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Sequential therapy or triple therapy for Helicobacter pylori infection in Asians: Systematic review and meta-analysis
Clinics and Research in Hepatology and Gastroenterology (2014) 38, 118—125
Available online at
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ORIGINAL ARTICLE
Sequential therapy or triple therapy for Helicobacter pylori infection in Asians: Systematic review and meta-analysis Joon Sung Kim a, Jeong-Seon Ji a,∗, Hwang Choi a, Joo Hyun Kim b a
Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, 56, Dongsu-ro, Bupyeong-gu, Incheon 403-720, Republic of Korea b Newport High School, Bellevue, WA, USA Available online 12 November 2013
Summary Background and objective: Eradication rate of Helicobacter pylori infection with triple therapy (TT) has declined in part to increased antibiotic resistance. Sequential therapy (ST) has shown promise in several meta-analyses. However, most of the studies included in previous metaanalyses were from Italy. The aim of this study was to compare the efficacy of ST with that of TT in Asia by performing a meta-analysis of studies from Asia. Materials and methods: We performed a comprehensive literature search for studies comparing the efficacy of ST with TT. Randomised controlled trials investigated in the Asian population were included. The odds ratios (OR) of eradicating H. pylori infection after ST compared with TT were pooled. The eradication rates were considered both on an intention-to-treat (ITT) and on a per-protocol basis (PP). Results: A total of nine studies provided data on 3074 adult patients. The odds ratio (OR) for eradication of H. pylori with ST compared with TT was 1.768 (95% CI: 1.476—2.117, P = 0.000) for ITT analysis and 1.997 (95% CI: 1.607—2.480, P = 0.000) for PP analysis. The pooled eradication rates of ITT analysis was 81.3% (95% CI: 76.5—85.3) for the ST group and 70.8% (95% CI: 64.6—76.4) for the TT group. The pooled eradication rates of PP analysis was 87.6% (95% CI: 84.1—90.5) for the ST group and 77.1% (95% CI: 70.9—82.3) for the TT group. There was no difference in the rate of adverse events between ST and TT (OR 0.945, 95% CI: 0.874-1.238, P = 0.658). Conclusion: ST appears to be better than TT in the eradication of H. pylori in Asia. These results suggest that ST may be a reasonable choice for first line therapy in Asia. © 2013 Elsevier Masson SAS. All rights reserved.
∗
Corresponding author. Tel.: +82 32 280 5051; fax: +82 32 280 5082. E-mail address: [email protected] (J.-S. Ji).
2210-7401/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2013.10.001
Sequential therapy for Helicobacter
Introduction Helicobacter pylori (H. pylori) infection is the major cause of gastritis, peptic ulcer, gastric adenocarcinoma and marginal zone B cell lymphoma of MALT type [1]. H. pylori infection has also been associated with idiopathic thrombocytopenic purpura and idiopathic iron deficiency anemia [1]. Although, there are several treatment regimens for treating H. pylori infection, controversy has emerged regarding the optimal treatment regimen. Primary resistance toward different antibiotics is the most important factor influencing treatment failure and has been reported to be different according to geographical locations. Triple therapy (TT) regimen has been regarded as firstline regimens for treating H. pylori infection. However, eradication rate of TT has declined during the last decade, which is primarily due to increased bacterial resistance to clarithromycin world widely. For this reason, several regimens have been proposed as an alternative to the TT regimen. The sequential therapy regimen (ST) was first introduced in Italy in 2000 and several meta-analyses have demonstrated ST regimens to achieve higher eradication rates than the standard TT regimen [2—6]. However, most of the studies included in these reports were from Italy and few studies from Asia were included. We cannot conclude that ST will be superior to TT based on the results of these metaanalyses because patterns of antimicrobial resistance may vary geographically. The Asia-Pacific guidelines currently states triple therapy as recommended first-line therapy for H. pylori [7]. However, recent studies published from Asia have reported sequential therapy to be more effective than triple therapy. The purpose of this study was to perform a meta-analysis of studies that targeted the Asian population and compare ST with TT for eradication of H. pylori.
Materials and methods Search method This systematic review and meta-analysis was performed according to the guidelines set forth in Cochrane Handbook for Systematic Reviews of Interventions [8]. A literature search was conducted using Medline (through PubMed), EMBASE, Cochrane Library, and Google Scholar with the key words of ‘‘Helicobacter pylori’’, ‘‘sequential therapy,’’ ‘‘triple therapy’’. Full texts of all relevant articles published from January 2001 to March 2013 were considered for our review.
Study selection Randomised controlled trials (RCT) that targeted the Asian population and compared ST with TT for H. pylori eradication were included. Inclusion criteria for selection in the meta-analysis were: (a) TT regimens consisted of a proton pump inhibitor (PPI), clarithromycin and amoxicillin; (b) ST regimen consisted of a PPI plus amoxicillin given for the first five days followed by a PPI, clarithromycin and tinidazole (or metronidazole) for the next five days; (c) Diagnosis of H. pylori infection was determined by histology,
119 fecal antigen test, urea breath test (UBT) or rapid urease test (RUT); (d) Eradication was assessed by either two of the tests used for diagnosis or UBT. Modified TT and ST regimens were excluded.
Data collection A data extraction manual was developed in advanced and information was collected independently by the two researchers (J.S.K., J.H.K.). Data extracted were year of publication, whether the study was a single or multicenter study, enrollment period, numbers of patients included in the ST and TT group, baseline characteristics of the patients, details related to the use of ST and TT (including dose and duration), methods of diagnosing infection and confirming eradication; incidence of side effects. Since the object of our review was to compare ST with TT, distinctions were not made regarding the duration of treatments. The quality of the included studies was assessed by using the Jadad scale and a score of ≥ 3 was considered as high quality [9].
Outcome measures The primary outcome of this study was odds ratios (OR) of eradication rates of ST and TT in Asians. Secondary outcome was OR of adverse events of ST and TT in Asians. The eradication rates were considered both on an intention-to-treat (ITT) and on a per-protocol basis (PP).
Statistical analysis Meta-analysis was performed by calculating pooled estimates of primary and secondary outcomes. Pooled results were derived by using the fixed effect model, unless significant heterogeneity was present. Heterogeneity between studies was evaluated with the Cochrane Q test and the inconsistency index (I2 ). When I2 value was < 50%, we used a fixed effect model, otherwise a random effects model was used. Funnel plots and Egger’s test were used to investigate publication bias. P < 0.05 indicated publication bias, while P > 0.05 indicated no publication bias. Statistical analyses were executed by the aid of Comprehensive Meta-analysis software version 2 (Biostat Inc, Englewood, NJ).
Results A flow diagram of this systematic review is shown in Fig. 1. In summary, 118 studies were identified by our literature search. Eighty-five were excluded after initial screening of title and abstracts. After reviewing the full text of the remaining studies, nine RCTs met our inclusion criteria for meta-analysis [10—18]. The main characteristics of the studies are listed in Tables 1 and 2. All but three of the included studies were a single-center study, and the enrollment period ranged from 2007 to 2011. All of the studies were published in English except for a Korean study by Choi et al. [10]. Three of the studies used tinidazole for their sequential therapy regimen and the rest used metronidazole.
120 Table 1
J.S. Kim et al. Main characteristic of included studies.
Study
Centers
Country
Type of patients
No. of patients
Study duration
Jadad score
Choi et al. [10] Gao et al. [11] Kim et al. [12] Park et al. [13] Choi et al. [14] Chung et al. [15] Oh et al. [16] Liou et al. [17] Javid et al. [18]
Single Single Single Multi Single Single Single Multi Single
Korea China Korea Korea Korea Korea Korea Taiwan India
PUD + NUD NUD PUD + NUD PUD + NUD PUD + NUD PUD PUD + NUD PUD + NUD PUD
158 143 410 326 460 159 246 900 272
Jan 2007 to Dec 2007 Jan 2005 to Dec 2009 Oct 2008 to Feb 2009 May 2009 to Dec 2010 Mar 2008 to Aug 2011 Nov 2010 to Aug 2011 Dec 2009 to Dec 2010 Dec 2009 to Sep 2011 2010 to 2011
2 3 3 3 3 3 3 5 3
PUD: peptic ulcer disease; NUD: non-ulcer dyspepsia.
ST vs. TT In all, 1564 patients were treated with ST and 1509 patients were treated with TT. The pooled OR of ITT eradication rates was 1.768 (95% CI, 1.476—2.117, P = 0.000) with the fixed effect model (Fig. 2). The pooled OR of PP eradication rates was 1.997 (95% CI, 1.607—2.480, P = 0.000) with the fixed effect model (Fig. 3). No evidence of publication bias was observed as indicated by a symmetric funnel plot and a non-significant Egger test (P = 0.17). All nine of the RCTs reported the frequency of adverse events with ST and TT. The pooled OR of adverse events of ST and TT was 0.949 (95% CI, 0.796—1.131, P = 0.557) with the fixed effect model (Fig. 4). The pooled eradication rates of ITT analysis was 81.3% (95% CI: 76.5—85.3) for the ST group and 70.8% (95% CI: 64.6—76.4) for the TT group. The pooled eradication rates of PP analysis was 87.6% (95% CI: 84.1—90.5) for the ST group and 77.1% (95% CI: 70.9—82.3) for the TT group. Significant heterogeneity existed for all of the pooled eradication rates and the random effects model was used.
the fixed effect model of ITT eradication rates and PP eradication rates was 1.648 (95% CI: 1.171—2.318, P = 0.004) and 1.990 (95% CI: 1.322—2.994, P = 0.001) (Fig. 6). Three studies compared ST with TT administered for 14 days and the pooled OR with the random effects model of ITT eradication rates and PP eradication rates was 1.447 (95% CI: 0.8782.385, P = 0.148) and 1.552 (95% CI: 0.929—2.595, P = 0.093) (Fig. 7).
Metronidazole vs. tinidazole Six of the RCTs used metronidazole in their ST regimen and 3 of the RCTs used tinidazole in their ST regimen. We performed a subgroup analysis of eradication rates in these two groups. The pooled OR of ITT eradication rates and PP eradication rates were 1.400 (95% CI: 0.679—2.885, P = 0.362) and 2.173 (95% CI: 1.670—2.827, P = 0.000) for the metronidazole group. The pooled OR of ITT eradication rates and PP eradication rates were 1.436 (95% CI: 1.027—2.007, P = 0.034) and 1.709 (95% CI: 0.951—3.072, P = 0.073) for the tinidazole group.
Duration of TT In all, five studies compared ST with TT administered for seven days and the pooled OR with the fixed effect model of ITT eradication rates and PP eradication rates was 1.793 (95% CI: 1.362—2.361, P = 0.000) and 1.999 (95% CI: 1.451—2.754, P = 0.000) (Fig. 5). Three studies compared ST with TT administered for ten days and the pooled OR with
Figure 1 analysis.
Flow diagram of studies included in this meta-
Discussion The standard TT regimen is recommended foremost by most treatment guidelines, however recent reports show that the eradication rates of TT have declined to a level below 80% [1]. Thus, several treatment regimens have been proposed as an alternative to the TT regimen with ST obtaining the most data. The ST regimen consists of a PPI with amoxicillin for the first five days followed by a PPI with clarithromycin and metronidazole (or tinidazole) for the next five days. Earlier reports have demonstrated ST to be superior to TT for eradication of H. pylori but most of these studies were reported from Italy raising concerns that similar results may not uphold in other countries. Many studies from other countries have been published over the last 5 years and the ST regimen achieved higher eradication rates than the TT regimen in most of the studies. However, an RCT including seven Latin America countries reported TT to be superior to ST while another study from Belgium did not find significant difference between the two treatments in clarithromycin and metronidazole resistant strains [19,20]. These results suggest that successful eradication with the ST regimen depends on the local resistance of clarithromycin
Data abstracted from included studies.
Study
Duration of TT
Test for confirming infection
Tests for confirming eradication
Triple therapy
Sequential therapy (first 5 days)
Sequential therapy (second 5 days)
Choi et al. [10]
7
NC
UBT + RUT
Omeprazole 20 mg bid + amoxicillin 1000 mg bid
Gao et al. [11]
7
RUT + histology
UBT
Omeprazole 20 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Omeprazole 20 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid
Kim et al. [12]
14
RUT + UBT + histology
UBT
Omeprazole 20 mg + clarithromycin 500 mg bid + amoxicillin 1000 mg bid Omeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid Pantoprazole 40 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Park et al. [13]
7
RUT + UBT + histology
UBT
Rabeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Rabeprazole 20 mg bid + amoxicillin 1000 mg bid
Choi et al. [14]
7, 10, 14
RUT + UBT + histology
UBT + histology
Rabeprazole 20 mg bid + amoxicillin 1000 mg bid
Chung et al. [15]
10
RUT + histology + culture
UBT
Rabeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid Lansoprazole 30 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Oh et al. [16]
7
RUT + histology
UBT
Rabeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Rabeprazole 20 mg bid + amoxicillin 1000 mg bid
Liou et al. [17]
14
RUT + histology + culture + serology + UBT
UBT
Lansoprazole 30 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Lansoprazole 30 mg bid + amoxicillin 1000 mg bid
Javid et al. [18]
10
RUT + histology
RUT + histology
Pantoprazole 40 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Pantoprazole 40 mg bid + amoxicillin 1000 mg bid
Omeprazole 20 mg bid + amoxicillin 1000 mg bid
Pantoprazole 40 mg bid + amoxicillin 1000 mg bid
Lansoprazole 30 mg bid + amoxicillin 1000 mg bid
Sequential therapy for Helicobacter
Table 2
Pantoprazole 40 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Rabeprazole 20 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Rabeprazole 20 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid Lansoprazole 30 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Rabeprazole 20 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Lansoprazole 30 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Pantoprazole 40 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid
RUT: rapid urease test; UBT: urea breath test.
121
122
J.S. Kim et al.
Figure 2
Forest plot of intention-to-treat analysis of sequential therapy compared with triple therapy.
and metronidazole resistance. The Maastricht IV guideline recommends TT for first line treatment in areas of low clarithromycin resistance and bismuth-containing quadruple treatments in areas of high clarithromycin resistance [21]. Sequential therapy was recommended as an alternative when bismuth-containing regimens was not available. The Asia-Pacific guidelines state insufficient data to recommend ST as an alternative first line therapy [7]. However, multiple studies comparing ST and TT in the Asian population have been published during the past 5 years. The majority
Figure 3
of these studies showed ST to be superior to TT, thus we performed this meta-analysis. The results of our meta-analysis suggest that ST is superior to TT in the eradication of H. pylori in Asia and is consistent with previous meta-analysis. However, the pooled crude eradication rates of ST for ITT analysis and PP analysis were 81.1 and 87.6% which is substantially lower than previous meta-analysis performed world widely that reported a rate of over 90%. This is also substantially below the treatment success of 95% per protocol that should be expected for
Forest plot of per-protocol analysis of sequential therapy compared with triple therapy.
Sequential therapy for Helicobacter
Figure 4
Forest plot of adverse events of sequential therapy compared with triple therapy.
Figure 5
Forest plot of intention-to-treat analysis of sequential therapy compared with 7-day triple therapy.
Figure 6
Forest plot of intention-to-treat analysis of sequential therapy compared with 10-day triple therapy.
123
124
J.S. Kim et al.
Figure 7
Forest plot of intention-to-treat analysis of sequential therapy compared with 14-day triple therapy.
an infectious disease. Our results suggest that ST is superior to TT in Asia but the eradication rates were not sufficient suggesting the need for alternative regimens. Although they were not included in our analysis, modified ST regimens using tetracycline or quinolone has been proved to be more effective than standard TT regimens [22]. Further studies in the future should allow us to determine whether the modified ST regimen is an effective alternative to the ST or TT regimen in the Asian population. Another alternative to ST is concomitant therapy (CT). The CT regimen consists of concomitant administration of the four drugs used in ST. This is based on the assumption that sequential administration of drugs does not play a significant role in eradication and that concurrent prescription using the same drugs would have similar efficacy. The Maastricht guidelines recommend CT as an alternative first line regimen when bismuth containing quadruple regimen is not available in areas of high clarithromycin resistance. However, there is no reference to CT in the Asia-Pacific guidelines. Few studies have compared the CT regimen and ST regimen for H. pylori eradication in a randomised trial. A recent study by McNicholl et al. [23] reported non-statistically significant (5%) advantage of CT over ST. However, another study by Zullo et al. [24] failed to demonstrate a superiority of the CT regimen over the ST regimen. More randomised controlled trials comparing the eradication rates of CT with TT and ST is required before we can decide on the usefulness of CT as first line therapy in Asia. The main concern regarding ST is the lack of an appropriate second-line therapy after treatment failure. Zullo et al. [3] reported a levofloxacin-amoxicillin based triple therapy to be successful in 85.7% of patients who failed ST. However, levofloxacin resistance is reported to be high in Asian countries raising doubt as to the efficacy of this rescue regimen in Asia [25]. Liou et al. [17] treated 41 patients after failing first line ST with a MS-14 regimen consisting of lansoprazole and amoxicillin for the first seven days followed by lansoprazole, metronidazole and levofloxacin for the next seven days. The eradication rate of the MS-14 regimen was 80.5% (33 of 41 patients). More studies involving more patients will be needed to decide the optimal regimen for ST failure patients.
There are some limitations to our meta-analysis. The duration of TT and ST was not uniform among the RCTs. Duration of TT ranged from 7, 10, 14 days among the studies and the duration of ST ranged from 10 to 14 days. Several metaanalyses reported that increasing the TT regimen to 10 days and 14 days may increase the eradication rates of the TT regimen compared to the 7-day regimen [26—28]. In our subgroup analysis, ST was more effective than TT regimens of seven and ten days. However, ST regimens failed to achieve higher eradication rates compared to TT of 14 days. These results suggest that merely extending to a 14-day TT regimen may achieve similar eradication rates as the ST regimen. Future studies comparing the 14-day TT regimen with ST is required to validate this theory. Another limitation was that there was heterogeneity in the type of antibiotics used in the ST regimen. Three of the studies used tinidazole for their ST regimen and six of the studies used metronidazole for their ST regimen. It has been reported that the eradication rate of ST was significantly lower when tinidazole was substituted with metronidazole [29]. In our subgroup analysis, ST regimens using metronidazole and tinidazole were both more effective than the TT regimen. Also, six of the studies included in our meta-analysis were from Korea a region with high resistance to clarithromycin and metronidazole and no studies from Japan were included in our analysis. In conclusion, meta-analysis of nine RCTs from Asia showed eradication rates of ST to be better than TT and rates of adverse events to be similar. Although pooled eradication rates of the ST regimen was lower than previous reported results, its eradication rate was distinctly higher than the TT regimen. These results suggest that ST may be a reasonable choice for first line therapy in Asia, especially since ST is generally less expensive than TT [30]. However, there are few studies investigating the optimal treatment regimen for eradication failed patients after ST in Asia and thus more studies are required in the future.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Sequential therapy for Helicobacter
References [1] Vakil N, Megraud F. Eradication therapy for Helicobacter pylori. Gastroenterology 2007;133:985—1001. [2] Zullo A, Rinaldi V, Winn S, et al. A new highly effective shortterm therapy schedule for Helicobacter pylori eradication. Aliment Pharmacol Ther 2000;14:715—8. [3] 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. [4] 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. [5] Tong JL, Ran ZH, Shen J, Xiao SD. Sequential therapy vs. standard triple therapies for Helicobacter pylori infection: a meta-analysis. J Clin Pharm Ther 2009;34:41—53. [6] Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Ann Intern Med 2008;148:923—31. [7] Fock KM, Katelaris P, Sugano K, et al. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol 2009;24:1587—600. [8] Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Chichester: Wiley: The Cochrane collaboration, 2011; 2011. [9] Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1—12. [10] Choi WH, Park DI, Oh SJ, et al. Effectiveness of 10 daysequential therapy for Helicobacter pylori eradication in Korea. Korean J Gastroenterol 2008;51:280—4. [11] Gao XZ, Qiao XL, Song WC, Wang XF, Liu F. Standard triple, bismuth pectin quadruple and sequential therapies for Helicobacter pylori eradication. World J Gastroenterol 2010;16:4357—62. [12] Kim YS, Kim SJ, Yoon JH, et al. Randomised clinical trial: the efficacy of a 10-day sequential therapy vs. a 14-day standard proton pump inhibitor-based triple therapy for Helicobacter pylori in Korea. Aliment Pharmacol Ther 2011;34: 1098—105. [13] 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. [14] Choi HS, Chun HJ, Park SH, et al. Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection. World J Gastroenterol 2012;18:2377—82. [15] Chung JW, Jung YK, Kim YJ, et al. Ten-day sequential versus triple therapy for Helicobacter pylori eradication: a prospective, open-label, randomized trial. J Gastroenterol Hepatol 2012;27:1675—80.
125 [16] Oh HS, Lee DH, Seo JY, et al. Ten-day sequential therapy is more effective than proton pump inhibitor-based therapy in Korea: a prospective, randomized study. J Gastroenterol Hepatol 2012;27:504—9. [17] Liou JM, Chen CC, Chen MJ, et al. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet 2013;381:205—13. [18] Javid G, Zargar SA, Bhat K, et al. Efficacy and safety of sequential therapy versus standard triple therapy in Helicobacter pylori eradication in Kashmir India: a randomized comparative trial. Indian J Gastroenterol 2013;32:190—4. [19] 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. [20] Bontems P, Kalach N, Oderda G, et al. Sequential therapy versus tailored triple therapies for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 2011;53:646—50. [21] 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. [22] Zullo A, De Francesco V, Hassan C, et al. Modified sequential therapy regimens for Helicobacter pylori eradication: a systematic review. Dig Liver Dis 2013;45:18—22. [23] 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 2013. [Epub ahead of print]. [24] Zullo A, Scaccianoce G, De Francesco V, et al. Concomitant, sequential, and hybrid therapy for H. pylori eradication: a pilot study. Clin Res Hepatol Gastroenterol 2013. [Epub ahead of print]. [25] De Francesco V, Giorgio F, Hassan C, et al. Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis 2010;19:409—14. [26] Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E, Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxycillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther 2000;14:603—9. [27] Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori eradication therapy be improved? Can J Gastroenterol 2003;17 Suppl B:36B—40B. [28] Fuccio L, Minardi ME, Zagari RM, Grilli D, 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. [29] Vaira D, Zullo A, Hassan C, Fiorini G, Vakil N. Sequential therapy for Helicobacter pylori eradication: the time is now! Therap Adv Gastroenterol 2009;2:317—22. [30] Kate V, Kalayarasan R, Ananthakrishnan N. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a systematic review of recent evidence. Drugs 2013;73:815—24.
Available online at
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE
Sequential therapy or triple therapy for Helicobacter pylori infection in Asians: Systematic review and meta-analysis Joon Sung Kim a, Jeong-Seon Ji a,∗, Hwang Choi a, Joo Hyun Kim b a
Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, 56, Dongsu-ro, Bupyeong-gu, Incheon 403-720, Republic of Korea b Newport High School, Bellevue, WA, USA Available online 12 November 2013
Summary Background and objective: Eradication rate of Helicobacter pylori infection with triple therapy (TT) has declined in part to increased antibiotic resistance. Sequential therapy (ST) has shown promise in several meta-analyses. However, most of the studies included in previous metaanalyses were from Italy. The aim of this study was to compare the efficacy of ST with that of TT in Asia by performing a meta-analysis of studies from Asia. Materials and methods: We performed a comprehensive literature search for studies comparing the efficacy of ST with TT. Randomised controlled trials investigated in the Asian population were included. The odds ratios (OR) of eradicating H. pylori infection after ST compared with TT were pooled. The eradication rates were considered both on an intention-to-treat (ITT) and on a per-protocol basis (PP). Results: A total of nine studies provided data on 3074 adult patients. The odds ratio (OR) for eradication of H. pylori with ST compared with TT was 1.768 (95% CI: 1.476—2.117, P = 0.000) for ITT analysis and 1.997 (95% CI: 1.607—2.480, P = 0.000) for PP analysis. The pooled eradication rates of ITT analysis was 81.3% (95% CI: 76.5—85.3) for the ST group and 70.8% (95% CI: 64.6—76.4) for the TT group. The pooled eradication rates of PP analysis was 87.6% (95% CI: 84.1—90.5) for the ST group and 77.1% (95% CI: 70.9—82.3) for the TT group. There was no difference in the rate of adverse events between ST and TT (OR 0.945, 95% CI: 0.874-1.238, P = 0.658). Conclusion: ST appears to be better than TT in the eradication of H. pylori in Asia. These results suggest that ST may be a reasonable choice for first line therapy in Asia. © 2013 Elsevier Masson SAS. All rights reserved.
∗
Corresponding author. Tel.: +82 32 280 5051; fax: +82 32 280 5082. E-mail address: [email protected] (J.-S. Ji).
2210-7401/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2013.10.001
Sequential therapy for Helicobacter
Introduction Helicobacter pylori (H. pylori) infection is the major cause of gastritis, peptic ulcer, gastric adenocarcinoma and marginal zone B cell lymphoma of MALT type [1]. H. pylori infection has also been associated with idiopathic thrombocytopenic purpura and idiopathic iron deficiency anemia [1]. Although, there are several treatment regimens for treating H. pylori infection, controversy has emerged regarding the optimal treatment regimen. Primary resistance toward different antibiotics is the most important factor influencing treatment failure and has been reported to be different according to geographical locations. Triple therapy (TT) regimen has been regarded as firstline regimens for treating H. pylori infection. However, eradication rate of TT has declined during the last decade, which is primarily due to increased bacterial resistance to clarithromycin world widely. For this reason, several regimens have been proposed as an alternative to the TT regimen. The sequential therapy regimen (ST) was first introduced in Italy in 2000 and several meta-analyses have demonstrated ST regimens to achieve higher eradication rates than the standard TT regimen [2—6]. However, most of the studies included in these reports were from Italy and few studies from Asia were included. We cannot conclude that ST will be superior to TT based on the results of these metaanalyses because patterns of antimicrobial resistance may vary geographically. The Asia-Pacific guidelines currently states triple therapy as recommended first-line therapy for H. pylori [7]. However, recent studies published from Asia have reported sequential therapy to be more effective than triple therapy. The purpose of this study was to perform a meta-analysis of studies that targeted the Asian population and compare ST with TT for eradication of H. pylori.
Materials and methods Search method This systematic review and meta-analysis was performed according to the guidelines set forth in Cochrane Handbook for Systematic Reviews of Interventions [8]. A literature search was conducted using Medline (through PubMed), EMBASE, Cochrane Library, and Google Scholar with the key words of ‘‘Helicobacter pylori’’, ‘‘sequential therapy,’’ ‘‘triple therapy’’. Full texts of all relevant articles published from January 2001 to March 2013 were considered for our review.
Study selection Randomised controlled trials (RCT) that targeted the Asian population and compared ST with TT for H. pylori eradication were included. Inclusion criteria for selection in the meta-analysis were: (a) TT regimens consisted of a proton pump inhibitor (PPI), clarithromycin and amoxicillin; (b) ST regimen consisted of a PPI plus amoxicillin given for the first five days followed by a PPI, clarithromycin and tinidazole (or metronidazole) for the next five days; (c) Diagnosis of H. pylori infection was determined by histology,
119 fecal antigen test, urea breath test (UBT) or rapid urease test (RUT); (d) Eradication was assessed by either two of the tests used for diagnosis or UBT. Modified TT and ST regimens were excluded.
Data collection A data extraction manual was developed in advanced and information was collected independently by the two researchers (J.S.K., J.H.K.). Data extracted were year of publication, whether the study was a single or multicenter study, enrollment period, numbers of patients included in the ST and TT group, baseline characteristics of the patients, details related to the use of ST and TT (including dose and duration), methods of diagnosing infection and confirming eradication; incidence of side effects. Since the object of our review was to compare ST with TT, distinctions were not made regarding the duration of treatments. The quality of the included studies was assessed by using the Jadad scale and a score of ≥ 3 was considered as high quality [9].
Outcome measures The primary outcome of this study was odds ratios (OR) of eradication rates of ST and TT in Asians. Secondary outcome was OR of adverse events of ST and TT in Asians. The eradication rates were considered both on an intention-to-treat (ITT) and on a per-protocol basis (PP).
Statistical analysis Meta-analysis was performed by calculating pooled estimates of primary and secondary outcomes. Pooled results were derived by using the fixed effect model, unless significant heterogeneity was present. Heterogeneity between studies was evaluated with the Cochrane Q test and the inconsistency index (I2 ). When I2 value was < 50%, we used a fixed effect model, otherwise a random effects model was used. Funnel plots and Egger’s test were used to investigate publication bias. P < 0.05 indicated publication bias, while P > 0.05 indicated no publication bias. Statistical analyses were executed by the aid of Comprehensive Meta-analysis software version 2 (Biostat Inc, Englewood, NJ).
Results A flow diagram of this systematic review is shown in Fig. 1. In summary, 118 studies were identified by our literature search. Eighty-five were excluded after initial screening of title and abstracts. After reviewing the full text of the remaining studies, nine RCTs met our inclusion criteria for meta-analysis [10—18]. The main characteristics of the studies are listed in Tables 1 and 2. All but three of the included studies were a single-center study, and the enrollment period ranged from 2007 to 2011. All of the studies were published in English except for a Korean study by Choi et al. [10]. Three of the studies used tinidazole for their sequential therapy regimen and the rest used metronidazole.
120 Table 1
J.S. Kim et al. Main characteristic of included studies.
Study
Centers
Country
Type of patients
No. of patients
Study duration
Jadad score
Choi et al. [10] Gao et al. [11] Kim et al. [12] Park et al. [13] Choi et al. [14] Chung et al. [15] Oh et al. [16] Liou et al. [17] Javid et al. [18]
Single Single Single Multi Single Single Single Multi Single
Korea China Korea Korea Korea Korea Korea Taiwan India
PUD + NUD NUD PUD + NUD PUD + NUD PUD + NUD PUD PUD + NUD PUD + NUD PUD
158 143 410 326 460 159 246 900 272
Jan 2007 to Dec 2007 Jan 2005 to Dec 2009 Oct 2008 to Feb 2009 May 2009 to Dec 2010 Mar 2008 to Aug 2011 Nov 2010 to Aug 2011 Dec 2009 to Dec 2010 Dec 2009 to Sep 2011 2010 to 2011
2 3 3 3 3 3 3 5 3
PUD: peptic ulcer disease; NUD: non-ulcer dyspepsia.
ST vs. TT In all, 1564 patients were treated with ST and 1509 patients were treated with TT. The pooled OR of ITT eradication rates was 1.768 (95% CI, 1.476—2.117, P = 0.000) with the fixed effect model (Fig. 2). The pooled OR of PP eradication rates was 1.997 (95% CI, 1.607—2.480, P = 0.000) with the fixed effect model (Fig. 3). No evidence of publication bias was observed as indicated by a symmetric funnel plot and a non-significant Egger test (P = 0.17). All nine of the RCTs reported the frequency of adverse events with ST and TT. The pooled OR of adverse events of ST and TT was 0.949 (95% CI, 0.796—1.131, P = 0.557) with the fixed effect model (Fig. 4). The pooled eradication rates of ITT analysis was 81.3% (95% CI: 76.5—85.3) for the ST group and 70.8% (95% CI: 64.6—76.4) for the TT group. The pooled eradication rates of PP analysis was 87.6% (95% CI: 84.1—90.5) for the ST group and 77.1% (95% CI: 70.9—82.3) for the TT group. Significant heterogeneity existed for all of the pooled eradication rates and the random effects model was used.
the fixed effect model of ITT eradication rates and PP eradication rates was 1.648 (95% CI: 1.171—2.318, P = 0.004) and 1.990 (95% CI: 1.322—2.994, P = 0.001) (Fig. 6). Three studies compared ST with TT administered for 14 days and the pooled OR with the random effects model of ITT eradication rates and PP eradication rates was 1.447 (95% CI: 0.8782.385, P = 0.148) and 1.552 (95% CI: 0.929—2.595, P = 0.093) (Fig. 7).
Metronidazole vs. tinidazole Six of the RCTs used metronidazole in their ST regimen and 3 of the RCTs used tinidazole in their ST regimen. We performed a subgroup analysis of eradication rates in these two groups. The pooled OR of ITT eradication rates and PP eradication rates were 1.400 (95% CI: 0.679—2.885, P = 0.362) and 2.173 (95% CI: 1.670—2.827, P = 0.000) for the metronidazole group. The pooled OR of ITT eradication rates and PP eradication rates were 1.436 (95% CI: 1.027—2.007, P = 0.034) and 1.709 (95% CI: 0.951—3.072, P = 0.073) for the tinidazole group.
Duration of TT In all, five studies compared ST with TT administered for seven days and the pooled OR with the fixed effect model of ITT eradication rates and PP eradication rates was 1.793 (95% CI: 1.362—2.361, P = 0.000) and 1.999 (95% CI: 1.451—2.754, P = 0.000) (Fig. 5). Three studies compared ST with TT administered for ten days and the pooled OR with
Figure 1 analysis.
Flow diagram of studies included in this meta-
Discussion The standard TT regimen is recommended foremost by most treatment guidelines, however recent reports show that the eradication rates of TT have declined to a level below 80% [1]. Thus, several treatment regimens have been proposed as an alternative to the TT regimen with ST obtaining the most data. The ST regimen consists of a PPI with amoxicillin for the first five days followed by a PPI with clarithromycin and metronidazole (or tinidazole) for the next five days. Earlier reports have demonstrated ST to be superior to TT for eradication of H. pylori but most of these studies were reported from Italy raising concerns that similar results may not uphold in other countries. Many studies from other countries have been published over the last 5 years and the ST regimen achieved higher eradication rates than the TT regimen in most of the studies. However, an RCT including seven Latin America countries reported TT to be superior to ST while another study from Belgium did not find significant difference between the two treatments in clarithromycin and metronidazole resistant strains [19,20]. These results suggest that successful eradication with the ST regimen depends on the local resistance of clarithromycin
Data abstracted from included studies.
Study
Duration of TT
Test for confirming infection
Tests for confirming eradication
Triple therapy
Sequential therapy (first 5 days)
Sequential therapy (second 5 days)
Choi et al. [10]
7
NC
UBT + RUT
Omeprazole 20 mg bid + amoxicillin 1000 mg bid
Gao et al. [11]
7
RUT + histology
UBT
Omeprazole 20 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Omeprazole 20 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid
Kim et al. [12]
14
RUT + UBT + histology
UBT
Omeprazole 20 mg + clarithromycin 500 mg bid + amoxicillin 1000 mg bid Omeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid Pantoprazole 40 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Park et al. [13]
7
RUT + UBT + histology
UBT
Rabeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Rabeprazole 20 mg bid + amoxicillin 1000 mg bid
Choi et al. [14]
7, 10, 14
RUT + UBT + histology
UBT + histology
Rabeprazole 20 mg bid + amoxicillin 1000 mg bid
Chung et al. [15]
10
RUT + histology + culture
UBT
Rabeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid Lansoprazole 30 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Oh et al. [16]
7
RUT + histology
UBT
Rabeprazole 20 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Rabeprazole 20 mg bid + amoxicillin 1000 mg bid
Liou et al. [17]
14
RUT + histology + culture + serology + UBT
UBT
Lansoprazole 30 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Lansoprazole 30 mg bid + amoxicillin 1000 mg bid
Javid et al. [18]
10
RUT + histology
RUT + histology
Pantoprazole 40 mg bid + clarithromycin 500 mg bid + amoxicillin 1000 mg bid
Pantoprazole 40 mg bid + amoxicillin 1000 mg bid
Omeprazole 20 mg bid + amoxicillin 1000 mg bid
Pantoprazole 40 mg bid + amoxicillin 1000 mg bid
Lansoprazole 30 mg bid + amoxicillin 1000 mg bid
Sequential therapy for Helicobacter
Table 2
Pantoprazole 40 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Rabeprazole 20 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Rabeprazole 20 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid Lansoprazole 30 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Rabeprazole 20 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Lansoprazole 30 mg bid + clarithromycin 500 mg bid + metronidazole 500 mg bid Pantoprazole 40 mg bid + clarithromycin 500 mg bid + tinidazole 500 mg bid
RUT: rapid urease test; UBT: urea breath test.
121
122
J.S. Kim et al.
Figure 2
Forest plot of intention-to-treat analysis of sequential therapy compared with triple therapy.
and metronidazole resistance. The Maastricht IV guideline recommends TT for first line treatment in areas of low clarithromycin resistance and bismuth-containing quadruple treatments in areas of high clarithromycin resistance [21]. Sequential therapy was recommended as an alternative when bismuth-containing regimens was not available. The Asia-Pacific guidelines state insufficient data to recommend ST as an alternative first line therapy [7]. However, multiple studies comparing ST and TT in the Asian population have been published during the past 5 years. The majority
Figure 3
of these studies showed ST to be superior to TT, thus we performed this meta-analysis. The results of our meta-analysis suggest that ST is superior to TT in the eradication of H. pylori in Asia and is consistent with previous meta-analysis. However, the pooled crude eradication rates of ST for ITT analysis and PP analysis were 81.1 and 87.6% which is substantially lower than previous meta-analysis performed world widely that reported a rate of over 90%. This is also substantially below the treatment success of 95% per protocol that should be expected for
Forest plot of per-protocol analysis of sequential therapy compared with triple therapy.
Sequential therapy for Helicobacter
Figure 4
Forest plot of adverse events of sequential therapy compared with triple therapy.
Figure 5
Forest plot of intention-to-treat analysis of sequential therapy compared with 7-day triple therapy.
Figure 6
Forest plot of intention-to-treat analysis of sequential therapy compared with 10-day triple therapy.
123
124
J.S. Kim et al.
Figure 7
Forest plot of intention-to-treat analysis of sequential therapy compared with 14-day triple therapy.
an infectious disease. Our results suggest that ST is superior to TT in Asia but the eradication rates were not sufficient suggesting the need for alternative regimens. Although they were not included in our analysis, modified ST regimens using tetracycline or quinolone has been proved to be more effective than standard TT regimens [22]. Further studies in the future should allow us to determine whether the modified ST regimen is an effective alternative to the ST or TT regimen in the Asian population. Another alternative to ST is concomitant therapy (CT). The CT regimen consists of concomitant administration of the four drugs used in ST. This is based on the assumption that sequential administration of drugs does not play a significant role in eradication and that concurrent prescription using the same drugs would have similar efficacy. The Maastricht guidelines recommend CT as an alternative first line regimen when bismuth containing quadruple regimen is not available in areas of high clarithromycin resistance. However, there is no reference to CT in the Asia-Pacific guidelines. Few studies have compared the CT regimen and ST regimen for H. pylori eradication in a randomised trial. A recent study by McNicholl et al. [23] reported non-statistically significant (5%) advantage of CT over ST. However, another study by Zullo et al. [24] failed to demonstrate a superiority of the CT regimen over the ST regimen. More randomised controlled trials comparing the eradication rates of CT with TT and ST is required before we can decide on the usefulness of CT as first line therapy in Asia. The main concern regarding ST is the lack of an appropriate second-line therapy after treatment failure. Zullo et al. [3] reported a levofloxacin-amoxicillin based triple therapy to be successful in 85.7% of patients who failed ST. However, levofloxacin resistance is reported to be high in Asian countries raising doubt as to the efficacy of this rescue regimen in Asia [25]. Liou et al. [17] treated 41 patients after failing first line ST with a MS-14 regimen consisting of lansoprazole and amoxicillin for the first seven days followed by lansoprazole, metronidazole and levofloxacin for the next seven days. The eradication rate of the MS-14 regimen was 80.5% (33 of 41 patients). More studies involving more patients will be needed to decide the optimal regimen for ST failure patients.
There are some limitations to our meta-analysis. The duration of TT and ST was not uniform among the RCTs. Duration of TT ranged from 7, 10, 14 days among the studies and the duration of ST ranged from 10 to 14 days. Several metaanalyses reported that increasing the TT regimen to 10 days and 14 days may increase the eradication rates of the TT regimen compared to the 7-day regimen [26—28]. In our subgroup analysis, ST was more effective than TT regimens of seven and ten days. However, ST regimens failed to achieve higher eradication rates compared to TT of 14 days. These results suggest that merely extending to a 14-day TT regimen may achieve similar eradication rates as the ST regimen. Future studies comparing the 14-day TT regimen with ST is required to validate this theory. Another limitation was that there was heterogeneity in the type of antibiotics used in the ST regimen. Three of the studies used tinidazole for their ST regimen and six of the studies used metronidazole for their ST regimen. It has been reported that the eradication rate of ST was significantly lower when tinidazole was substituted with metronidazole [29]. In our subgroup analysis, ST regimens using metronidazole and tinidazole were both more effective than the TT regimen. Also, six of the studies included in our meta-analysis were from Korea a region with high resistance to clarithromycin and metronidazole and no studies from Japan were included in our analysis. In conclusion, meta-analysis of nine RCTs from Asia showed eradication rates of ST to be better than TT and rates of adverse events to be similar. Although pooled eradication rates of the ST regimen was lower than previous reported results, its eradication rate was distinctly higher than the TT regimen. These results suggest that ST may be a reasonable choice for first line therapy in Asia, especially since ST is generally less expensive than TT [30]. However, there are few studies investigating the optimal treatment regimen for eradication failed patients after ST in Asia and thus more studies are required in the future.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Sequential therapy for Helicobacter
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