and adverse events. Adherence to the regimen (≥ 90%) was higher in the hybrid group (95.0%) than in the concomitant group (90.1%), a difference that was borderline significant (P = 0.051) (Table 3). During the study, seven patients discontinued medication because of adverse events, all of whom belonged to the concomitant group (Fig. 1). Adverse event rates were higher in the concomitant group than in the hybrid group for nausea (15.8% vs 8.8%; P = 0.028) and regurgitation (17.6% vs
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Table 2
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Univariate analysis of the clinical factors influencing therapeutic outcome of the two regimens
Clinical factor Gender Male Female Age < 60 ≥ 60 Smoking Nonsmoker Smoker Endoscopic finding Ulcer related Non-ulcer related Density of Helicobacter pylori† Low High Compliance Good‡ Poor
Concomitant therapy (n = 209)
P value
Hybrid therapy (n = 213)
P value
92.0% (115/125) 85.7% (72/84)
0.147
92.1% (116/126) 87.1% (61/70)
0.105
87.1% (101/116) 92.5% (86/93)
0.206
90.8% (109/120) 87.1% (81/93)
0.383
88.1% (126/143) 92.4% (61/66)
0.345
87.9% (123/140) 91.8% (67/73)
0.381
90.9% (40/44) 89.1% (147/165)
1.000
87.8% (36/41) 89.5% (154/172)
0.780
88.7% (94/106) 88.5% (54/61)
0.976
90.3% (102/113) 86.7% (52/60)
0.471
90.3% (176/195) 78.6% (11/14)
0.171
89.6% (181/202) 81.8% (9/11)
0.337
† Data were available for 167 and 173 patients in the concomitant and hybrid therapy groups, respectively. Low- and high- density of Helicobacter pylori corresponds to “mild” and “moderate” or “marked” colonization. ‡ ≥ 90% of medication.
Table 3
Adverse events
Adverse events
Concomitant therapy (n = 222), n (%)
Hybrid therapy (n = 215), n (%)
P value
Diarrhea Bloating Regurgitation Headache Glossitis Constipation Vomiting Abdominal pain Nausea Itching sense Changes in sense of taste Vaginitis Compliance†
64 (28.8) 31 (14.0) 39 (17.6) 33 (14.9) 19 (8.6) 9 (4.1) 6 (2.7) 28 (12.6) 35 (15.8) 21 (9.5) 86 (38.7) 3 (1.4) 201/223 (90.1)
63 (29.3) 40 (18.6) 23 (10.7) 23 (10.7) 20 (9.3) 14 (6.5) 7 (3.3) 39 (18.1) 19 (8.8) 13 (6.0) 69 (32.1) 1 (0.5) 209/220 (95.0)
0.913 0.189 0.040 0.193 0.785 0.250 0.734 0.109 0.028 0.183 0.147 0.331 0.051
†
Data were available in 223 patients of the concomitant therapy group and 220 patients of the hybrid therapy.
10.7%; P = 0.040) (Table 3). The rates of other adverse events did not differ between the two groups.
Discussion The standard triple therapy should not be recommended as a firstline treatment, especially in areas with high rates of antibiotic resistance.11 Since Zullo et al.12 highlighted sequential therapy in a recent study, this non-bismuth quadruple regimen has been regarded as an attractive treatment option. We also conducted the first randomized controlled trial of sequential (n = 162) and stan1364
dard triple (n = 164) therapies. Sequential therapy produced an eradication rate that was unsatisfactory (87.9% in the PP analysis), but significantly higher than the eradication rate conferred by standard triple therapy (77.8% in the PP analysis).13 According to a recent meta-analysis,8 there has been a tendency toward decreased efficacy in sequential therapy. Further, sequential therapy could not completely overcome infections, even in patients who only faced clarithromycin resistance.14,15 Therefore, the focus of attention shifted to two other nonbismuth quadruple regimens: concomitant and hybrid therapy. In a recent systemic review, concomitant therapy demonstrated approximately 90% effectiveness in ITT and PP analyses.16 In addition, the effect of clarithromycin resistance amounted to a minor obstacle in concomitant treatment.17 In an area with high antibiotic resistance, hybrid therapy also showed a higher eradication rate than did sequential therapy (92.9% [183/197] vs 79.9% [159/199], P = 0.001).18 In the current study, we have demonstrated that concomitant and hybrid therapies showed similar eradication rates for H. pylori infection (78.6% vs 78.8% in ITT, P = 0.943; 89.8% vs 89.6% in PP, P = 0.829). The eradication rates in our ITT analysis may have been reduced by the relatively high proportion of cases that were lost to follow-up. Considering the effects of loss to follow-up, the eradication rates of these two kinds of non-bismuth quadruple regimens were similar to eradication rates that have been reported by previous studies conducted in areas with high antibiotic resistance.9,14,19 In areas with high antibiotic resistance, the non-bismuth quadruple regimen has been regarded as a first-line treatment option.20 However, when applying non-bismuth quadruple regimens, it is not easy to achieve eradication rates that exceed 90% in PP or ITT analyses, as has been shown in our study.14,18 In a previous study with a relatively small cohort, researchers suggested that the administration of a non-bismuth quadruple regimen over a reasonable medication period was key to overcoming resistance to
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clarithromycin alone.9 However, metronidazole resistance is another obstacle that reduces the efficacy of non-bismuth regimens.21 In addition, higher metronidazole resistance rates implicate the high dual resistance of clarithromycin. This dual resistance is thought to be the main weakness of both concomitant and hybrid regimens. It may be difficult to achieve eradication rates of ≥ 90% in Korea,5 Iran,22 Italy, and Spain9 because there is ≥ 20% clarithromycin resistance and 30% metronidazole resistance in these regions. We have demonstrated that concomitant and hybrid regimens achieved similar eradication rates. Compliance is another important factor that determines the optimal treatment regimen. In our study, patients receiving hybrid therapy showed a higher rate of adherence than patients receiving concomitant therapy, although the difference was only borderline significant (95.1% vs 90.1%, P = 0.051). In addition, the incidences of nausea and regurgitation were significantly higher in the concomitant group, and all of the patients who withdrew because of adverse effects had belonged to the concomitant therapy group. In actuality, the concomitant and hybrid regimens consisted of the same kinds of antibiotics. However, they differed in terms of the number of antibiotics. As compared with the hybrid regimen, the concomitant regimen included twice the total dose of metronidazole and clarithromycin. It is well known that the adverse effects of metronidazole include nausea and regurgitation. In addition, both metronidazole and clarithromycin have bitter tastes. Considering that participation in a clinical trial could enhance patients’ compliance, the compliance gap between the concomitant and hybrid regimens might be wider in actual clinical practice. Moreover, the smaller number of drugs in the hybrid therapy makes it more cost-effective than the concomitant therapy. In the present study, we used a 10-day course of medication in the hybrid therapy, which provided similar results to 14-day hybrid therapies that have been used in previous studies.14,18 Although further studies are needed to confirm its efficacy, the 10-day hybrid therapy might achieve both high efficacy and compliance. The Maastricht IV guidelines recommend levofloxacin-based triple therapy containing a proton-pump inhibitor with amoxicillin as a rescue treatment in areas of high clarithromycin resistance.20 However, levofloxacin resistance has been increasing because of the use of quinolone for infections, such as pneumonia. In Korea, quinolone resistance (e.g., resistance to levofloxacin and moxifloxacin) was reported to be > 20%.23 In a recent study in Korea, disappointing results were observed for the administration of 14-day moxifloxacin-based triple therapy after various first-line treatment failures. The eradication rate of moxifloxacin-based rescue therapy was 70.7% for sequential therapy (n = 41) and 67.6% for concomitant therapy (n = 34).24 In a systemic review, a bismuth-based quadruple regimen showed a good eradication rate of 78% as a second-line regimen after the failure of conventional triple therapy.25 However, there is insufficient evidence regarding bismuth quadruple therapy after the failure of non-bismuth quadruple therapy in areas of high antibiotic resistance.26 Our study included too few patients to truly confirm the value of the bismuth quadruple regimen as a rescue option after the failure of nonbismuth quadruple therapy. Nonetheless, we found an acceptable average eradication rate of 77.8% (14/18). Further studies are needed to confirm the value of bismuth quadruple regimen as a rescue therapy after the failure of concomitant or hybrid therapy.
Therapy for Helicobacter pylori infection
The current study is the first that has compared hybrid and concomitant regimens in an Asian region with high resistance to antibiotics. Nonetheless, our study has several limitations. First, we did not conduct antibiotic resistance tests in relation to treatment regimens and eradication rates. However, it is well known that the antibiotic resistance rate is high in Korea. Therefore, the results of our study may be applicable in areas of other countries that also have high rates of antibiotic resistance. Second, loss to follow-up and poor compliance were relatively common in both treatment groups. ITT analysis is a valuable component of clinical trials of specific medications. However, ITT analyses may underestimate the efficacy of some treatments in the presence of substantial loss to follow-up. To overcome this problem, we supplemented the ITT analysis with a modified ITT analysis and a PP analysis. In conclusion, concomitant and hybrid regimens achieved similar, acceptable rates of eradication when they were employed to treat H. pylori infection in a region with high antibiotic resistance. As compared with concomitant therapy, the 10-day hybrid therapy offered better compliance and fewer adverse events. Accordingly, we suggest that 10-day hybrid therapy could be a reasonable first-line treatment option for H. pylori infection in this region.
Acknowledgments This research (company reference no. ISSNEXI0049) was conducted with financial support from AstraZeneca Korea Ltd. AstraZeneca only supplied the market drugs of esomeprazole and funding. We thank all the investigators and study personnel for their contribution to the study.
References 1 Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 2001; 345: 784–9. 2 Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143–53. 3 Megraud F, Coenen S, Versporten A et al. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut 2013; 62: 34–42. 4 Kobayashi I, Murakami K, Kato M et al. Changing antimicrobial susceptibility epidemiology of Helicobacter pylori strains in Japan between 2002 and 2005. J. Clin. Microbiol. 2007; 45: 4006–10. 5 Lee JY, Kim N, Kim MS et al. Factors affecting first-line triple therapy of Helicobacter pylori including CYP2C19 genotype and antibiotic resistance. Dig. Dis. Sci. 2014; 59: 1235–43. 6 Gisbert JP, Calvet X. Review article: non-bismuth quadruple (concomitant) therapy for eradication of Helicobacter pylori. Aliment. Pharmacol. Ther. 2011; 34: 604–17. 7 Gatta L, Vakil N, Leandro G, Di Mario F, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am. J. Gastroenterol. 2009; 104: 3069–79, quiz 1080. 8 Zullo A, Hassan C, Ridola L, De Francesco V, Vaira D. Standard triple and sequential therapies for Helicobacter pylori eradication: an update. Eur. J. Intern. Med. 2013; 24: 16–19. 9 Molina-Infante J, Romano M, Fernandez-Bermejo M et al. Optimized nonbismuth quadruple therapies cure most patients with
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Helicobacter pylori infection in populations with high rates of antibiotic resistance. Gastroenterology 2013; 145: 121–8.e1. Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence-based medicine rather than medicine-based evidence. Clin. Gastroenterol. Hepatol. 2014; 12: 177–86.e3, Discussion e12-3. Fock KM, Katelaris P, Sugano K et al. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. J. Gastroenterol. Hepatol. 2009; 24: 1587–600. Zullo A, Vaira D, Vakil N et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment. Pharmacol. Ther. 2003; 17: 719–26. Park HG, Jung MK, Jung JT et al. Randomised clinical trial: a comparative study of 10-day sequential therapy with 7-day standard triple therapy for Helicobacter pylori infection in naive patients. Aliment. Pharmacol. Ther. 2012; 35: 56–65. Molina-Infante J, Pazos-Pacheco C, Vinagre-Rodriguez G et al. Nonbismuth quadruple (concomitant) therapy: empirical and tailored efficacy versus standard triple therapy for clarithromycinsusceptible Helicobacter pylori and versus sequential therapy for clarithromycin-resistant strains. Helicobacter 2012; 17: 269–76. Huang YK, Wu MC, Wang SS et al. Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. J Dig Dis 2012; 13: 232–8. Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009; 14: 109–18. Fischbach L, Evans EL. Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment. Pharmacol. Ther. 2007; 26: 343–57.
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18 Sardarian H, Fakheri H, Hosseini V, Taghvaei T, Maleki I, Mokhtare M. Comparison of hybrid and sequential therapies for Helicobacter pylori eradication in Iran: a prospective randomized trial. Helicobacter 2013; 18: 129–34. 19 McNicholl AG, Marin AC, Molina-Infante J et al. Randomised clinical trial comparing sequential and concomitant therapies for Helicobacter pylori eradication in routine clinical practice. Gut 2014; 63: 244–9. 20 Malfertheiner P, Megraud F, O’Morain CA et al. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut 2012; 61: 646–64. 21 Greenberg ER, Anderson GL, Morgan DR et al. 14-day triple, 5-day concomitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomised trial. Lancet 2011; 378: 507–14. 22 Kohanteb J, Bazargani A, Saberi-Firoozi M, Mobasser A. Antimicrobial susceptibility testing of Helicobacter pylori to selected agents by agar dilution method in Shiraz-Iran. Indian J. Med. Microbiol. 2007; 25: 374–7. 23 Lee JY, Kim N. Future trends of Helicobacter pylori eradication therapy in Korea. Korean J. Gastroenterol. 2014; 63: 158–70. 24 Kang KK, Lee DH, Oh DH et al. Helicobacter pylori eradication with moxifloxacin-containing therapy following failed first-line therapies in South Korea. World J. Gastroenterol. 2014; 20: 6932–8. 25 Marin AC, McNicholl AG, Gisbert JP. A review of rescue regimens after clarithromycin-containing triple therapy failure (for Helicobacter pylori eradication). Expert Opin. Pharmacother. 2013; 14: 843–61. 26 Hsu PI, Chen WC, Tsay FW et al. Ten-day quadruple therapy comprising proton-pump inhibitor, bismuth, tetracycline, and levofloxacin achieves a high eradication rate for Helicobacter pylori infection after failure of sequential therapy. Helicobacter 2014; 19: 74–9.
Journal of Gastroenterology and Hepatology 30 (2015) 1361–1366 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
doi:10.1111/jgh.12983
GASTROENTEROLOGY
Concomitant and hybrid therapy for Helicobacter pylori infection: A randomized clinical trial Jun Heo,* Seong Woo Jeon,* Jin Tae Jung,† Joong Goo Kwon,† Dong Wook Lee,† Hyun Soo Kim,‡ Chang Hun Yang,§ Jeong Bae Park,§ Kyung Sik Park,¶ Kwang Bum Cho,¶ Si Hyung Lee,** Byung Ik Jang** and Daegu-Gyeongbuk Gastrointestinal Study Group *Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University Hospital, †Division of Gastroenterology and Hepatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, ‡Division of Gastroenterology and Hepatology, Department of Internal Medicine, Daegu Fatima Hospital, ¶Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keimyung University School of Medicine, **Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, and §Division of Gastroenterology and Hepatology, Department of Internal Medicine, Dongguk University Gyeongju Hospital, Gyeongju, Korea
Key words Helicobacter pylori, peptic ulcer diseases, stomach, treatment and antimicrobial resistance. Accepted for publication 24 March 2015. Correspondence Dr Seong Woo Jeon, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University Hospital, 474 Hakjeongdong, Buk-gu, Daegu, South Korea. Email: [email protected] Conflict of interest: None. Guarantor of the article: Seong Woo Jeon, MD, PhD. Specific author contributions: Jun Heo was involved in the analysis and interpretation of data, drafting of the manuscript, statistical analysis. Seong Woo Jeon was involved in the study design, analysis and interpretation of data, critical revision of the manuscript, administrative, technical and material support, obtained funding. Jin Tae Jung, Joong Goo Kwon, Dong Wook Lee, Hyun Soo Kim, Chang Hun Yang, Jeong Bae Park, Kyung Sik Park, Kwang Bum Cho, Si Hyung Lee, Byung Ik Jang were involved in the acquisition of data, critical revision of the manuscript, study supervision. All authors read and approved the final manuscript.
Abstract Background and Aims: This study aimed to validate the equivalence of first-line concomitant and hybrid regimens for Helicobacter pylori infection in an era of increasing antibiotic resistance. The study also aimed to assess regimen compliance. Methods: H. pylori-infected patients from six hospitals in Korea were randomly assigned to either concomitant or hybrid regimens. The concomitant regimen consisted of 20 mg of esomeprazole, 1 g of amoxicillin, 500 mg of clarithromycin, and 500 mg metronidazole, twice daily for 10 days. The hybrid regimen consisted of a 5-day dual therapy (20 mg of esomeprazole and 1 g of amoxicillin, twice daily) followed by a 5-day quadruple therapy (20 mg of esomeprazole, 1 g of amoxicillin, 500 mg of clarithromycin, and 500 mg of metronidazole, twice daily). Results: Eradication rates for concomitant and hybrid therapy were 78.6% (187/238) and 78.8% (190/241) in the intention-to-treat analysis, and 89.8% (176/196) and 89.6% (181/ 202) in the per protocol analysis. For both analyses, 95% confidence intervals fell within the ± 8% equivalence margin. Adherence was better in the hybrid group (95.0%) than in the concomitant group (90.1%), a difference that was borderline significant (P = 0.051). Adverse event rates were higher in the concomitant group than in the hybrid group for nausea (15.8% vs 8.8%; P = 0.028) and regurgitation (17.6% vs 10.7%; P = 0.040). Conclusion: As compared with concomitant therapy, hybrid therapy offered similar efficacy, better compliance, and fewer adverse events. Hybrid therapy could be a reasonable first-line treatment option for H. pylori in areas with high antibiotics resistance.
Introduction Helicobacter pylori infection’s relationships with gastritis, gastric ulcer, and gastric cancer have been investigated in many studies.1 Treatment for Helicobacter was developed to decrease the involve-
ment of H. pylori infection in these diseases. However, resistance to antibiotic therapy has increased alongside rapid growth in the use of antibiotics for H. pylori and other infections. Consequently, the conventional triple regimen is no longer recommended for use in regions where the rate of clarithromycin resistance has been
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reported to exceed 20%, such as in Korea, Japan, Italy, and Greece.2–5 To overcome the antibiotic resistance, non-bismuth quadruple regimens, three major options—sequential, concomitant, and hybrid therapies—have been validated as the next generation of treatment through many years of studies. Sequential and concomitant regimens have shown higher eradication rates than that with triple therapy.6,7 However, the efficacy of sequential therapy has declined since 2008.8 On the other hand, hybrid regimen needs to be validated in through additional randomized controlled trials. Concomitant and hybrid therapies have been compared in only one previous study, which was conducted in Italy and Spain.9 No studies comparing both regimens have been conducted in Asia, which has high rates of clarithromycin and metronidazole resistance. Optimal eradication depends on two major factors: the regimen’s eradication ability and patient compliance.10 Each regimen’s eradication ability depends on several external factors, in addition to innate capacity. These external factors include gastric acidity, the density of infection, the patient’s metabolism, and more importantly, the antibiotic resistance of H. pylori. In Korea, rates of H. pylori resistance against clarithromycin and metronidazole have been reported to be as high as ≥ 20% and ≥ 30%, respectively.5 The extent of patient compliance with a regimen is usually a reflection of that regimen’s adverse events. In the present study, we compared concomitant and hybrid therapy in terms of both eradication ability and patient compliance, which were assessed in a multicenter, randomized, prospective trial.
Methods Study design. This prospective, randomized, controlled, open-label trial was conducted at six medical centers in the Daegu and Kyungsang territories, Korea, between March 2013 and April 2014. The study was approved by the institutional international review board of each participating center and was registered as a clinical trial (http://www.cris.nih.go.kr, approved number KCT 0000728). The trial was conducted in accordance with good clinical practices under the principles of the Declaration of Helsinki. Participants. This study enrolled patients who both required and were willing to receive treatment for H. pylori infection. There were eight criteria for inclusion in this study. (i) The patient had been diagnosed with H. pylori infection. The diagnosis of H. pylori infection was defined as the presence of positive results of any two of the following tests: a rapid urease test, a histologic assessment, or a 13 C-urea breath test (UBT). (ii) The patients had an active/inactive peptic ulcer diagnosed through endoscopy. (iii) The patient had dyspepsia without organic disorders, as determined by endoscopy. (iv) The patient underwent endoscopic mucosal resection or submucosal dissection to treat gastric adenoma or early gastric cancer. The exclusion criteria were as follows: (i) younger than 18 years old; (ii) refusal to participate in the study; (iii) previous treatment for Helicobacter infection; (iv) receiving steroids, aspirin, or an antithrombotic; (v) a history of gastric surgery (excluding endoscopic gastric mucosal resection or dissection); (vi) severe comorbidities that influenced his or her 1362
life; (vii) known allergy to antibiotics; and (viii) current pregnancy or the possibility of becoming pregnant. Written informed consent was obtained from all participants. Randomization and intervention. Once the H. pylori infection status was confirmed, participants were randomly assigned to either of the two groups using a computer-generated randomization procedure (SPSS software, version 18.0; Chicago, IL, USA) that was implemented by an external statistician. The patients were randomized in blocks of six without stratification. The randomized list was maintained by the study coordinator, who was involved in the randomization of only one of the participating centers. The study investigator enrolled the patients and ascertained their treatment assignments. The concomitant regimen consisted of esomeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, which were administered twice daily for 10 days. The hybrid regimen consisted of esomeprazole 20 mg and amoxicillin 1 g, which were administered twice daily for 10 days, and clarithromycin 500 mg and metronidazole 500 mg, which were administered twice daily for the last 5 days. Outcomes and follow-up. The study’s primary outcome was the eradication rate of H. pylori infection. Eradication rates were compared for the concomitant and hybrid therapies. The secondary outcomes were treatment adherence rates and the frequencies of adverse events resulting from the two different eradication regimens. Treatment success was determined by a follow-up UBT (UBITIR-300, Photal, Otsuka, Japan). UBTs were performed at least 4 weeks after the end of each treatment. After eradication failure, rescue therapy consisted of bismuth-containing quadruple therapy (20 mg of esomeprazole twice daily, 300 mg of bismuth subcitrate four times daily, 500 mg of metronidazole three times daily, and 500 mg of tetracycline four times daily, as administered for 14 days). Rescue therapy response was assessed by UBTs that were performed at least 4 weeks after treatment. Sample size and statistical analysis. Sample sizes were calculated based on an equivalence test for an 8% difference between 90% for concomitant therapy and 90% for hybrid therapy, with a power of 0.80 and a two-sided α of 0.05. The total number of subjects was 482, requiring 241 patients in each group. The eradication rates were assessed in intention-to-treat (ITT), per protocol (PP), and modified ITT analyses. The ITT analysis included patients who enrolled in the study, regardless of whether they received medication for H. pylori infection. The modified ITT analysis included patients who took at least one medication and could be assessed using a follow-up UBT. The PP population was defined as patients who took each regimen for more than 90% and for whom a follow-up UBT was possible. The primary outcome was assessed in the ITT, modified ITT, and PP analyses. Baseline characteristics and secondary outcomes were validated based on the modified ITT population. All data were analyzed using SPSS software. Chi-square tests, t-tests, and logistic regression analyses were used. Values of P < 0.05 were considered statistically significant.
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Figure 1 Flow chart of participants through study. *3 diarrhea, 1 nausea, 2 regurgitation, and 1 headache.
Results Demographic and clinical characteristics. A total of 485 patients were enrolled in this study. After excluding screening failures, 238 patients were assigned to concomitant therapy and 241 patients were assigned to hybrid therapy (Fig. 1). During the study, 29 patients in the concomitant therapy group and 28 patients in the hybrid therapy group were lost to follow-up, because of low compliance or adverse events. The modified ITT population comprised 209 patients assigned to concomitant therapy and 213 patients assigned to hybrid therapy. Among patients in the modified ITT population, 195 patients assigned to concomitant therapy and 192 patients assigned to hybrid therapy were available for the PP analysis. There were no significant differences between the two groups in terms of baseline or clinical characteristics (Table 1). Outcomes. The H. pylori eradication rate was 78.6% (187/ 238) in the concomitant group and 78.8% (190/241) in the hybrid group, as determined by the ITT analysis (95% confidence interval [CI] for the between-group difference: −7.6, 7.1%). In the modified ITT analysis, the eradication rate was 89.5% (187/209) in the concomitant group and 89.2% (190/213) in the hybrid group (95% CI for the between-group difference: −5.6, 6.2%). The PP analysis was similar to the modified ITT analysis, in that the eradication rate was 89.8% (176/196) in the concomitant group and 89.6% (181/202) in the hybrid group (95% CI for the between-group difference: −5.8, 6.2%). For each of the analyses (ITT, modified ITT, and PP), the 95% confidence interval for the difference fell within the ± 8% margin of equivalence. Univariate analysis showed that clinical factors did not influence the therapeutic outcomes in either regimen (Table 2). In the treatment failure group of each regimen, 9 of 22 patients in the concomitant and 9 of 23 patients in the hybrid group were treated with bismuth quadruple therapy as rescue therapy. The
Table 1 Baseline demographic and clinical characteristics of the patients Characteristic
Concomitant Hybrid therapy therapy (n = 209) (n = 213)
P value
Gender 0.891 Male 125 (59.8%) 126 (59.2%) Female 84 (40.2%) 87 (40.8%) Age (mean ± SD), y 57.0 ± 11.5 57.5 ± 11.6 0.653 Smoking 66 (31.6%) 73 (34.3%) 0.556 Endoscopic findings Gastric ulcer 25 (12.0%) 22 (10.3%) 0.594 Duodenal ulcer 23 (11.0%) 20 (9.4%) 0.583 Gastritis 123 (58.9%) 128 (60.1%) 0.795 0.904 Helicobacter pylori colonization† Mild 74 (44.3%) 93 (53.8%) Moderate 35 (21.0%) 41 (23.7%) Marked 26 (15.6%) 19 (11.0%) †
Data were available for 167 and 173 patients, in the concomitant and hybrid therapy groups, respectively. SD, standard deviation.
eradication rate for rescue therapy was 88.9% (8/9) in the concomitant group and 66.7% (6/9) in the hybrid group. Compliance and adverse events. Adherence to the regimen (≥ 90%) was higher in the hybrid group (95.0%) than in the concomitant group (90.1%), a difference that was borderline significant (P = 0.051) (Table 3). During the study, seven patients discontinued medication because of adverse events, all of whom belonged to the concomitant group (Fig. 1). Adverse event rates were higher in the concomitant group than in the hybrid group for nausea (15.8% vs 8.8%; P = 0.028) and regurgitation (17.6% vs
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Table 2
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Univariate analysis of the clinical factors influencing therapeutic outcome of the two regimens
Clinical factor Gender Male Female Age < 60 ≥ 60 Smoking Nonsmoker Smoker Endoscopic finding Ulcer related Non-ulcer related Density of Helicobacter pylori† Low High Compliance Good‡ Poor
Concomitant therapy (n = 209)
P value
Hybrid therapy (n = 213)
P value
92.0% (115/125) 85.7% (72/84)
0.147
92.1% (116/126) 87.1% (61/70)
0.105
87.1% (101/116) 92.5% (86/93)
0.206
90.8% (109/120) 87.1% (81/93)
0.383
88.1% (126/143) 92.4% (61/66)
0.345
87.9% (123/140) 91.8% (67/73)
0.381
90.9% (40/44) 89.1% (147/165)
1.000
87.8% (36/41) 89.5% (154/172)
0.780
88.7% (94/106) 88.5% (54/61)
0.976
90.3% (102/113) 86.7% (52/60)
0.471
90.3% (176/195) 78.6% (11/14)
0.171
89.6% (181/202) 81.8% (9/11)
0.337
† Data were available for 167 and 173 patients in the concomitant and hybrid therapy groups, respectively. Low- and high- density of Helicobacter pylori corresponds to “mild” and “moderate” or “marked” colonization. ‡ ≥ 90% of medication.
Table 3
Adverse events
Adverse events
Concomitant therapy (n = 222), n (%)
Hybrid therapy (n = 215), n (%)
P value
Diarrhea Bloating Regurgitation Headache Glossitis Constipation Vomiting Abdominal pain Nausea Itching sense Changes in sense of taste Vaginitis Compliance†
64 (28.8) 31 (14.0) 39 (17.6) 33 (14.9) 19 (8.6) 9 (4.1) 6 (2.7) 28 (12.6) 35 (15.8) 21 (9.5) 86 (38.7) 3 (1.4) 201/223 (90.1)
63 (29.3) 40 (18.6) 23 (10.7) 23 (10.7) 20 (9.3) 14 (6.5) 7 (3.3) 39 (18.1) 19 (8.8) 13 (6.0) 69 (32.1) 1 (0.5) 209/220 (95.0)
0.913 0.189 0.040 0.193 0.785 0.250 0.734 0.109 0.028 0.183 0.147 0.331 0.051
†
Data were available in 223 patients of the concomitant therapy group and 220 patients of the hybrid therapy.
10.7%; P = 0.040) (Table 3). The rates of other adverse events did not differ between the two groups.
Discussion The standard triple therapy should not be recommended as a firstline treatment, especially in areas with high rates of antibiotic resistance.11 Since Zullo et al.12 highlighted sequential therapy in a recent study, this non-bismuth quadruple regimen has been regarded as an attractive treatment option. We also conducted the first randomized controlled trial of sequential (n = 162) and stan1364
dard triple (n = 164) therapies. Sequential therapy produced an eradication rate that was unsatisfactory (87.9% in the PP analysis), but significantly higher than the eradication rate conferred by standard triple therapy (77.8% in the PP analysis).13 According to a recent meta-analysis,8 there has been a tendency toward decreased efficacy in sequential therapy. Further, sequential therapy could not completely overcome infections, even in patients who only faced clarithromycin resistance.14,15 Therefore, the focus of attention shifted to two other nonbismuth quadruple regimens: concomitant and hybrid therapy. In a recent systemic review, concomitant therapy demonstrated approximately 90% effectiveness in ITT and PP analyses.16 In addition, the effect of clarithromycin resistance amounted to a minor obstacle in concomitant treatment.17 In an area with high antibiotic resistance, hybrid therapy also showed a higher eradication rate than did sequential therapy (92.9% [183/197] vs 79.9% [159/199], P = 0.001).18 In the current study, we have demonstrated that concomitant and hybrid therapies showed similar eradication rates for H. pylori infection (78.6% vs 78.8% in ITT, P = 0.943; 89.8% vs 89.6% in PP, P = 0.829). The eradication rates in our ITT analysis may have been reduced by the relatively high proportion of cases that were lost to follow-up. Considering the effects of loss to follow-up, the eradication rates of these two kinds of non-bismuth quadruple regimens were similar to eradication rates that have been reported by previous studies conducted in areas with high antibiotic resistance.9,14,19 In areas with high antibiotic resistance, the non-bismuth quadruple regimen has been regarded as a first-line treatment option.20 However, when applying non-bismuth quadruple regimens, it is not easy to achieve eradication rates that exceed 90% in PP or ITT analyses, as has been shown in our study.14,18 In a previous study with a relatively small cohort, researchers suggested that the administration of a non-bismuth quadruple regimen over a reasonable medication period was key to overcoming resistance to
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clarithromycin alone.9 However, metronidazole resistance is another obstacle that reduces the efficacy of non-bismuth regimens.21 In addition, higher metronidazole resistance rates implicate the high dual resistance of clarithromycin. This dual resistance is thought to be the main weakness of both concomitant and hybrid regimens. It may be difficult to achieve eradication rates of ≥ 90% in Korea,5 Iran,22 Italy, and Spain9 because there is ≥ 20% clarithromycin resistance and 30% metronidazole resistance in these regions. We have demonstrated that concomitant and hybrid regimens achieved similar eradication rates. Compliance is another important factor that determines the optimal treatment regimen. In our study, patients receiving hybrid therapy showed a higher rate of adherence than patients receiving concomitant therapy, although the difference was only borderline significant (95.1% vs 90.1%, P = 0.051). In addition, the incidences of nausea and regurgitation were significantly higher in the concomitant group, and all of the patients who withdrew because of adverse effects had belonged to the concomitant therapy group. In actuality, the concomitant and hybrid regimens consisted of the same kinds of antibiotics. However, they differed in terms of the number of antibiotics. As compared with the hybrid regimen, the concomitant regimen included twice the total dose of metronidazole and clarithromycin. It is well known that the adverse effects of metronidazole include nausea and regurgitation. In addition, both metronidazole and clarithromycin have bitter tastes. Considering that participation in a clinical trial could enhance patients’ compliance, the compliance gap between the concomitant and hybrid regimens might be wider in actual clinical practice. Moreover, the smaller number of drugs in the hybrid therapy makes it more cost-effective than the concomitant therapy. In the present study, we used a 10-day course of medication in the hybrid therapy, which provided similar results to 14-day hybrid therapies that have been used in previous studies.14,18 Although further studies are needed to confirm its efficacy, the 10-day hybrid therapy might achieve both high efficacy and compliance. The Maastricht IV guidelines recommend levofloxacin-based triple therapy containing a proton-pump inhibitor with amoxicillin as a rescue treatment in areas of high clarithromycin resistance.20 However, levofloxacin resistance has been increasing because of the use of quinolone for infections, such as pneumonia. In Korea, quinolone resistance (e.g., resistance to levofloxacin and moxifloxacin) was reported to be > 20%.23 In a recent study in Korea, disappointing results were observed for the administration of 14-day moxifloxacin-based triple therapy after various first-line treatment failures. The eradication rate of moxifloxacin-based rescue therapy was 70.7% for sequential therapy (n = 41) and 67.6% for concomitant therapy (n = 34).24 In a systemic review, a bismuth-based quadruple regimen showed a good eradication rate of 78% as a second-line regimen after the failure of conventional triple therapy.25 However, there is insufficient evidence regarding bismuth quadruple therapy after the failure of non-bismuth quadruple therapy in areas of high antibiotic resistance.26 Our study included too few patients to truly confirm the value of the bismuth quadruple regimen as a rescue option after the failure of nonbismuth quadruple therapy. Nonetheless, we found an acceptable average eradication rate of 77.8% (14/18). Further studies are needed to confirm the value of bismuth quadruple regimen as a rescue therapy after the failure of concomitant or hybrid therapy.
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The current study is the first that has compared hybrid and concomitant regimens in an Asian region with high resistance to antibiotics. Nonetheless, our study has several limitations. First, we did not conduct antibiotic resistance tests in relation to treatment regimens and eradication rates. However, it is well known that the antibiotic resistance rate is high in Korea. Therefore, the results of our study may be applicable in areas of other countries that also have high rates of antibiotic resistance. Second, loss to follow-up and poor compliance were relatively common in both treatment groups. ITT analysis is a valuable component of clinical trials of specific medications. However, ITT analyses may underestimate the efficacy of some treatments in the presence of substantial loss to follow-up. To overcome this problem, we supplemented the ITT analysis with a modified ITT analysis and a PP analysis. In conclusion, concomitant and hybrid regimens achieved similar, acceptable rates of eradication when they were employed to treat H. pylori infection in a region with high antibiotic resistance. As compared with concomitant therapy, the 10-day hybrid therapy offered better compliance and fewer adverse events. Accordingly, we suggest that 10-day hybrid therapy could be a reasonable first-line treatment option for H. pylori infection in this region.
Acknowledgments This research (company reference no. ISSNEXI0049) was conducted with financial support from AstraZeneca Korea Ltd. AstraZeneca only supplied the market drugs of esomeprazole and funding. We thank all the investigators and study personnel for their contribution to the study.
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