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Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth
Arab Journal of Gastroenterology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original article
Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth Zehra Akpinar, Sinan Akay ⇑, Belkis Unsal Katip Çelebi University Izmir Ataturk Training and Research Hospital, Gastroenterology Clinic, Basin Sitesi, Karabaglar, Izmir, Turkey
a r t i c l e
i n f o
Article history: Received 8 June 2016 Accepted 2 May 2017 Available online xxxx Keywords: Helicobacter pylori Clarithromycin Amoxicillin Metronidazole Bismuth
a b s t r a c t Background and study aims: Standard sequential treatment for Helicobacter pylori (H. pylori) eradication has less success because of increasing clarithromycin resistance. Extended treatment and bismuth containing regimens were, therefore, investigated. Patients and methods: Consecutive H. pylori-positive patients with dyspepsia were randomly allocated to one of the three sequential regimens: The first group was given lansoprazole 30 mg b.i.d. plus amoxicillin 1 g b.i.d. for the first 5 days, followed by lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the second 5 days (standard sequential, SS). The second group was given the same regimen but for 7 + 7 days instead of 5 + 5 days (extended sequential, ES). In the third group, colloidal bismuth 600 mg b.i.d. was added to the second regimen for 14 days (extended sequential + bismuth subcitrate, ES + B). Urea breath test or histology was performed before enrolment and 6 weeks after the end of treatment to detect H. pylori. Results: A total of 280 patients were included in the study. Per-protocol eradication rates were 62% (56/90), 72% (56/78), and 75% (54/72) in patients who received SS, ES, and ES + B regimens, respectively. Moreover, intention-to-treat eradication rates were 53% (56/104), 62% (56/90) and 62% (54/86), respectively. The differences in eradication rates between the groups were not statistically significant. Conclusion: Although prolonging of the sequential treatment to 14 days may be considered, addition of bismuth to the regimen is of no avail. Ó 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Helicobacter pylori infection is considered the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. Even with 30 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection is yet to be found. Sequential therapy consisting of a proton pump inhibitor (PPI) plus amoxicillin for 5 days, followed by a PPI plus clarithromycin and tinidazole (or metronidazole) for another 5 days, has been shown to be more effective than the standard triple therapy as the first-line treatment in Italy [1–4]. Sequential regimen would be a promising alternative first-line therapy. Sequential regimen was largely heralded as being able to overcome clarithromycin resistance. Recent studies have shown that eradication rates can be influenced by clarithromycin resistance, and in the presence of clarithromycin resistance mutation, eradication rates decrease to 65% [5]. A study from Turkey, where eradica⇑ Corresponding author. E-mail addresses: [email protected] (Z. Akpinar), sinanakay72@hotmail. com (S. Akay), [email protected] (B. Unsal).
tion rates are low, showed 78% eradication with sequential therapy versus 53% with standard triple therapy based on a per-protocol (PP) analysis [6]. Thus, standard 5-day sequential therapy could not achieve beyond the 80% intention-to-treat (ITT) eradication rate, which is considered to be the minimal acceptable level according to the Maastricht guidelines [7]. Data have shown that bismuth subsalicylate is hydrolysed in the gut to oxychloride and salicylic acid and less commonly to bismuth hydroxide. Bismuth oxychloride and bismuth hydroxide are both considered to have bactericidal effects [8]. The aim of this study was to evaluate the success of sequential therapy and whether prolonging the treatment duration to 14 days or adding bismuth to the 14-day treatment improves eradication rates.
Patients and methods Patients who visited the Gastroenterology Clinics of Izmir Ataturk Training and Research Hospital between May 2011 and May 2012 for upper gastrointestinal symptoms were tested for H. pylori
http://dx.doi.org/10.1016/j.ajg.2017.05.003 1687-1979/Ó 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
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Z. Akpinar et al. / Arab Journal of Gastroenterology xxx (2017) xxx–xxx
infection, and those who were H. pylori positive were recruited. Pre-enrolment procedures included urea breath test (UBT) or biopsy of gastric mucosa, where the presence of H. pylori was assessed by histological examination. Endoscopy was performed if alarming symptoms were present or in new-onset dyspepsia after the age of 45. Blood samples were obtained for routine laboratory tests including complete blood count, renal function, and liver biochemical tests to ascertain that there were no abnormal results that would preclude entry into the trial. Exclusion criteria included the following: (1) previous attempts at H. pylori-eradication therapy; (2) intake of antibiotics, bismuth, or PPIs within the last 4 weeks; (3) patients with a history of allergy to the medications used; (4) patients who underwent previous gastric surgery; (5) coexistence of serious concomitant illness (decompensated liver cirrhosis, uraemia, etc.); and (6) pregnancy or lactation. Participants were randomly assigned to one of three treatment groups: 1) standard sequential therapy of lansoprazole 30 mg b.i.d. plus amoxicillin 1000 mg b.i.d. for the first 5 days and lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the following 5 days; (standard sequential, SS group); 2) extended sequential therapy of lansoprazole 30 mg b.i.d. plus amoxicillin 1000 mg b.i.d. for the first 7 days and lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the following 7 days; (extended sequential, ES group); 3) extended sequential plus bismuth therapy of lansoprazole 30 mg b.i.d., amoxicillin 1000 b.i.d. mg, and bismuth subcitrate 600 mg b.i.d. for the first 7 days and lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., metronidazole 500 mg t.i.d., and bismuth 600 mg b.i.d. for the following 7 days. (extended sequential plus bismuth, ES + B group). Eradication rates were assessed by 13C-UBT or a follow-up endoscopy (in case of gastric ulcer) and histological examination 6 weeks after the end of the regimen. Eradication was defined as a negative result of histology or UBT. Written informed consent was obtained from all patients, and the study was approved by the local ethical committee. Histologic examination Two specimens of gastric biopsies were obtained from the lesser curvature site of the antrum and the lesser curvature site of the corpus for histological examination, fixed in 10% buffered formalin, embedded in paraffin, and sectioned. The sections were
stained with haematoxylin and eosin and a modified Giemsa stain to observe the presence of curved rod-shaped bacteria on the mucosal surface. Biopsy specimens were assessed by histopathologists who were blinded to the patient’s status. Urea breath test The UBT was performed as described in previous studies. The cut-off value was set at 4.8 of d13-CO2 [9]. The staff who performed the test were also blinded to the H. pylori status of the patients. Statistical analysis ITT and PP analyses were used to assess the eradication rates of H. pylori in the three groups. The eradication rates and frequencies of adverse effects were compared using the chi-squared test. The significance level was set at p < 0.05. Patients were randomly allocated to the three treatment groups using a random numbers table. Results A total of 280 subjects admitted to the outpatient clinic for dyspeptic symptoms were included in the study, and 240 patients were able to complete the study. The treatment groups did not differ in baseline demograph and anthropometric data at entry and during follow-up (Table 1). The mean ages of patients in SS, ES, and ES + B groups were 46.4 ± 45, 50.5 ± 39, and 50.8 ± 36, respectively, and the number of males was 28 (26%), 24 (26%), and 34 (39%), respectively. Sixty endoscopies were performed at the beginning of the study; 6 patients had duodenal ulcers and 4 patients had gastric ulcers. Seven patients in the SS group, 7 patients in the ES group, and 9 patients in the ES + B group were excluded from the study because of protocol violation. Moreover, 7 patients in the SS group, 5 patients in the ES group, and 5 patients in the ES + B group did not return for control. Treatment was discontinued in three patients in the SS group and 2 each from the ES and ES + B groups because of adverse drug effects. Patients with adverse drug reactions were included in the protocol violation group. In total, 90 patients in the SS group, 78 patients in the ES group, and 72 patients in the ES + B group completed their regimens and made up the PP population. The cumulative ‘‘PP” and ‘‘ITT” eradication rates were 69.1% (166/240) and 59.2% (166/280) for all patients, respectively. H. pylori eradication was achieved in 56 of 104 (ITT) patients in the SS group (PP eradication = 62.2% and ITT eradication = 53.8%), 56 of 90 (ITT) patients in the ES group (PP eradication = 71.7% and ITT eradication = 62.2%), and 54 of 86 (ITT) patients in the ES + B group (PP eradication = 75% and ITT eradication = 62.7%).
Table 1 Number of patients with regard to treatment groups and treatment success and their demograph characteristics.
Number of Number of Number of Mean age Number of
patients (ITT) patients (PP) eradication-positive patients
Total number of patients
Standard sequential
Extended sequential
Extended sequential plus bismuth
280 240 166
104 90 56 46.4 ± 45 28 (31%)
90 78 56 50.5 ± 39 24 (30%)
86 72 54 50.8 ± 36 34 (47%)
males
Table 2 H. pylori eradication rates.
Intention to treat Per protocol
Standard sequential
Extended sequential
Extended sequential plus bismuth
Significance
53.8% 56/104 62.2% 56/90
62.2% 56/90 71.7% 56/78
62.7% 54/86 75% 54/72
p > 0.05 p > 0.05
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
Z. Akpinar et al. / Arab Journal of Gastroenterology xxx (2017) xxx–xxx
Fig. 1. Eradication success and failure amongst treated groups.
Both ‘‘PP” and ‘‘ITT” eradication rates were better in the ES and ES + B groups than in the SS group, but the differences were not statistically significant (Table 2, Fig. 1).
Discussion Prolonging the 10-day sequential treatment to 14 days increased the eradication rate from 62% to 71%. Adding bismuth subcitrate to a 14-day sequential treatment increased the eradication rate from 71% to 75%. The resistance rates for the commonly used antimicrobial agents in current treatment regimens have increased, and it has been shown that this is the most important cause of treatment failure [10]. The primary goal of the sequential regimen is to overcome clarithromycin resistance. During the first 5 days of therapy, amoxicillin is taken with PPIs to weaken the bacterial cell wall, which prevents the formation of channels that block clarithromycin from binding to the bacterium and hence cause resistance to the antibiotic. In the second phase of therapy, amoxicillin is discontinued and clarithromycin and nitroimidazole are added for a further 5 days. PPI is continued throughout treatment [11]. The frequency of resistance varies widely according to geographical regions and subgroups within a given study population. A study evaluated the change in primary resistance to clarithromycin from 1997 to 2008. It showed that the resistance rate rose from 8.7% to 34.5% during this period, and the eradication rate of triple therapy decreased significantly, which was consistent with raising clarithromycin resistance [12,13]. Clarithromycin resistance was found to be 24.2% in a study conducted in 1999– 2001 in Turkey [14]. However, two studies reported 48.2% and 51.4% clarithromycin resistance rates of H. pylori isolates [15,16]. Data on primary clarithromycin resistance and H. pylori eradication following sequential regimen are available in three trials. Overall, the infection was cured in 82% and 33.3% of the patients infected with clarithromycin (with or without metronidazole)resistant strains following sequential and standard triple therapy, respectively. Therefore, sequential regimen was much more effective than triple therapy even in patients harbouring H. pylori with clarithromycin resistance [17]. However, treatment success with standard sequential therapy was reported to fall under 80% recently, probably because of dual (clarithromycin and metronidazole) antibiotic resistance [18,19]. A longer duration of treatment (14 vs. 10 days) may prove more effective in curing infection, but this hypothesis remains
3
controversial. A meta-analysis suggested that extension of the PPI-based triple therapy from 7 to 14 days was associated with 5% increase in eradication rates [20]. On the contrary, extending the duration of sequential therapy from 10 to 14 days was not associated with an increased eradication rate [21]. Bacterial eradication rate by PP analysis was increased from 62% to 71% with a 14-day treatment in our study compared to the 10-day treatment. However, the difference did not reach statistical significance. Traditional triple therapy can easily be converted to this quadruple therapy with the addition of bismuth twice daily. Bismuth has been used to treat H. pylori infection for over 20 years. It exerts its antibacterial action by decreasing mucus viscosity, binding toxins produced by H. pylori, and preventing bacterial colonisation and adherence to gastric epithelium [22]. In addition, bismuth co-administered with antibiotics against H. pylori can hinder the emergence of antibiotic resistance, inhibit the growth of H. pylori, and improve the efficacy of the eradication treatment [23]. In addition, longer durations of bismuth-based therapy appear to be more efficacious. A study of a bismuth–omeprazole–amoxicil lin and clarithromycin regimen showed superior eradication of 94% in the group treated for 14 days versus 80% in the group treated for 7 days [24]. Moreover, recently Alboraie et al. in Kuwait showed the efficacy of a bismuth-containing regimen as the first-line therapy [25]. However, according to our results, addition of bismuth to the 14-day sequential therapy resulted in a 4-point increase in the eradication rate, which is not statistically significant. One of the drawbacks of our study may be the use of lansoprazole instead of rabeprazole or esomeprazole, which show more consistent eradication rates with regard to the CYP2C19 status of the patients [26]. Moreover, Hsu et al. indicated that the average body weight of the patient is important in the potency of H. pylori eradication regimens. Therefore, it is not surprising that higher eradication rates will be found in lower weight populations such as Asians if the same dose of PPIs and antibiotics are used [27]. Therefore, in our study, higher eradication rates might be achieved if 3 g/day amoxicillin is prescribed to overweight patients. In conclusion, neither extending the sequential therapy to 14 days nor adding bismuth to sequential therapy resulted in an improved outcome.
References [1] Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection inpatients naive to treatment. Ann Intern Med 2008;148:923–31. [2] Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, et al. Sequential therapy versus standardtriple-drug therapy for Helicobacter pylori eradication: a randomizedtrial. Ann Intern Med 2007;146:556–63. [3] Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapyregimen for Helicobacter pylori eradication: a pooled-data analysis. Gut 2007;56:1353–7. [4] Seyyedmajidi M, Falaknazi K, Mirsattari D, Zojaji H, Roshani M, Lahmi F, et al. Correlation between creatinine clearance and Helicobacter pylori infection eradication with sequential and triple therapeutic regimens: a randomised clinical trial. Arab J Gastroenterol 2011;12:150–3. [5] Abuhammour A, Dajani A, Nounou M, Zakaria M. Standard triple therapy versus sequential therapy for eradication of Helicobacter pylori in treatment naïve and retreat patients. Arab J Gastroenterol 2016 Sep;17(3):131–6. [6] Nadir I, Yonem O, Ozin Y, Kilic ZM, Sezgin O. Comparison of two different treatment protocols in Helicobacter pylori eradication. South Med J 2011;104:102–5. [7] Malfertheiner P, Megraud F, O’Morain C, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection the Maastricht IV/Florenca Consensus Report. Gut 2012;61:646–64. [8] Sox TE, Olson CA. Binding and killing of bacteria by bismuth subsalicylate. Antimicrob Agents Chemother 1989;33:2075–82. [9] Peng NJ, Lai KH, Liu RS, Lee SC, Tsay DG, Lo CC, et al. Clinical significance of oral urease in diagnosis of Helicobacter pylori infection by [13C]urea breath test. Dig Dis Sci 2001;46:1772–8. [10] De Francesco V, Margiotta M, Zullo A, Hassan C, Troiani L, Burattini O, et al. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori. Ann Intern Med 2006;144:94–100.
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
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[11] Mahachai V, Sirimontaporn N, Tumwasorn S, Thong-Ngam D, Vilaichone RK. Sequential therapy in clarithromycin-sensitive and -resistant Helicobacter pylori based on polymerase chain reaction molecular test. J Gastroenterol Hepatol 2011;26:825–8. [12] Sasaki M, Ogasawara N, Utsumi K, Kawamura N, Kamiya T, Kataoka H, et al. Changes in 12-year first-line eradication rate of Helicobacter pylori based on tripletherapy with proton pump inhibitor, amoxicillin and clarithromycin. J Clin Biochem Nutr 2010;47:53–8. [13] Dib Jr J, Alvarez B, Mendez L, Cruz ME. Efficacy of PPI, levofloxacin and amoxicillin in the eradication of Helicobacter pylori compared to conventional triple therapy at a Venezuelan hospital. Arab J Gastroenterol 2013;14:123–5. [14] Simsek H, Balaban YH, Gunes DD, Hascelik G, Ozarlan E, Tatar G. Alarming clarithromycin resistance of Helicobacter pylori in Turkish population. Helicobacter 2005;10:360–1. [15] Onder G, Aydin A, Akarca U, Tekin F, Ozutemiz O, Ilter T. High Helicobacter pylori resistance rate to clarithromycin in Turkey. J Clin Gastroenterol 2007;41:747–50. [16] Aydin A, Onder G, Akarca U, Tekin F, Tuncyurek M, Ilter T. Comparison of 1and 2-week pantoprazole-based triple therapies in clarithromycin-sensitive and resistant cases. Eur J Intern Med 2007;18:496–500. [17] Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis. Gut 2007;56:1353–7. [18] Aydin A, Oruc N, Sezak M, Akgun A, Ozutemiz O. The effectivity of sequential therapy including clarithromycin for eradication of H. pylori. Turk J Gastroenterol 2010;21:343. [19] Choi WH, Park DI, Oh SJ, Baek YH, Hong CH, Hong EJ, et al. Effectiveness of 10 daysequential therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 2008;51:280–4.
[20] Magrini N, Bazzoli F. Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med 2007;147:553–62. [21] Hsu PI, Wu DC, Wu JY, Graham DY. Is there a benefit to extending the duration of Helicobacter pylori sequential therapy to 14 days? Helicobacter 2011;16:146–52. [22] Alboraie M, Saad M, Al-Ali J, Malik M, Asem N, Schmidt I, et al. Quadruple therapy versus standard triple therapy for eradication of Helicobacter pylori in Kuwait. Arab J Gastroenterol 2015;16:131–5. [23] Bland MV, Ismail S, Heinemann JA, Keenan JI. The action of bismuth against Helicobacter pylori mimics but is not caused by intracellular iron deprivation. Antimicrob Agents Chemother 2004;48:1983–8. [24] Sun Q, Liang X, Zheng Q, Liu W, Xiao S, Gu W, et al. High efficacy of 14-day triple therapy-based, bismuth-containing quadruple therapy for initial Helicobacter pylori eradication. Helicobacter 2010;15:233–8. [25] Alboraie M, Saad M, Al-Ali J, Malik M, Asem N, Schmidt I, et al. Quadruple therapy versus standard triple therapy for eradication of Helicobacter pylori in Kuwait. 2015 Sep-Dec;16(3–4):131–5. [26] Tang HL, Li Y, Hu YF, Xie HG, Zhai SD. Effects of CYP2C19 loss of function variants on eradication of H. pylori infection in patients treated with proton pump inhibitor based triple regimens: a meta-analysis of randomized clinical trials. PLoS One 2013;8:e62162. [27] Hsu PI, Lai KH, Wu CJ, et al. High-dose versus low-dose esomeprazole-based triple therapy for Helicobacter pylori infection. Eur J Clin Invest 2007;37:724–30.
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
Contents lists available at ScienceDirect
Arab Journal of Gastroenterology journal homepage: www.elsevier.com/locate/ajg
Original article
Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth Zehra Akpinar, Sinan Akay ⇑, Belkis Unsal Katip Çelebi University Izmir Ataturk Training and Research Hospital, Gastroenterology Clinic, Basin Sitesi, Karabaglar, Izmir, Turkey
a r t i c l e
i n f o
Article history: Received 8 June 2016 Accepted 2 May 2017 Available online xxxx Keywords: Helicobacter pylori Clarithromycin Amoxicillin Metronidazole Bismuth
a b s t r a c t Background and study aims: Standard sequential treatment for Helicobacter pylori (H. pylori) eradication has less success because of increasing clarithromycin resistance. Extended treatment and bismuth containing regimens were, therefore, investigated. Patients and methods: Consecutive H. pylori-positive patients with dyspepsia were randomly allocated to one of the three sequential regimens: The first group was given lansoprazole 30 mg b.i.d. plus amoxicillin 1 g b.i.d. for the first 5 days, followed by lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the second 5 days (standard sequential, SS). The second group was given the same regimen but for 7 + 7 days instead of 5 + 5 days (extended sequential, ES). In the third group, colloidal bismuth 600 mg b.i.d. was added to the second regimen for 14 days (extended sequential + bismuth subcitrate, ES + B). Urea breath test or histology was performed before enrolment and 6 weeks after the end of treatment to detect H. pylori. Results: A total of 280 patients were included in the study. Per-protocol eradication rates were 62% (56/90), 72% (56/78), and 75% (54/72) in patients who received SS, ES, and ES + B regimens, respectively. Moreover, intention-to-treat eradication rates were 53% (56/104), 62% (56/90) and 62% (54/86), respectively. The differences in eradication rates between the groups were not statistically significant. Conclusion: Although prolonging of the sequential treatment to 14 days may be considered, addition of bismuth to the regimen is of no avail. Ó 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Introduction Helicobacter pylori infection is considered the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. Even with 30 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection is yet to be found. Sequential therapy consisting of a proton pump inhibitor (PPI) plus amoxicillin for 5 days, followed by a PPI plus clarithromycin and tinidazole (or metronidazole) for another 5 days, has been shown to be more effective than the standard triple therapy as the first-line treatment in Italy [1–4]. Sequential regimen would be a promising alternative first-line therapy. Sequential regimen was largely heralded as being able to overcome clarithromycin resistance. Recent studies have shown that eradication rates can be influenced by clarithromycin resistance, and in the presence of clarithromycin resistance mutation, eradication rates decrease to 65% [5]. A study from Turkey, where eradica⇑ Corresponding author. E-mail addresses: [email protected] (Z. Akpinar), sinanakay72@hotmail. com (S. Akay), [email protected] (B. Unsal).
tion rates are low, showed 78% eradication with sequential therapy versus 53% with standard triple therapy based on a per-protocol (PP) analysis [6]. Thus, standard 5-day sequential therapy could not achieve beyond the 80% intention-to-treat (ITT) eradication rate, which is considered to be the minimal acceptable level according to the Maastricht guidelines [7]. Data have shown that bismuth subsalicylate is hydrolysed in the gut to oxychloride and salicylic acid and less commonly to bismuth hydroxide. Bismuth oxychloride and bismuth hydroxide are both considered to have bactericidal effects [8]. The aim of this study was to evaluate the success of sequential therapy and whether prolonging the treatment duration to 14 days or adding bismuth to the 14-day treatment improves eradication rates.
Patients and methods Patients who visited the Gastroenterology Clinics of Izmir Ataturk Training and Research Hospital between May 2011 and May 2012 for upper gastrointestinal symptoms were tested for H. pylori
http://dx.doi.org/10.1016/j.ajg.2017.05.003 1687-1979/Ó 2017 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
2
Z. Akpinar et al. / Arab Journal of Gastroenterology xxx (2017) xxx–xxx
infection, and those who were H. pylori positive were recruited. Pre-enrolment procedures included urea breath test (UBT) or biopsy of gastric mucosa, where the presence of H. pylori was assessed by histological examination. Endoscopy was performed if alarming symptoms were present or in new-onset dyspepsia after the age of 45. Blood samples were obtained for routine laboratory tests including complete blood count, renal function, and liver biochemical tests to ascertain that there were no abnormal results that would preclude entry into the trial. Exclusion criteria included the following: (1) previous attempts at H. pylori-eradication therapy; (2) intake of antibiotics, bismuth, or PPIs within the last 4 weeks; (3) patients with a history of allergy to the medications used; (4) patients who underwent previous gastric surgery; (5) coexistence of serious concomitant illness (decompensated liver cirrhosis, uraemia, etc.); and (6) pregnancy or lactation. Participants were randomly assigned to one of three treatment groups: 1) standard sequential therapy of lansoprazole 30 mg b.i.d. plus amoxicillin 1000 mg b.i.d. for the first 5 days and lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the following 5 days; (standard sequential, SS group); 2) extended sequential therapy of lansoprazole 30 mg b.i.d. plus amoxicillin 1000 mg b.i.d. for the first 7 days and lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and metronidazole 500 mg t.i.d. for the following 7 days; (extended sequential, ES group); 3) extended sequential plus bismuth therapy of lansoprazole 30 mg b.i.d., amoxicillin 1000 b.i.d. mg, and bismuth subcitrate 600 mg b.i.d. for the first 7 days and lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., metronidazole 500 mg t.i.d., and bismuth 600 mg b.i.d. for the following 7 days. (extended sequential plus bismuth, ES + B group). Eradication rates were assessed by 13C-UBT or a follow-up endoscopy (in case of gastric ulcer) and histological examination 6 weeks after the end of the regimen. Eradication was defined as a negative result of histology or UBT. Written informed consent was obtained from all patients, and the study was approved by the local ethical committee. Histologic examination Two specimens of gastric biopsies were obtained from the lesser curvature site of the antrum and the lesser curvature site of the corpus for histological examination, fixed in 10% buffered formalin, embedded in paraffin, and sectioned. The sections were
stained with haematoxylin and eosin and a modified Giemsa stain to observe the presence of curved rod-shaped bacteria on the mucosal surface. Biopsy specimens were assessed by histopathologists who were blinded to the patient’s status. Urea breath test The UBT was performed as described in previous studies. The cut-off value was set at 4.8 of d13-CO2 [9]. The staff who performed the test were also blinded to the H. pylori status of the patients. Statistical analysis ITT and PP analyses were used to assess the eradication rates of H. pylori in the three groups. The eradication rates and frequencies of adverse effects were compared using the chi-squared test. The significance level was set at p < 0.05. Patients were randomly allocated to the three treatment groups using a random numbers table. Results A total of 280 subjects admitted to the outpatient clinic for dyspeptic symptoms were included in the study, and 240 patients were able to complete the study. The treatment groups did not differ in baseline demograph and anthropometric data at entry and during follow-up (Table 1). The mean ages of patients in SS, ES, and ES + B groups were 46.4 ± 45, 50.5 ± 39, and 50.8 ± 36, respectively, and the number of males was 28 (26%), 24 (26%), and 34 (39%), respectively. Sixty endoscopies were performed at the beginning of the study; 6 patients had duodenal ulcers and 4 patients had gastric ulcers. Seven patients in the SS group, 7 patients in the ES group, and 9 patients in the ES + B group were excluded from the study because of protocol violation. Moreover, 7 patients in the SS group, 5 patients in the ES group, and 5 patients in the ES + B group did not return for control. Treatment was discontinued in three patients in the SS group and 2 each from the ES and ES + B groups because of adverse drug effects. Patients with adverse drug reactions were included in the protocol violation group. In total, 90 patients in the SS group, 78 patients in the ES group, and 72 patients in the ES + B group completed their regimens and made up the PP population. The cumulative ‘‘PP” and ‘‘ITT” eradication rates were 69.1% (166/240) and 59.2% (166/280) for all patients, respectively. H. pylori eradication was achieved in 56 of 104 (ITT) patients in the SS group (PP eradication = 62.2% and ITT eradication = 53.8%), 56 of 90 (ITT) patients in the ES group (PP eradication = 71.7% and ITT eradication = 62.2%), and 54 of 86 (ITT) patients in the ES + B group (PP eradication = 75% and ITT eradication = 62.7%).
Table 1 Number of patients with regard to treatment groups and treatment success and their demograph characteristics.
Number of Number of Number of Mean age Number of
patients (ITT) patients (PP) eradication-positive patients
Total number of patients
Standard sequential
Extended sequential
Extended sequential plus bismuth
280 240 166
104 90 56 46.4 ± 45 28 (31%)
90 78 56 50.5 ± 39 24 (30%)
86 72 54 50.8 ± 36 34 (47%)
males
Table 2 H. pylori eradication rates.
Intention to treat Per protocol
Standard sequential
Extended sequential
Extended sequential plus bismuth
Significance
53.8% 56/104 62.2% 56/90
62.2% 56/90 71.7% 56/78
62.7% 54/86 75% 54/72
p > 0.05 p > 0.05
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
Z. Akpinar et al. / Arab Journal of Gastroenterology xxx (2017) xxx–xxx
Fig. 1. Eradication success and failure amongst treated groups.
Both ‘‘PP” and ‘‘ITT” eradication rates were better in the ES and ES + B groups than in the SS group, but the differences were not statistically significant (Table 2, Fig. 1).
Discussion Prolonging the 10-day sequential treatment to 14 days increased the eradication rate from 62% to 71%. Adding bismuth subcitrate to a 14-day sequential treatment increased the eradication rate from 71% to 75%. The resistance rates for the commonly used antimicrobial agents in current treatment regimens have increased, and it has been shown that this is the most important cause of treatment failure [10]. The primary goal of the sequential regimen is to overcome clarithromycin resistance. During the first 5 days of therapy, amoxicillin is taken with PPIs to weaken the bacterial cell wall, which prevents the formation of channels that block clarithromycin from binding to the bacterium and hence cause resistance to the antibiotic. In the second phase of therapy, amoxicillin is discontinued and clarithromycin and nitroimidazole are added for a further 5 days. PPI is continued throughout treatment [11]. The frequency of resistance varies widely according to geographical regions and subgroups within a given study population. A study evaluated the change in primary resistance to clarithromycin from 1997 to 2008. It showed that the resistance rate rose from 8.7% to 34.5% during this period, and the eradication rate of triple therapy decreased significantly, which was consistent with raising clarithromycin resistance [12,13]. Clarithromycin resistance was found to be 24.2% in a study conducted in 1999– 2001 in Turkey [14]. However, two studies reported 48.2% and 51.4% clarithromycin resistance rates of H. pylori isolates [15,16]. Data on primary clarithromycin resistance and H. pylori eradication following sequential regimen are available in three trials. Overall, the infection was cured in 82% and 33.3% of the patients infected with clarithromycin (with or without metronidazole)resistant strains following sequential and standard triple therapy, respectively. Therefore, sequential regimen was much more effective than triple therapy even in patients harbouring H. pylori with clarithromycin resistance [17]. However, treatment success with standard sequential therapy was reported to fall under 80% recently, probably because of dual (clarithromycin and metronidazole) antibiotic resistance [18,19]. A longer duration of treatment (14 vs. 10 days) may prove more effective in curing infection, but this hypothesis remains
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controversial. A meta-analysis suggested that extension of the PPI-based triple therapy from 7 to 14 days was associated with 5% increase in eradication rates [20]. On the contrary, extending the duration of sequential therapy from 10 to 14 days was not associated with an increased eradication rate [21]. Bacterial eradication rate by PP analysis was increased from 62% to 71% with a 14-day treatment in our study compared to the 10-day treatment. However, the difference did not reach statistical significance. Traditional triple therapy can easily be converted to this quadruple therapy with the addition of bismuth twice daily. Bismuth has been used to treat H. pylori infection for over 20 years. It exerts its antibacterial action by decreasing mucus viscosity, binding toxins produced by H. pylori, and preventing bacterial colonisation and adherence to gastric epithelium [22]. In addition, bismuth co-administered with antibiotics against H. pylori can hinder the emergence of antibiotic resistance, inhibit the growth of H. pylori, and improve the efficacy of the eradication treatment [23]. In addition, longer durations of bismuth-based therapy appear to be more efficacious. A study of a bismuth–omeprazole–amoxicil lin and clarithromycin regimen showed superior eradication of 94% in the group treated for 14 days versus 80% in the group treated for 7 days [24]. Moreover, recently Alboraie et al. in Kuwait showed the efficacy of a bismuth-containing regimen as the first-line therapy [25]. However, according to our results, addition of bismuth to the 14-day sequential therapy resulted in a 4-point increase in the eradication rate, which is not statistically significant. One of the drawbacks of our study may be the use of lansoprazole instead of rabeprazole or esomeprazole, which show more consistent eradication rates with regard to the CYP2C19 status of the patients [26]. Moreover, Hsu et al. indicated that the average body weight of the patient is important in the potency of H. pylori eradication regimens. Therefore, it is not surprising that higher eradication rates will be found in lower weight populations such as Asians if the same dose of PPIs and antibiotics are used [27]. Therefore, in our study, higher eradication rates might be achieved if 3 g/day amoxicillin is prescribed to overweight patients. In conclusion, neither extending the sequential therapy to 14 days nor adding bismuth to sequential therapy resulted in an improved outcome.
References [1] Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection inpatients naive to treatment. Ann Intern Med 2008;148:923–31. [2] Vaira D, Zullo A, Vakil N, Gatta L, Ricci C, Perna F, et al. Sequential therapy versus standardtriple-drug therapy for Helicobacter pylori eradication: a randomizedtrial. Ann Intern Med 2007;146:556–63. [3] Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapyregimen for Helicobacter pylori eradication: a pooled-data analysis. Gut 2007;56:1353–7. [4] Seyyedmajidi M, Falaknazi K, Mirsattari D, Zojaji H, Roshani M, Lahmi F, et al. Correlation between creatinine clearance and Helicobacter pylori infection eradication with sequential and triple therapeutic regimens: a randomised clinical trial. Arab J Gastroenterol 2011;12:150–3. [5] Abuhammour A, Dajani A, Nounou M, Zakaria M. Standard triple therapy versus sequential therapy for eradication of Helicobacter pylori in treatment naïve and retreat patients. Arab J Gastroenterol 2016 Sep;17(3):131–6. [6] Nadir I, Yonem O, Ozin Y, Kilic ZM, Sezgin O. Comparison of two different treatment protocols in Helicobacter pylori eradication. South Med J 2011;104:102–5. [7] Malfertheiner P, Megraud F, O’Morain C, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection the Maastricht IV/Florenca Consensus Report. Gut 2012;61:646–64. [8] Sox TE, Olson CA. Binding and killing of bacteria by bismuth subsalicylate. Antimicrob Agents Chemother 1989;33:2075–82. [9] Peng NJ, Lai KH, Liu RS, Lee SC, Tsay DG, Lo CC, et al. Clinical significance of oral urease in diagnosis of Helicobacter pylori infection by [13C]urea breath test. Dig Dis Sci 2001;46:1772–8. [10] De Francesco V, Margiotta M, Zullo A, Hassan C, Troiani L, Burattini O, et al. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori. Ann Intern Med 2006;144:94–100.
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003
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Z. Akpinar et al. / Arab Journal of Gastroenterology xxx (2017) xxx–xxx
[11] Mahachai V, Sirimontaporn N, Tumwasorn S, Thong-Ngam D, Vilaichone RK. Sequential therapy in clarithromycin-sensitive and -resistant Helicobacter pylori based on polymerase chain reaction molecular test. J Gastroenterol Hepatol 2011;26:825–8. [12] Sasaki M, Ogasawara N, Utsumi K, Kawamura N, Kamiya T, Kataoka H, et al. Changes in 12-year first-line eradication rate of Helicobacter pylori based on tripletherapy with proton pump inhibitor, amoxicillin and clarithromycin. J Clin Biochem Nutr 2010;47:53–8. [13] Dib Jr J, Alvarez B, Mendez L, Cruz ME. Efficacy of PPI, levofloxacin and amoxicillin in the eradication of Helicobacter pylori compared to conventional triple therapy at a Venezuelan hospital. Arab J Gastroenterol 2013;14:123–5. [14] Simsek H, Balaban YH, Gunes DD, Hascelik G, Ozarlan E, Tatar G. Alarming clarithromycin resistance of Helicobacter pylori in Turkish population. Helicobacter 2005;10:360–1. [15] Onder G, Aydin A, Akarca U, Tekin F, Ozutemiz O, Ilter T. High Helicobacter pylori resistance rate to clarithromycin in Turkey. J Clin Gastroenterol 2007;41:747–50. [16] Aydin A, Onder G, Akarca U, Tekin F, Tuncyurek M, Ilter T. Comparison of 1and 2-week pantoprazole-based triple therapies in clarithromycin-sensitive and resistant cases. Eur J Intern Med 2007;18:496–500. [17] Zullo A, De Francesco V, Hassan C, Morini S, Vaira D. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis. Gut 2007;56:1353–7. [18] Aydin A, Oruc N, Sezak M, Akgun A, Ozutemiz O. The effectivity of sequential therapy including clarithromycin for eradication of H. pylori. Turk J Gastroenterol 2010;21:343. [19] Choi WH, Park DI, Oh SJ, Baek YH, Hong CH, Hong EJ, et al. Effectiveness of 10 daysequential therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 2008;51:280–4.
[20] Magrini N, Bazzoli F. Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med 2007;147:553–62. [21] Hsu PI, Wu DC, Wu JY, Graham DY. Is there a benefit to extending the duration of Helicobacter pylori sequential therapy to 14 days? Helicobacter 2011;16:146–52. [22] Alboraie M, Saad M, Al-Ali J, Malik M, Asem N, Schmidt I, et al. Quadruple therapy versus standard triple therapy for eradication of Helicobacter pylori in Kuwait. Arab J Gastroenterol 2015;16:131–5. [23] Bland MV, Ismail S, Heinemann JA, Keenan JI. The action of bismuth against Helicobacter pylori mimics but is not caused by intracellular iron deprivation. Antimicrob Agents Chemother 2004;48:1983–8. [24] Sun Q, Liang X, Zheng Q, Liu W, Xiao S, Gu W, et al. High efficacy of 14-day triple therapy-based, bismuth-containing quadruple therapy for initial Helicobacter pylori eradication. Helicobacter 2010;15:233–8. [25] Alboraie M, Saad M, Al-Ali J, Malik M, Asem N, Schmidt I, et al. Quadruple therapy versus standard triple therapy for eradication of Helicobacter pylori in Kuwait. 2015 Sep-Dec;16(3–4):131–5. [26] Tang HL, Li Y, Hu YF, Xie HG, Zhai SD. Effects of CYP2C19 loss of function variants on eradication of H. pylori infection in patients treated with proton pump inhibitor based triple regimens: a meta-analysis of randomized clinical trials. PLoS One 2013;8:e62162. [27] Hsu PI, Lai KH, Wu CJ, et al. High-dose versus low-dose esomeprazole-based triple therapy for Helicobacter pylori infection. Eur J Clin Invest 2007;37:724–30.
Please cite this article in press as: Akpinar Z et al. Improving the standard sequential treatment of Helicobacter pylori with either extended treatment or by adding bismuth. Arab J Gastroenterol (2017), http://dx.doi.org/10.1016/j.ajg.2017.05.003