Original Paper Received: September 10, 2014 Accepted after revision: May 28, 2015 Published online: July 11, 2015
Digestion 2015;92:55–59 DOI: 10.1159/000434627
Current Status of Five Different Regimens for Empiric First-Line Helicobacter pylori Eradication in Turkey Gokhan Gungor a Murat Baglıcakoglu e Ertugrul Kayacetin f Murat Biyik c Ramazan Ucar b Hakan Goktepe d Huseyin Ataseven c Ali Demir c
Departments of a Gastroenterology, and b Internal Medicine, Konya Education and Research Hospital, c Department of Gastroenterology, Meram School of Medicine, Konya NE University, d Department of Internal Medicine, Sarayonu State Hospital, Konya, e Department of Internal Medicine, Çorum State Hospital, Çorum, f Department of Gastroenterology, Türkiye Yüksek İhtisas Education and Training Hospital, Ankara, Turkey
Abstract Background/Aims: This study aimed at comparing the efficacy and tolerability of 5 different regimens for Helicobacter pylori eradication in recent years. Methods: H. pylori-positive patients with dyspeptic symptoms were included and separated into 5 groups. The ‘PAC group’ was given pantoprazole, amoxicillin and clarithromycin for 14 days. The ‘PAM group’ was given pantoprazole, amoxicillin and metronidazole for 14 days. The ‘bismuth-containing group’ was given pantoprazole, bismuth subsalicylate, tetracycline and metronidazole for 14 days. The ‘sequential group’ was given pantoprazole and amoxicillin for 5 days, followed by pantoprazole, tetracycline, and metronidazole for the next 5 days. The ‘concomitant group’ was given pantoprazole, amoxicillin, tetracycline, and metronidazole for 10 days. Eradication was assessed through the urea breath test on 6 weeks after eradication therapy. Results: The eradication rate of intention-to-treat/per protocol were 42/48.3% in the PAC group, 52/54.2% in the PAM group, 62/77.5% in the bismuth group, 71/80.7% in the sequential group and 72/83.7% in concomi-
© 2015 S. Karger AG, Basel 0012–2823/15/0922–0055$39.50/0 E-Mail [email protected] www.karger.com/dig
tant group. The frequency of mild and moderate side effects was similar between groups. Conclusion: The concomitant and sequential therapies are an effective treatment for H. pylori. Bismuth-containing therapy is superior to conventional triple therapies; however, the eradication rate is not satisfactory. In our country, conventional triple therapies are not effective for eradication. © 2015 S. Karger AG, Basel
Introduction
Helicobacter pylori is one of the most common infectious diseases in developing countries. In Turkey, the prevalence of this disease is 70–85% [1, 2]. The infection of H. pylori is associated with the development of chronic gastritis, increased risk of peptic ulcer disease, gastric cancer and MALT lymphoma [3]. The eradication of the infection provides decrease in the activity of gastritis [4], prevention of peptic ulcer recurrence [5], decrease in the risk of development of gastric cancer [6] and the regression of the MALT lymphoma [7]. There are several treatment protocols for H. pylori, but none of them are perfect regimen and there is no monotype regimen that can be applied to all patients. ThereGokhan Gungor, MD Department of Gastroenterology Konya Education and Research Hospital Meram/Konya (Turkey) E-Mail drgokhangungor @ hotmail.com
Downloaded by: McMaster University 198.143.32.65 - 1/28/2016 12:11:45 AM
Key Words Helicobacter eradication · Concomitant · Sequential · Bismuth containing · Triple treatments
Materials and Methods Patients Five-hundred patients who were diagnosed H. pylori-positive using the 14C-urea breath test (UBT), stool antigen test, rapid urease test or histopathology were included consecutively to study. The patients were naive to H. pylori treatment and aged ≥18 years with dyspeptic symptoms. The exclusion criteria were pregnancy, lactation, history of gastric surgery, previous attempt of H. pylori eradication, liver or renal failure, alcohol abuse, known allergy to the prescribed antibiotics and usage of proton pump inhibitors (PPIs), histamin-2 receptor antagonists (H2RA), non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and bismuth salts in the last 4 weeks. The study was approved by the local ethics committee and conducted according to the Declaration of Helsinki and the guidelines for good clinical practice. Study Design and Treatment This was a prospective, randomized, parallel-arm, single-center study. All patients were included consecutively into study groups. The first group used the standard 2-week triple therapy consisting of pantoprazole 40 mg BID, amoxicillin 1 g BID and clarithromycin 500 mg BID (PAC group). The second group used the other 2-week triple therapy consisting of pantoprazole 40 mg BID, amoxicillin 1 g BID and metronidazole 500 mg BID (PAM group). The third group used 14-day bismuth-based quadruple therapy consisting of pantoprazole 40 mg BID, bismuth subsalicylate 300 mg QID, tetracycline 500 mg QID and metronidazole 500 mg TID (bismuth group). The fourth group used 10-day sequential therapy: pantoprazole 40 mg BID and amoxicillin 1 g BID for 5 days, followed by pantoprazole 40 mg BID, tetracycline 500 mg QID, and metronidazole 500 mg BID for the next 5 days (sequential group).
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Digestion 2015;92:55–59 DOI: 10.1159/000434627
The fifth group used 10-day, 4-drug, 3-antibiotic, non-bismuth-containing ‘concomitant’ therapy: pantoprazole 40 mg BID, amoxicillin 1 g BID, tetracycline 500 mg QID, and metronidazole 500 mg BID (concomitant group). For all groups, pantoprazole was prescribed before breakfast and dinner; all antibiotics were to be taken after meals. Patient compliance was evaluated at the end of treatment by pill count from the packet of the drugs and was considered acceptable if >80% of the medication had been administered and also patients were questioned for any adverse effects (AEs). Patients who were noncompliant were withdrawn from the study. A control UBT test was performed 6 weeks after the end of treatment and successful eradication was defined as a negative UBT test. No antibiotics, PPIs or H2RA were allowed prior to the control eradication test. Statistical Analyses Non-categorical values are given as mean and standard deviation. Statistical analyses were performed using ANOVA, t test and χ2 test. Intent-to-treat (ITT – all patients included in the protocols) and per-protocol (PP – the number of patients adherent to protocol) population analyses were performed for eradication rates. ITT and PP eradication rates were compared with χ2 test. Calculations were performed using the SPSS version 10.0 for Windows statistical package. p < 0.05 was considered to be statistically significant.
Results
One-hundred patients were distributed consecutively to each group. Four hundred and thirty-seven of 500 patients (87.4%) completed the study protocol. Forty-six patients (9.2%) were lost to follow-up. Seven patients (1.4%) discontinued because of AEs. Ten patients were excluded due to protocol violations (2%). The baseline demographic-clinical characteristics and study data of each group were shown table 1. There was no statistically significant difference in terms of age, gender and smoking patterns in each group. The ITT and PP eradication rates of eradication regimens are shown in table 2 and comparison of the eradication rates between each groups and p values is shown in table 3. According to these results, there were no statistical differences between the eradication rates of PAC and PAM groups. The eradication rates of the bismuthcontaining sequential and concomitant regimens were significantly higher compared with PAC and PAM groups. The eradication rates of sequential and concomitant regimens were higher than the bismuth-containing regimen, but this difference was not statistically significant. The sequential and concomitant regimens were similar; there were no statistical differences between the eradication rates of the sequential and concomitant groups. Gungor/Baglıcakoglu/Kayacetin/Biyik/ Ucar/Goktepe/Ataseven/Demir
Downloaded by: McMaster University 198.143.32.65 - 1/28/2016 12:11:45 AM
fore, the most appropriate treatment for patients should be selected according to antibiotic resistance of each region, eradication rates of regimens, H. pylori prevalence, consensus reports and clinical observations. In recent studies, an important decrease in the efficacy of standard eradication regimens was reported [8]. Bismuth-containing quadruple treatment [9], sequential [10, 11] and non-bismuth quadruple ‘concomitant’ treatment [12], regimens may be an effective first-line antiHelicobacter therapy and alternative for standard triple regimens. In our country, there is not enough information especially about concomitant treatment for H. pylori eradication. The aim of this study was to compare the current status of regimens and the success and tolerability of sequential and concomitant therapies with conventional triples and bismuth-containing regimens for first-line H. pylori eradication in the middle Anatolian region of Turkey.
Table 1. The baseline demographic-clinical characteristics and study data of each group Groups
ITT population Lost to follow-up Discontinued due to AEs Excluded due to poor compliance PP population Median age, years Male/female Smoking (>5 cigarettes/day) Alcohol (>40 g/day)
p
PAC
PAM
bismuth
sequential
concomitant
100 10 2 1 87 43.1±16.4 39/61 10 1
100 4 0 0 96 42.9±16.4 45/55 10 2
100 13 3 4 80 43.7±15.8 43/57 12 2
100 8 1 3 88 40.7±14.5 49/51 12 –
100 11 1 2 86 45.6±14.8 37/63 9 1
0.28 0.44 0.14
ANOVA analysis, p > 0.05 non-significantly.
Discussion
Triple treatment consisting of a PPI and 2 antimicrobial agents (clarithromycin, amoxicillin and metronidazole combinations) is the first-line option for eradication of H. pylori according to the Maastricht III Consensus Report [13]. In the Maastricht IV Report [14], clarithromycin-containing treatments are recommended for firstline empirical treatment in areas that have low clarithromycin resistance (
Digestion 2015;92:55–59 DOI: 10.1159/000434627
Current Status of Five Different Regimens for Empiric First-Line Helicobacter pylori Eradication in Turkey Gokhan Gungor a Murat Baglıcakoglu e Ertugrul Kayacetin f Murat Biyik c Ramazan Ucar b Hakan Goktepe d Huseyin Ataseven c Ali Demir c
Departments of a Gastroenterology, and b Internal Medicine, Konya Education and Research Hospital, c Department of Gastroenterology, Meram School of Medicine, Konya NE University, d Department of Internal Medicine, Sarayonu State Hospital, Konya, e Department of Internal Medicine, Çorum State Hospital, Çorum, f Department of Gastroenterology, Türkiye Yüksek İhtisas Education and Training Hospital, Ankara, Turkey
Abstract Background/Aims: This study aimed at comparing the efficacy and tolerability of 5 different regimens for Helicobacter pylori eradication in recent years. Methods: H. pylori-positive patients with dyspeptic symptoms were included and separated into 5 groups. The ‘PAC group’ was given pantoprazole, amoxicillin and clarithromycin for 14 days. The ‘PAM group’ was given pantoprazole, amoxicillin and metronidazole for 14 days. The ‘bismuth-containing group’ was given pantoprazole, bismuth subsalicylate, tetracycline and metronidazole for 14 days. The ‘sequential group’ was given pantoprazole and amoxicillin for 5 days, followed by pantoprazole, tetracycline, and metronidazole for the next 5 days. The ‘concomitant group’ was given pantoprazole, amoxicillin, tetracycline, and metronidazole for 10 days. Eradication was assessed through the urea breath test on 6 weeks after eradication therapy. Results: The eradication rate of intention-to-treat/per protocol were 42/48.3% in the PAC group, 52/54.2% in the PAM group, 62/77.5% in the bismuth group, 71/80.7% in the sequential group and 72/83.7% in concomi-
© 2015 S. Karger AG, Basel 0012–2823/15/0922–0055$39.50/0 E-Mail [email protected] www.karger.com/dig
tant group. The frequency of mild and moderate side effects was similar between groups. Conclusion: The concomitant and sequential therapies are an effective treatment for H. pylori. Bismuth-containing therapy is superior to conventional triple therapies; however, the eradication rate is not satisfactory. In our country, conventional triple therapies are not effective for eradication. © 2015 S. Karger AG, Basel
Introduction
Helicobacter pylori is one of the most common infectious diseases in developing countries. In Turkey, the prevalence of this disease is 70–85% [1, 2]. The infection of H. pylori is associated with the development of chronic gastritis, increased risk of peptic ulcer disease, gastric cancer and MALT lymphoma [3]. The eradication of the infection provides decrease in the activity of gastritis [4], prevention of peptic ulcer recurrence [5], decrease in the risk of development of gastric cancer [6] and the regression of the MALT lymphoma [7]. There are several treatment protocols for H. pylori, but none of them are perfect regimen and there is no monotype regimen that can be applied to all patients. ThereGokhan Gungor, MD Department of Gastroenterology Konya Education and Research Hospital Meram/Konya (Turkey) E-Mail drgokhangungor @ hotmail.com
Downloaded by: McMaster University 198.143.32.65 - 1/28/2016 12:11:45 AM
Key Words Helicobacter eradication · Concomitant · Sequential · Bismuth containing · Triple treatments
Materials and Methods Patients Five-hundred patients who were diagnosed H. pylori-positive using the 14C-urea breath test (UBT), stool antigen test, rapid urease test or histopathology were included consecutively to study. The patients were naive to H. pylori treatment and aged ≥18 years with dyspeptic symptoms. The exclusion criteria were pregnancy, lactation, history of gastric surgery, previous attempt of H. pylori eradication, liver or renal failure, alcohol abuse, known allergy to the prescribed antibiotics and usage of proton pump inhibitors (PPIs), histamin-2 receptor antagonists (H2RA), non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics and bismuth salts in the last 4 weeks. The study was approved by the local ethics committee and conducted according to the Declaration of Helsinki and the guidelines for good clinical practice. Study Design and Treatment This was a prospective, randomized, parallel-arm, single-center study. All patients were included consecutively into study groups. The first group used the standard 2-week triple therapy consisting of pantoprazole 40 mg BID, amoxicillin 1 g BID and clarithromycin 500 mg BID (PAC group). The second group used the other 2-week triple therapy consisting of pantoprazole 40 mg BID, amoxicillin 1 g BID and metronidazole 500 mg BID (PAM group). The third group used 14-day bismuth-based quadruple therapy consisting of pantoprazole 40 mg BID, bismuth subsalicylate 300 mg QID, tetracycline 500 mg QID and metronidazole 500 mg TID (bismuth group). The fourth group used 10-day sequential therapy: pantoprazole 40 mg BID and amoxicillin 1 g BID for 5 days, followed by pantoprazole 40 mg BID, tetracycline 500 mg QID, and metronidazole 500 mg BID for the next 5 days (sequential group).
56
Digestion 2015;92:55–59 DOI: 10.1159/000434627
The fifth group used 10-day, 4-drug, 3-antibiotic, non-bismuth-containing ‘concomitant’ therapy: pantoprazole 40 mg BID, amoxicillin 1 g BID, tetracycline 500 mg QID, and metronidazole 500 mg BID (concomitant group). For all groups, pantoprazole was prescribed before breakfast and dinner; all antibiotics were to be taken after meals. Patient compliance was evaluated at the end of treatment by pill count from the packet of the drugs and was considered acceptable if >80% of the medication had been administered and also patients were questioned for any adverse effects (AEs). Patients who were noncompliant were withdrawn from the study. A control UBT test was performed 6 weeks after the end of treatment and successful eradication was defined as a negative UBT test. No antibiotics, PPIs or H2RA were allowed prior to the control eradication test. Statistical Analyses Non-categorical values are given as mean and standard deviation. Statistical analyses were performed using ANOVA, t test and χ2 test. Intent-to-treat (ITT – all patients included in the protocols) and per-protocol (PP – the number of patients adherent to protocol) population analyses were performed for eradication rates. ITT and PP eradication rates were compared with χ2 test. Calculations were performed using the SPSS version 10.0 for Windows statistical package. p < 0.05 was considered to be statistically significant.
Results
One-hundred patients were distributed consecutively to each group. Four hundred and thirty-seven of 500 patients (87.4%) completed the study protocol. Forty-six patients (9.2%) were lost to follow-up. Seven patients (1.4%) discontinued because of AEs. Ten patients were excluded due to protocol violations (2%). The baseline demographic-clinical characteristics and study data of each group were shown table 1. There was no statistically significant difference in terms of age, gender and smoking patterns in each group. The ITT and PP eradication rates of eradication regimens are shown in table 2 and comparison of the eradication rates between each groups and p values is shown in table 3. According to these results, there were no statistical differences between the eradication rates of PAC and PAM groups. The eradication rates of the bismuthcontaining sequential and concomitant regimens were significantly higher compared with PAC and PAM groups. The eradication rates of sequential and concomitant regimens were higher than the bismuth-containing regimen, but this difference was not statistically significant. The sequential and concomitant regimens were similar; there were no statistical differences between the eradication rates of the sequential and concomitant groups. Gungor/Baglıcakoglu/Kayacetin/Biyik/ Ucar/Goktepe/Ataseven/Demir
Downloaded by: McMaster University 198.143.32.65 - 1/28/2016 12:11:45 AM
fore, the most appropriate treatment for patients should be selected according to antibiotic resistance of each region, eradication rates of regimens, H. pylori prevalence, consensus reports and clinical observations. In recent studies, an important decrease in the efficacy of standard eradication regimens was reported [8]. Bismuth-containing quadruple treatment [9], sequential [10, 11] and non-bismuth quadruple ‘concomitant’ treatment [12], regimens may be an effective first-line antiHelicobacter therapy and alternative for standard triple regimens. In our country, there is not enough information especially about concomitant treatment for H. pylori eradication. The aim of this study was to compare the current status of regimens and the success and tolerability of sequential and concomitant therapies with conventional triples and bismuth-containing regimens for first-line H. pylori eradication in the middle Anatolian region of Turkey.
Table 1. The baseline demographic-clinical characteristics and study data of each group Groups
ITT population Lost to follow-up Discontinued due to AEs Excluded due to poor compliance PP population Median age, years Male/female Smoking (>5 cigarettes/day) Alcohol (>40 g/day)
p
PAC
PAM
bismuth
sequential
concomitant
100 10 2 1 87 43.1±16.4 39/61 10 1
100 4 0 0 96 42.9±16.4 45/55 10 2
100 13 3 4 80 43.7±15.8 43/57 12 2
100 8 1 3 88 40.7±14.5 49/51 12 –
100 11 1 2 86 45.6±14.8 37/63 9 1
0.28 0.44 0.14
ANOVA analysis, p > 0.05 non-significantly.
Discussion
Triple treatment consisting of a PPI and 2 antimicrobial agents (clarithromycin, amoxicillin and metronidazole combinations) is the first-line option for eradication of H. pylori according to the Maastricht III Consensus Report [13]. In the Maastricht IV Report [14], clarithromycin-containing treatments are recommended for firstline empirical treatment in areas that have low clarithromycin resistance (
