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doi:10.1111/jgh.12984
M E TA - A N A LY S I S A N D S Y S T E M AT I C R E V I E W
Sequential or concomitant therapy for eradication of Helicobacter pylori infection: A systematic review and meta-analysis Joon Sung Kim, Sung Min Park and Byung-Wook Kim Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea
Key words concomitant therapy, Helicobacter pylori, meta-analysis, sequential therapy. Accepted for publication 21 March 2015. Correspondence Byung-Wook Kim, Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 56, Dongsu-ro, Bupyeong-gu, Incheon, 403-720, Republic of Korea. Email: [email protected] Declaration of conflict of interest: All authors have no potential conflict of interest relevant to this article.
Abstract Background and Aim: Eradication of Helicobacter pylori (H. pylori) infection with triple therapy (TT) has declined in many countries prompting the search for alternative regimens. Sequential therapy (ST) and concomitant therapy (CT) have been suggested as first-line regimens in areas of high clarithromycin resistance. We performed a metaanalysis to compare the eradication rates of CT with ST for H. pylori. Methods: A comprehensive literature search for studies comparing the efficacy of CT with ST was performed. Dichotomous data were pooled to obtain the odds ratio (OR) of the eradication rate with 95% confidence intervals (CIs). The eradication rates were considered both on an intention-to-treat (ITT) and on a per-protocol (PP) bases. Results: A total of 7 studies provided data on 2412 adult patients. Pooled estimates of the studies revealed no significant differences between CT and ST. The pooled OR was 1.116 (95% CI: 0.795–1.567, P = 0.526) for ITT analysis and 1.153 (95% CI: 0.793–1.677, P = 0.455) for PP analysis. There was no difference in the rate of adverse events (OR: 1.229, 95% CI: 0.971–1.556, P = 0.086) and compliance (OR: 0.945, 95% CI: 0.722– 1.237, P = 0.681) between the two regimens. Subgroup analysis was performed to compare CT of 10 days and 5 days with ST of 10 days. The pooled OR was 1.518 for CT of 10days and 0.636 for CT of 5 days. Conclusions: CT regimens did not achieve higher eradication rates compared with the ST regimen. The adverse events and adherence to medications were not different between the two regimens.
Introduction Helicobacter pylori (H. pylori) plays an essential role in the pathogenesis of peptic ulcer disease, low-grade gastric marginal zone mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric malignancy.1 Triple therapy consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole has been recommended as first-line therapy for H. pylori infection by most international guidelines in the past decade.1–4 However, eradication rates of triple therapy have fallen below the acceptable range of 80% in most counties mainly due to increased clarithromycin resistance.5,6 The recent European guidelines recommend sequential therapy (ST) and concomitant therapy (CT) as alternative first-line therapies in areas with high rates of clarithromycin resistance.1 ST regimens consist of a proton pump inhibitor (PPI) and amoxicillin administered for the first 5 days followed by a PPI and two other antibiotics for the following 5 days.7 The sequential administration was thought to weaken bacterial cell walls in the initial phase and 1338
help increase eradication rates even in clarithromycin-resistant strains.8 CT regimen consists of all the medication administered in ST given simultaneously. This is based on the assumption that sequential administration of drugs has no additional benefits and only increases patients inconvenience in taking medicine.9 Several studies compared the eradication rates of CT with ST, yielding conflicting results; thus, we decided to perform this systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the eradication rates of the two regimens.
Methods Search. This systematic review and meta-analysis was performed according to the preferred reporting items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines.10 We searched PubMed, EMBASE, and the Cochrane Library for RCTs comparing sequential with concomitant therapy for H. pylori infection. There was no restriction on language or age. The key words used in the
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search were “Helicobacter pylori,” “sequential therapy,” “concomitant therapy,” “quadruple therapy,” “sequential,” “concomitant,” “disease eradication,” “therapeutics,” and “drug therapy.” We also searched the reference of screened articles and review articles to identify any additional studies. The results of the search were independently reviewed by the two authors (JS Kim, SM Park). Study selection. Studies were included if they were RCTs that compared CT with ST. Inclusion criteria were as follows: (i) patients were confirmed of H. pylori infection with at least one of the following methods: rapid urease test, culture, histology, or urea breath test (UBT) before treatment and at least 4 weeks after the end of treatment; (ii) studies included at least two branches of treatment consisting of sequential therapy and concomitant therapy; (iii) sequential regimens consisted of a PPI and amoxicillin for the first 5–7 days followed by a triple therapy including a PPI, clarithromycin, and tinidazole or metronidazole for the remaining 5–7 days; (iv) concomitant regimen consisted of a PPI, amoxicillin, clarithromycin, and tinidazole or metronidazole given concomitantly for 5–14 days. Nonrandomized studies, case reports, letters, editorials, commentaries, reviews, and abstracts were excluded. Data extraction. A data extraction manual was developed in advanced, and information was collected independently by the two authors (JS Kim, SM Park) using the predefined extraction manual. Abstracted information included baseline characteristics of the patients, year of publication, country of origin, study design, diagnostic methods of testing H. pylori infection before enrollment and after the end of treatment, treatment regimens, duration of treatment, eradication rates for corresponding regimens, and incidence of adverse events. If an RCT had an additional treatment arm in addition to ST and CT, only relevant data were extracted, and results of the additional treatment arm were not included in our analysis. The extracted data were investigated independently by the two authors, and disagreements were resolved by consensus. We attempted to contact the original authors for additional information when necessary. Risk of bias in individual studies. The two authors assessed the risk of bias according to the assessment tool developed by the Cochrane collaboration.11 The criteria address whether studies might be related to random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases. Each criterion was scored as yes (Y), no (N), or unclear (U) and any disagreement was resolved by consensus. Statistical analysis. The primary outcome of this study was the odds ratio (OR) of successful H. pylori eradication of CT compared with ST. Secondary outcomes were OR of adverse events during eradication and compliance to the medication. The eradication rates were considered both on an intention-to-treat (ITT) and a per-protocol (PP) bases. Heterogeneity of the pooled estimates was tested using Cochran’s Q rest and the inconsistency
Sequential or concomitant therapy
index (I2). When significant heterogeneity existed (P < 0.1 or I2 > 50), the random-effects model should be used to combine the effect sizes of the included studies. However, a nonsignificant test (P ≥ 0.1 or I2 ≤ 50) only indicates a lack of evidence for heterogeneity, as there may have been insufficient power to able to detect heterogeneity. We decided on a conservative approach by calculating the pooled OR by using a random-effects model. The presence of publication bias was determined using Egger’s regression intercept, and funnel plots were constructed when necessary. Subgroup analysis was performed based on the duration of the treatment and antibiotic resistance. Statistical analyses were executed by the aid of Comprehensive Meta-analysis software version 2 (Biostat Inc., Englewood, NJ, USA).
Results Study identification and selection. The detailed process of selection is shown in Figure 1. In summary, 8206 studies were identified by our literature search. A total of 7353 studies remained after removal of duplications with identical titles, and 7342 studies were removed after review of titles and abstracts. The full texts of the remaining 11 articles were reviewed. The study by Zullo et al.12 was a pilot study with patients recruited from three centers in Italy. The study by De Francesco et al.13 was a later study with patients recruited from one center, which was included in the study by Zullo et al. We attempted to contact the corresponding authors of these two studies to identify the possibility of overlapping data; however, no reply was received. To avoid counting the same patients twice, we decided to include only the study by De Francesco et al.13 because this was the later study involving a greater number of patients. After reviewing the full text of the remaining studies, seven RCTs were included in our metaanalysis.13–19 Study characteristics. The main characteristics of the studies are listed in Tables 1 and 2. Four of the studies were single-center studies, whereas the remaining three were multicenter studies. The enrollment period ranged from 2007 to 2013. All of the studies were published in English. One study used tinidazole for their CT and ST regimens, and the rest used metronidazole. Treatment durations were 5, 7, 10, and 14 days for CT and 10 and 14 days for ST. Geographically, four of the studies were from Asia, two of the studies were from Europe, and one study was from Latin America. Risk of bias in individual studies. Table 3 provides a summary of methodological domain assessments for each included study. Among the seven studies, six provided an adequate randomization method. Allocation concealment was adequate in only one study, and none of the studies reported blinding. Eradication rates of CT compared with ST. In all patients, 1256 were treated with CT and 1156 were treated with ST. The pooled OR of ITT eradication rates was 1.116 (95% CI: 0.795–1.567, P = 0.526 (Fig. 2). The pooled eradication rates were 86.1% (95% CI: 79.6–90.7) for CT and 83.8% (95% CI: 78.3– 88.2) for ST. The pooled OR of PP eradication rates was 1.153
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Records identified through database searching (n = 8206) PubMed (n = 3714) EMBASE (n = 1682) Cochrane Library (n = 2180)
Records after duplication removal (n = 7353) Evaluated by title and abstracts Excluded because irrelevant studies. (n = 7342) Full-text articles assessed for eligibility (n = 11)
Studies included in meta-analysis (n = 7)
Table 1
Evaluated by full text Review article (n = 2) Overlap of patients among included studies (n = 1) Comparison with other regimens (n = 1)
Figure 1 Flow diagram of studies included in this meta-analysis.
Main characteristics of included studies
Study 14
Wu et al. Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
Centers
Year of publication
Country
Type of patients
No. of patients
Study duration
Multi Multi Single Single Multi Single Single
2010 2011 2012 2013 2014 2014 2014
Taiwan Latin America China Korea Spain Italy Taiwan
PUD + NUD PUD + NUD NUD PUD + NUD PUD + NUD NUD PUD + NUD
232 975 169 164 338 330 205
June 2007 to May 2008 September 2009 to June 2010 July 2008 to February 2010 May 2011 to April 2012 December 2010 to May 2012 January 2012 to July 2013 —
NUD, nonulcer disease; PUD, peptic ulcer disease.
(95% CI: 0.793–1.677, P = 0.455) (Fig. 3). The pooled eradication rates were 89.5% (95% CI: 82.7–93.8) for CT and 86.8% (95% CI: 81.3–90.8) for ST. There was some funnel plot asymmetry compatible with publication bias; however, statistical analysis using Egger’s test was nonsignificant (P = 0.17). These results should be interpreted with caution because the asymmetry test is probably underpowered as there were only seven studies included in the meta-analysis.19 Adverse events and adherence to the medications. Low heterogeneity was observed among the studies for adverse events (P = 0.563, I2 = 0.0 %). The pooled OR for developing adverse events was 1.229 (95% CI: 0.971–1.556, P = 0.086) and the corresponding rates were 37.8% (95% CI: 22.7–55.8) for CT and 33.5% (95% CI: 0.196–0.508) for ST (Fig. 4). Low heterogeneity was observed among the studies for adherence to medications (P = 0.691, I2 = 0.0 %). The pooled OR for adherence to the medications was 0.945 (95% CI: 0.722–1.237, P = 0.681) and the corresponding rates were 92.7% (95% CI: 0.854–0.965) for CT and 92.4% (95% CI: 85.9–96.0) for ST (Fig. 5). Subgroup analysis according to duration of CT. Except for the study by Lim et al.,17 all the other studies 1340
tested a sequential therapy lasting 10 days. However, the duration of CT varied from 5, 7, 10, and 14 days. Therefore, we performed a subgroup analysis according to the duration of CT. Three studies compared 10 days of concomitant therapy with 10 days of sequential therapy. The pooled OR of eradication rates were 1.518 (95% CI: 0.982–2.345, P = 0.060) favoring CT. Two studies compared 5 days of concomitant therapy with 10 days of ST. The pooled OR of eradication rates were 0.636 (95% CI: 0.307–1.320, P = 0.225) favoring sequential therapy. We did not perform a subgroup analysis according to the duration of ST because all but one of the studies reported ST of 10 days.
Subgroup analysis according to antibiotic resistance. Three studies provided available data on the efficacy of H. pylori eradication in patients with antibiotic resistance (supplementary table).13,15,18 For clarithromycin-resistant strains, the eradication rates of ST were 50% to 100% and that of CT was 100%. For metronidazole resistant strains, the eradication rates of ST were 85.7% to 96.3% and that of CT were 95.5% and 100%. For dual resistant strains, the eradication rates of ST were 33.3% to 50% and that of CT were 66.7% to 100%. We decided not to perform a subgroup analysis according to antibiotic resistance because the number of patients in each group was small.
Journal of Gastroenterology and Hepatology 30 (2015) 1338–1345 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology 30 (2015) 1338–1345
© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Culture or RUT + histology
UBT
Culture or RUT + histology
RUT or histology
Culture or RUT or histology or UBT
RUT + histology
Culture and/or RUT + histology
Wu et al.14
Greenberg et al.15
Huang et al.16
Lim et al.17
McNicholl et al.18
De Francesco et al.20
Hsu et al.19 Culture + RUT + histology or UBT
UBT
UBT
UBT
Culture + RUT + histology or UBT
UBT
Culture + RUT + histology or UBT
Tests for confirming eradication
7
5, 14
10
14
10
5
10
Duration of CT
Pantoprazole 40-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Ompeprazole 20-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Tinidazole 500-mg bid
Ompeprazole 20-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Rabeprazole 20-mg Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500 mg bid
Esomeprazole 40-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
CT regimen
CT, concomitant therapy; RUT, rapid urease test; ST, sequential therapy; UBT, urea breath test.
Tests for confirming infection
Data abstracted from included studies
Study
Table 2
10
10
10
14
10
10
10
Duration of ST
Pantoprazole 40-mg bid Amoxicillin 1-g bid
Omeprazole 20-mg bid Amoxicillin 1-g bid
Omeprazole 20-mg bid Amoxicillin 1-g bid
Rabeprazole 20-mg bid Amoxicillin 1-g bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid
Esomeprazole 40-mg bid Amoxicillin 1-g bid
ST regimen (first 5 days)
Pantoprazole 40-mg bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Omeprazole 20-mg bid Clarithromycin 500-mg bid Tinidazole 500-mg bid
Omeprazole 20-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
Lansoprazole 30-mg bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Esomeprazole 40-mg bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
ST regimen (second 5 days)
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Table 3
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Quality assessment and characteristics of included studies
Study
Randomization
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
Yes Yes Yes Yes Yes Unclear Yes
Unclear Unclear Unclear Unclear Yes Unclear Unclear
Unclear Unclear No No No No No
Unclear Unclear No No No No No
Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes No Yes
Yes Yes Yes Yes Yes Yes Yes
“Yes” indicates a low risk of bias and “No” indicates high risk of bias. “Unclear” indicates insufficient or unknown details.
Study name
Events / Total
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
1.115 0.855 1.850 1.357 1.539 0.516 1.934 1.116
0.414 0.640 0.793 0.642 0.853 0.253 0.687 0.795
2.997 0.215 1.144 –1.055 4.318 1.422 2.866 0.800 2.778 1.430 1.052 –1.822 5.446 1.249 1.567 0.633
0.830 0.292 0.155 0.424 0.153 0.069 0.212 0.526
107/115 360/489 74/84 63/78 146/168 181/220 96/102
108/117 372/486 68/85 65/86 138/170 99/110 91/102 0.01
0.1
1
Favors ST Figure 2
10
100
Favors CT
Forest plot of intention-to-treat analysis of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
Study name
Events / Total
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
0.991 0.837 3.008 1.314 1.751 0.548 1.778 1.153
0.359 0.614 0.912 0.605 0.820 0.213 0.621 0.793
2.736 1.140 9.922 2.852 3.738 1.411 5.091 1.677
–0.018 –1.128 1.808 0.691 1.447 –1.246 1.072 0.747
0.986 0.259 0.071 0.490 0.148 0.213 0.284 0.455
107/115 360/471 70/74 61/75 125/137 181/201 96/102
108/116 372/468 64/75 63/82 119/139 99/105 90/100 0.01
0.1 Favors ST
Figure 3
10
100
Favors CT
Forest plot of per-protocol analysis of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
Discussion Nonbismuth quadruple therapies consisting of ST and CT have been recommend as alternative first-line regimens in areas with high rates of clarithromycin resistance.1 Several studies have compared ST with CT, but controversy still exists as to which regimen is better. The ST regimen was developed in Italy as a replacement 1342
1
for TT and initially showed promising results with eradication rates consistently higher than 90%.20–22 However, later studies found that although the ST regimen remained significantly better than triple therapy, its eradications rates dropped dramatically compared with original reports.23,24 A recent meta-analysis found that although ST was superior to 7 days of conventional triple therapy, its eradication rates were similar to regimens of longer
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Sequential or concomitant therapy
Events / Total
Statistics for each study
Study name
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
0.830 0.933 1.311 1.450 1.447 1.644 1.229
0.470 0.500 0.705 0.938 0.823 0.677 0.971
1.467 –0.640 1.741 –0.218 2.438 0.855 2.239 1.673 2.544 1.284 3.990 1.099 1.556 1.714
0.522 0.827 0.392 0.094 0.199 0.272 0.086
31/115 52/84 36/78 106/168 56/220 14/102
36/117 54/85 34/86 92/170 21/110 9/102 0.01
0.1
1
Favors ST Figure 4
10
100
Favors CT
Forest plot of adverse events of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
Events / Total
Statistics for each study
Study name
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 Hsu et al.19
2.522 0.866 0.780 1.220 1.027 5.100 0.945
0.479 13.273 1.092 0.622 1.204 –0.857 0.202 3.012 –0.360 0.264 5.628 0.254 0.586 1.801 0.093 0.242 107.549 1.047 0.722 1.237 –0.412
0.275 0.391 0.719 0.799 0.926 0.295 0.681
113/115 348/442 79/84 75/78 139/168 102/102
112/117 355/438 81/85 82/86 140/170 100/102 0.01
0.1 Favors ST
Figure 5
1
10
100
Favors CT
Forest plot of adherence to medication of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
duration or including more than two antimicrobial agents.25 There is accumulating evidence that sequential therapy offers a small advantage over standard triple therapy in clarithromycin and/or metronidazole-resistant strains.26–28 This has lead to the argument that ST may not be considered a good therapeutic option when dual resistance to clarithromycin and metronidazole is greater than 5%.29 In addition, the ST regimens require the patient switching of antibiotics halfway through the course, which has raised concerns of decreased compliance in clinical practice. Recently, the CT regimen has been suggested as an alternative to ST and TT regimens. Ideally, CT should achieve higher eradication rates compared with ST because it is a more aggressive treatment using antibiotics for a longer course. It is also reported to be less impaired by dual resistant strains and therefore seems to be the best replacement for TT.29 Several studies have compared the eradication rates of CT with ST. Although the eradication rates of CT tended to be higher than ST, none of the studies achieved statistical significance. Because antibiotic susceptibility testing is rarely performed in routine clinical practice, the prescription of CT regimens may not be cost-effective if it does not achieve substantially better eradication rates compared with ST regimens.12 Also, the increased use of antibiotics may increase patient’s side effects and thus reduce compliance. Currently, no study has yet demonstrated a definite statistical superiority for each regimens and a
previous meta-analysis reported difference in eradication rates of 0.4%.25 The major goal of our study was to examine if CT regimens indeed achieved higher eradication rates compared with the ST regimens. We also examined whether the development of adverse events and compliance to medication was different between the two regimens. In our analysis, the pooled eradication rates of CT and ST were 86.1% and 83.8% for ITT analysis and 89.5% and 86.8% for PP analysis. The pooled OR was 1.116 (95% CI: 0.795–1.567, P = 0.526) for ITT analysis and 1.153 (95% CI: 0.793–1.677, P = 0.455) for PP analysis. Although the eradication rate of CT was slightly higher than ST, there was no statistical significance. Also, there was no significant difference in the number of adverse events and adherence to the medication between the two groups. However, the results of our analysis should be interpreted with caution. The duration of CT varied from 5 days to 14days, and the duration of ST varied from 10 days to 14 days. The results of our meta-analysis suggest that the increased use of antibiotics in CT does not affect the development of adverse events and thus compliance compared with ST. Likewise, switching of antibiotics also does not seem to affect compliance compared with CT. When compared head-to-head with 10 days of duration, CT tended to achieved slightly better eradication rates compared with ST without statistical significance. Because CT contains the same
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drugs as ST for a longer duration, it should always achieve equal or superior results. However, when given in the same duration, the CT regimen contains approximately twice the number of antibiotic pills compared with the ST regimen. It can be argued that by reducing the number of drugs, there may be a cost–benefit in using ST regimens. There are several limitations to our meta-analysis. First, the number of studies included in our analysis was small and the duration of regimens varied among the studies. The results might have been more convincing if statistical significance having additional number of studies were analyzed. A large amount of heterogeneity existed in the pooled OR eradication rates, which may have resulted from the different duration of the treatment regimens. Second, we were not able to examine antibiotic resistance and its association with eradication rates. Among the seven studies, only three reported data on antibiotic resistance. The results of these studies seem to confirm that CT is effective in dual resistant strains compared with ST. However, the sample size was too small in each group and thus we did not perform a subgroup analysis. Future studies investigating efficacy of each regimen in antibiotic-resistant strains are warranted. Third, we could not perform a cost-effective analysis. Whether the slight increase in eradication rates of CT over ST is worth the increased costs of the regimen could not be evaluated in this meta-analysis. In summary, CT failed to show higher eradication rates compared with ST. The adverse events and adherence to medications were not different between the two regimens. Further, high-quality RCTs are needed to reach a definite conclusion.
Acknowledgment The authors thank Na Jin Kim, MS, Medical Librarian, The Catholic University of Korea, for her aid during the literature search.
References 1 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. 2 Fock KM, Katelaris P, Sugano K et al. Second Asia-Pacific consensus guidelines for Helicobacter pylori infection. J. Gastroenterol. Hepatol. 2009; 24: 1587–600. 3 Chey WD, Wong BC, Practice Parameters Committee of the American College of G. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am. J. Gastroenterol. 2007; 102: 1808–25. 4 Coelho LG, Leon-Barua R, Quigley EM. Latin-American consensus conference on Helicobacter pylori infection. Latin-American national gastroenterological societies affiliated with the inter-American Association of Gastroenterology (AIGE). Am. J. Gastroenterol. 2000; 95: 2688–91. 5 Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter 2007; 12: 275–8. 6 Megraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut 2004; 53: 1374–84. 7 Zullo A, Rinaldi V, Winn S et al. A new highly effective short-term therapy schedule for Helicobacter pylori eradication. Aliment. Pharmacol. Ther. 2000; 14: 715–18. 8 De Francesco V, Margiotta M, Zullo A et al. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori. Ann. Intern. Med. 2006; 144: 94–100.
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9 Gisbert JP, Calvet X, O’Connor A et al. Sequential therapy for Helicobacter pylori eradication: a critical review. J. Clin. Gastroenterol. 2010; 44: 313–25. 10 Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700. 11 Higgins JPT, Thompson SG, Deeks JJ et al. Cochrane Handbook for Systematic Reviews of Interventions 5.0.2. 2009. Available from URL: http://handbook.cochrange.org 12 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; 37: 647–50. 13 De Francesco V, Hassan C, Ridola L et al. Sequential, concomitant and hybrid first-line therapies for Helicobacter pylori eradication: a prospective randomized study. J. Med. Microbiol. 2014; 63: 748–52. 14 Wu DC, Hsu PI, Wu JY et al. Sequential and concomitant therapy with four drugs is equally effective for eradication of H. pylori infection. Clin. Gastroenterol. Hepatol. 2010; 8: 36–41.e1. 15 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. 16 Huang YK, Wu MC, Wang SS et al. Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. J. Dig. Dis. 2012; 13: 232–8. 17 Lim JH, Lee DH, Choi C et al. Clinical outcomes of two-week sequential and concomitant therapies for Helicobacter pylori eradication: a randomized pilot study. Helicobacter 2013; 18: 180–6. 18 McNicholl AG, Marin AC, Molina-Infante J et al. Randomised clinical trial comparing sequential and concomitant therapies for Helicobacter pylori eradication in routine clinical practice. Gut 2014; 63: 244–9. 19 Hsu PI, Wu DC, Chen WC et al. Randomized controlled trial comparing 7-day triple, 10-day sequential, and 7-day concomitant therapies for Helicobacter pylori infection. Antimicrob. Agents Chemother. 2014; 58: 5936–42. 20 De Francesco V, Zullo A, Hassan C et al. Two new treatment regimens for Helicobacter pylori eradication: a randomised study. Dig. Liver Dis. 2001; 33: 676–9. 21 Zullo A, Gatta L, De Francesco V et al. High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment. Pharmacol. Ther. 2005; 21: 1419–24. 22 Zullo A, Vaira D, Vakil N et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment. Pharmacol. Ther. 2003; 17: 719–26. 23 Kim JS, Ji JS, Choi H et al. Sequential therapy or triple therapy for Helicobacter pylori infection in Asians: systematic review and meta-analysis. Clin. Res. Hepatol. Gastroenterol. 2014; 38: 118–25. 24 Kim JS, Kim BW, Ham JH et al. Sequential therapy for Helicobacter pylori infection in Korea: systematic review and meta-analysis. Gut Liver 2013; 7: 546–51. 25 Gatta L, Vakil N, Vaira D et al. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. BMJ 2013; 347: f4587. 26 Dolapcioglu C, Koc-Yesiltoprak A, Ahishali E et al. Sequential therapy versus standard triple therapy in Helicobacter pylori eradication in a high clarithromycin resistance setting. Int. J. Clin. Exp. Med. 2014; 7: 2324–8.
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27 Kutluk G, Tutar E, Bayrak A et al. Sequential therapy versus standard triple therapy for Helicobacter pylori eradication in children: any advantage in clarithromycin-resistant strains? Eur. J. Gastroenterol. Hepatol. 2014; 26: 1202–8. 28 Zhou L, Zhang J, Chen M et al. A comparative study of sequential therapy and standard triple therapy for Helicobacter pylori infection: a randomized multicenter trial. Am. J. Gastroenterol. 2014; 109: 535–41. 29 Molina-Infante J, Gisbert JP. Optimizing clarithromycin-containing therapy for Helicobacter pylori in the era of antibiotic resistance. World J. Gastroenterol. 2014; 20: 10338–47.
Sequential or concomitant therapy
Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Eradication rates of each regimen in antibiotic resistant strains.
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doi:10.1111/jgh.12984
M E TA - A N A LY S I S A N D S Y S T E M AT I C R E V I E W
Sequential or concomitant therapy for eradication of Helicobacter pylori infection: A systematic review and meta-analysis Joon Sung Kim, Sung Min Park and Byung-Wook Kim Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea
Key words concomitant therapy, Helicobacter pylori, meta-analysis, sequential therapy. Accepted for publication 21 March 2015. Correspondence Byung-Wook Kim, Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 56, Dongsu-ro, Bupyeong-gu, Incheon, 403-720, Republic of Korea. Email: [email protected] Declaration of conflict of interest: All authors have no potential conflict of interest relevant to this article.
Abstract Background and Aim: Eradication of Helicobacter pylori (H. pylori) infection with triple therapy (TT) has declined in many countries prompting the search for alternative regimens. Sequential therapy (ST) and concomitant therapy (CT) have been suggested as first-line regimens in areas of high clarithromycin resistance. We performed a metaanalysis to compare the eradication rates of CT with ST for H. pylori. Methods: A comprehensive literature search for studies comparing the efficacy of CT with ST was performed. Dichotomous data were pooled to obtain the odds ratio (OR) of the eradication rate with 95% confidence intervals (CIs). The eradication rates were considered both on an intention-to-treat (ITT) and on a per-protocol (PP) bases. Results: A total of 7 studies provided data on 2412 adult patients. Pooled estimates of the studies revealed no significant differences between CT and ST. The pooled OR was 1.116 (95% CI: 0.795–1.567, P = 0.526) for ITT analysis and 1.153 (95% CI: 0.793–1.677, P = 0.455) for PP analysis. There was no difference in the rate of adverse events (OR: 1.229, 95% CI: 0.971–1.556, P = 0.086) and compliance (OR: 0.945, 95% CI: 0.722– 1.237, P = 0.681) between the two regimens. Subgroup analysis was performed to compare CT of 10 days and 5 days with ST of 10 days. The pooled OR was 1.518 for CT of 10days and 0.636 for CT of 5 days. Conclusions: CT regimens did not achieve higher eradication rates compared with the ST regimen. The adverse events and adherence to medications were not different between the two regimens.
Introduction Helicobacter pylori (H. pylori) plays an essential role in the pathogenesis of peptic ulcer disease, low-grade gastric marginal zone mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric malignancy.1 Triple therapy consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin or metronidazole has been recommended as first-line therapy for H. pylori infection by most international guidelines in the past decade.1–4 However, eradication rates of triple therapy have fallen below the acceptable range of 80% in most counties mainly due to increased clarithromycin resistance.5,6 The recent European guidelines recommend sequential therapy (ST) and concomitant therapy (CT) as alternative first-line therapies in areas with high rates of clarithromycin resistance.1 ST regimens consist of a proton pump inhibitor (PPI) and amoxicillin administered for the first 5 days followed by a PPI and two other antibiotics for the following 5 days.7 The sequential administration was thought to weaken bacterial cell walls in the initial phase and 1338
help increase eradication rates even in clarithromycin-resistant strains.8 CT regimen consists of all the medication administered in ST given simultaneously. This is based on the assumption that sequential administration of drugs has no additional benefits and only increases patients inconvenience in taking medicine.9 Several studies compared the eradication rates of CT with ST, yielding conflicting results; thus, we decided to perform this systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the eradication rates of the two regimens.
Methods Search. This systematic review and meta-analysis was performed according to the preferred reporting items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines.10 We searched PubMed, EMBASE, and the Cochrane Library for RCTs comparing sequential with concomitant therapy for H. pylori infection. There was no restriction on language or age. The key words used in the
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search were “Helicobacter pylori,” “sequential therapy,” “concomitant therapy,” “quadruple therapy,” “sequential,” “concomitant,” “disease eradication,” “therapeutics,” and “drug therapy.” We also searched the reference of screened articles and review articles to identify any additional studies. The results of the search were independently reviewed by the two authors (JS Kim, SM Park). Study selection. Studies were included if they were RCTs that compared CT with ST. Inclusion criteria were as follows: (i) patients were confirmed of H. pylori infection with at least one of the following methods: rapid urease test, culture, histology, or urea breath test (UBT) before treatment and at least 4 weeks after the end of treatment; (ii) studies included at least two branches of treatment consisting of sequential therapy and concomitant therapy; (iii) sequential regimens consisted of a PPI and amoxicillin for the first 5–7 days followed by a triple therapy including a PPI, clarithromycin, and tinidazole or metronidazole for the remaining 5–7 days; (iv) concomitant regimen consisted of a PPI, amoxicillin, clarithromycin, and tinidazole or metronidazole given concomitantly for 5–14 days. Nonrandomized studies, case reports, letters, editorials, commentaries, reviews, and abstracts were excluded. Data extraction. A data extraction manual was developed in advanced, and information was collected independently by the two authors (JS Kim, SM Park) using the predefined extraction manual. Abstracted information included baseline characteristics of the patients, year of publication, country of origin, study design, diagnostic methods of testing H. pylori infection before enrollment and after the end of treatment, treatment regimens, duration of treatment, eradication rates for corresponding regimens, and incidence of adverse events. If an RCT had an additional treatment arm in addition to ST and CT, only relevant data were extracted, and results of the additional treatment arm were not included in our analysis. The extracted data were investigated independently by the two authors, and disagreements were resolved by consensus. We attempted to contact the original authors for additional information when necessary. Risk of bias in individual studies. The two authors assessed the risk of bias according to the assessment tool developed by the Cochrane collaboration.11 The criteria address whether studies might be related to random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases. Each criterion was scored as yes (Y), no (N), or unclear (U) and any disagreement was resolved by consensus. Statistical analysis. The primary outcome of this study was the odds ratio (OR) of successful H. pylori eradication of CT compared with ST. Secondary outcomes were OR of adverse events during eradication and compliance to the medication. The eradication rates were considered both on an intention-to-treat (ITT) and a per-protocol (PP) bases. Heterogeneity of the pooled estimates was tested using Cochran’s Q rest and the inconsistency
Sequential or concomitant therapy
index (I2). When significant heterogeneity existed (P < 0.1 or I2 > 50), the random-effects model should be used to combine the effect sizes of the included studies. However, a nonsignificant test (P ≥ 0.1 or I2 ≤ 50) only indicates a lack of evidence for heterogeneity, as there may have been insufficient power to able to detect heterogeneity. We decided on a conservative approach by calculating the pooled OR by using a random-effects model. The presence of publication bias was determined using Egger’s regression intercept, and funnel plots were constructed when necessary. Subgroup analysis was performed based on the duration of the treatment and antibiotic resistance. Statistical analyses were executed by the aid of Comprehensive Meta-analysis software version 2 (Biostat Inc., Englewood, NJ, USA).
Results Study identification and selection. The detailed process of selection is shown in Figure 1. In summary, 8206 studies were identified by our literature search. A total of 7353 studies remained after removal of duplications with identical titles, and 7342 studies were removed after review of titles and abstracts. The full texts of the remaining 11 articles were reviewed. The study by Zullo et al.12 was a pilot study with patients recruited from three centers in Italy. The study by De Francesco et al.13 was a later study with patients recruited from one center, which was included in the study by Zullo et al. We attempted to contact the corresponding authors of these two studies to identify the possibility of overlapping data; however, no reply was received. To avoid counting the same patients twice, we decided to include only the study by De Francesco et al.13 because this was the later study involving a greater number of patients. After reviewing the full text of the remaining studies, seven RCTs were included in our metaanalysis.13–19 Study characteristics. The main characteristics of the studies are listed in Tables 1 and 2. Four of the studies were single-center studies, whereas the remaining three were multicenter studies. The enrollment period ranged from 2007 to 2013. All of the studies were published in English. One study used tinidazole for their CT and ST regimens, and the rest used metronidazole. Treatment durations were 5, 7, 10, and 14 days for CT and 10 and 14 days for ST. Geographically, four of the studies were from Asia, two of the studies were from Europe, and one study was from Latin America. Risk of bias in individual studies. Table 3 provides a summary of methodological domain assessments for each included study. Among the seven studies, six provided an adequate randomization method. Allocation concealment was adequate in only one study, and none of the studies reported blinding. Eradication rates of CT compared with ST. In all patients, 1256 were treated with CT and 1156 were treated with ST. The pooled OR of ITT eradication rates was 1.116 (95% CI: 0.795–1.567, P = 0.526 (Fig. 2). The pooled eradication rates were 86.1% (95% CI: 79.6–90.7) for CT and 83.8% (95% CI: 78.3– 88.2) for ST. The pooled OR of PP eradication rates was 1.153
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Records identified through database searching (n = 8206) PubMed (n = 3714) EMBASE (n = 1682) Cochrane Library (n = 2180)
Records after duplication removal (n = 7353) Evaluated by title and abstracts Excluded because irrelevant studies. (n = 7342) Full-text articles assessed for eligibility (n = 11)
Studies included in meta-analysis (n = 7)
Table 1
Evaluated by full text Review article (n = 2) Overlap of patients among included studies (n = 1) Comparison with other regimens (n = 1)
Figure 1 Flow diagram of studies included in this meta-analysis.
Main characteristics of included studies
Study 14
Wu et al. Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
Centers
Year of publication
Country
Type of patients
No. of patients
Study duration
Multi Multi Single Single Multi Single Single
2010 2011 2012 2013 2014 2014 2014
Taiwan Latin America China Korea Spain Italy Taiwan
PUD + NUD PUD + NUD NUD PUD + NUD PUD + NUD NUD PUD + NUD
232 975 169 164 338 330 205
June 2007 to May 2008 September 2009 to June 2010 July 2008 to February 2010 May 2011 to April 2012 December 2010 to May 2012 January 2012 to July 2013 —
NUD, nonulcer disease; PUD, peptic ulcer disease.
(95% CI: 0.793–1.677, P = 0.455) (Fig. 3). The pooled eradication rates were 89.5% (95% CI: 82.7–93.8) for CT and 86.8% (95% CI: 81.3–90.8) for ST. There was some funnel plot asymmetry compatible with publication bias; however, statistical analysis using Egger’s test was nonsignificant (P = 0.17). These results should be interpreted with caution because the asymmetry test is probably underpowered as there were only seven studies included in the meta-analysis.19 Adverse events and adherence to the medications. Low heterogeneity was observed among the studies for adverse events (P = 0.563, I2 = 0.0 %). The pooled OR for developing adverse events was 1.229 (95% CI: 0.971–1.556, P = 0.086) and the corresponding rates were 37.8% (95% CI: 22.7–55.8) for CT and 33.5% (95% CI: 0.196–0.508) for ST (Fig. 4). Low heterogeneity was observed among the studies for adherence to medications (P = 0.691, I2 = 0.0 %). The pooled OR for adherence to the medications was 0.945 (95% CI: 0.722–1.237, P = 0.681) and the corresponding rates were 92.7% (95% CI: 0.854–0.965) for CT and 92.4% (95% CI: 85.9–96.0) for ST (Fig. 5). Subgroup analysis according to duration of CT. Except for the study by Lim et al.,17 all the other studies 1340
tested a sequential therapy lasting 10 days. However, the duration of CT varied from 5, 7, 10, and 14 days. Therefore, we performed a subgroup analysis according to the duration of CT. Three studies compared 10 days of concomitant therapy with 10 days of sequential therapy. The pooled OR of eradication rates were 1.518 (95% CI: 0.982–2.345, P = 0.060) favoring CT. Two studies compared 5 days of concomitant therapy with 10 days of ST. The pooled OR of eradication rates were 0.636 (95% CI: 0.307–1.320, P = 0.225) favoring sequential therapy. We did not perform a subgroup analysis according to the duration of ST because all but one of the studies reported ST of 10 days.
Subgroup analysis according to antibiotic resistance. Three studies provided available data on the efficacy of H. pylori eradication in patients with antibiotic resistance (supplementary table).13,15,18 For clarithromycin-resistant strains, the eradication rates of ST were 50% to 100% and that of CT was 100%. For metronidazole resistant strains, the eradication rates of ST were 85.7% to 96.3% and that of CT were 95.5% and 100%. For dual resistant strains, the eradication rates of ST were 33.3% to 50% and that of CT were 66.7% to 100%. We decided not to perform a subgroup analysis according to antibiotic resistance because the number of patients in each group was small.
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© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Culture or RUT + histology
UBT
Culture or RUT + histology
RUT or histology
Culture or RUT or histology or UBT
RUT + histology
Culture and/or RUT + histology
Wu et al.14
Greenberg et al.15
Huang et al.16
Lim et al.17
McNicholl et al.18
De Francesco et al.20
Hsu et al.19 Culture + RUT + histology or UBT
UBT
UBT
UBT
Culture + RUT + histology or UBT
UBT
Culture + RUT + histology or UBT
Tests for confirming eradication
7
5, 14
10
14
10
5
10
Duration of CT
Pantoprazole 40-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Ompeprazole 20-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Tinidazole 500-mg bid
Ompeprazole 20-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Rabeprazole 20-mg Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500 mg bid
Esomeprazole 40-mg bid Amoxicillin 1-g bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
CT regimen
CT, concomitant therapy; RUT, rapid urease test; ST, sequential therapy; UBT, urea breath test.
Tests for confirming infection
Data abstracted from included studies
Study
Table 2
10
10
10
14
10
10
10
Duration of ST
Pantoprazole 40-mg bid Amoxicillin 1-g bid
Omeprazole 20-mg bid Amoxicillin 1-g bid
Omeprazole 20-mg bid Amoxicillin 1-g bid
Rabeprazole 20-mg bid Amoxicillin 1-g bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid
Lansoprazole 30-mg bid Amoxicillin 1-g bid
Esomeprazole 40-mg bid Amoxicillin 1-g bid
ST regimen (first 5 days)
Pantoprazole 40-mg bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Omeprazole 20-mg bid Clarithromycin 500-mg bid Tinidazole 500-mg bid
Omeprazole 20-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
Lansoprazole 30-mg bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
Esomeprazole 40-mg bid Clarithromycin 500-mg bid Metronidazole 500-mg bid
ST regimen (second 5 days)
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Table 3
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Quality assessment and characteristics of included studies
Study
Randomization
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
Yes Yes Yes Yes Yes Unclear Yes
Unclear Unclear Unclear Unclear Yes Unclear Unclear
Unclear Unclear No No No No No
Unclear Unclear No No No No No
Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes No Yes
Yes Yes Yes Yes Yes Yes Yes
“Yes” indicates a low risk of bias and “No” indicates high risk of bias. “Unclear” indicates insufficient or unknown details.
Study name
Events / Total
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
1.115 0.855 1.850 1.357 1.539 0.516 1.934 1.116
0.414 0.640 0.793 0.642 0.853 0.253 0.687 0.795
2.997 0.215 1.144 –1.055 4.318 1.422 2.866 0.800 2.778 1.430 1.052 –1.822 5.446 1.249 1.567 0.633
0.830 0.292 0.155 0.424 0.153 0.069 0.212 0.526
107/115 360/489 74/84 63/78 146/168 181/220 96/102
108/117 372/486 68/85 65/86 138/170 99/110 91/102 0.01
0.1
1
Favors ST Figure 2
10
100
Favors CT
Forest plot of intention-to-treat analysis of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
Study name
Events / Total
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
0.991 0.837 3.008 1.314 1.751 0.548 1.778 1.153
0.359 0.614 0.912 0.605 0.820 0.213 0.621 0.793
2.736 1.140 9.922 2.852 3.738 1.411 5.091 1.677
–0.018 –1.128 1.808 0.691 1.447 –1.246 1.072 0.747
0.986 0.259 0.071 0.490 0.148 0.213 0.284 0.455
107/115 360/471 70/74 61/75 125/137 181/201 96/102
108/116 372/468 64/75 63/82 119/139 99/105 90/100 0.01
0.1 Favors ST
Figure 3
10
100
Favors CT
Forest plot of per-protocol analysis of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
Discussion Nonbismuth quadruple therapies consisting of ST and CT have been recommend as alternative first-line regimens in areas with high rates of clarithromycin resistance.1 Several studies have compared ST with CT, but controversy still exists as to which regimen is better. The ST regimen was developed in Italy as a replacement 1342
1
for TT and initially showed promising results with eradication rates consistently higher than 90%.20–22 However, later studies found that although the ST regimen remained significantly better than triple therapy, its eradications rates dropped dramatically compared with original reports.23,24 A recent meta-analysis found that although ST was superior to 7 days of conventional triple therapy, its eradication rates were similar to regimens of longer
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Events / Total
Statistics for each study
Study name
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Huang et al.16 Lim et al.17 McNicholl et al.18 De Francesco et al.20 Hsu et al.19
0.830 0.933 1.311 1.450 1.447 1.644 1.229
0.470 0.500 0.705 0.938 0.823 0.677 0.971
1.467 –0.640 1.741 –0.218 2.438 0.855 2.239 1.673 2.544 1.284 3.990 1.099 1.556 1.714
0.522 0.827 0.392 0.094 0.199 0.272 0.086
31/115 52/84 36/78 106/168 56/220 14/102
36/117 54/85 34/86 92/170 21/110 9/102 0.01
0.1
1
Favors ST Figure 4
10
100
Favors CT
Forest plot of adverse events of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
Events / Total
Statistics for each study
Study name
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value P-Value Concomitant Sequential Wu et al.14 Greenberg et al.15 Huang et al.16 Lim et al.17 McNicholl et al.18 Hsu et al.19
2.522 0.866 0.780 1.220 1.027 5.100 0.945
0.479 13.273 1.092 0.622 1.204 –0.857 0.202 3.012 –0.360 0.264 5.628 0.254 0.586 1.801 0.093 0.242 107.549 1.047 0.722 1.237 –0.412
0.275 0.391 0.719 0.799 0.926 0.295 0.681
113/115 348/442 79/84 75/78 139/168 102/102
112/117 355/438 81/85 82/86 140/170 100/102 0.01
0.1 Favors ST
Figure 5
1
10
100
Favors CT
Forest plot of adherence to medication of concomitant therapy (CT) compared with sequential therapy (ST). CI, confidence interval.
duration or including more than two antimicrobial agents.25 There is accumulating evidence that sequential therapy offers a small advantage over standard triple therapy in clarithromycin and/or metronidazole-resistant strains.26–28 This has lead to the argument that ST may not be considered a good therapeutic option when dual resistance to clarithromycin and metronidazole is greater than 5%.29 In addition, the ST regimens require the patient switching of antibiotics halfway through the course, which has raised concerns of decreased compliance in clinical practice. Recently, the CT regimen has been suggested as an alternative to ST and TT regimens. Ideally, CT should achieve higher eradication rates compared with ST because it is a more aggressive treatment using antibiotics for a longer course. It is also reported to be less impaired by dual resistant strains and therefore seems to be the best replacement for TT.29 Several studies have compared the eradication rates of CT with ST. Although the eradication rates of CT tended to be higher than ST, none of the studies achieved statistical significance. Because antibiotic susceptibility testing is rarely performed in routine clinical practice, the prescription of CT regimens may not be cost-effective if it does not achieve substantially better eradication rates compared with ST regimens.12 Also, the increased use of antibiotics may increase patient’s side effects and thus reduce compliance. Currently, no study has yet demonstrated a definite statistical superiority for each regimens and a
previous meta-analysis reported difference in eradication rates of 0.4%.25 The major goal of our study was to examine if CT regimens indeed achieved higher eradication rates compared with the ST regimens. We also examined whether the development of adverse events and compliance to medication was different between the two regimens. In our analysis, the pooled eradication rates of CT and ST were 86.1% and 83.8% for ITT analysis and 89.5% and 86.8% for PP analysis. The pooled OR was 1.116 (95% CI: 0.795–1.567, P = 0.526) for ITT analysis and 1.153 (95% CI: 0.793–1.677, P = 0.455) for PP analysis. Although the eradication rate of CT was slightly higher than ST, there was no statistical significance. Also, there was no significant difference in the number of adverse events and adherence to the medication between the two groups. However, the results of our analysis should be interpreted with caution. The duration of CT varied from 5 days to 14days, and the duration of ST varied from 10 days to 14 days. The results of our meta-analysis suggest that the increased use of antibiotics in CT does not affect the development of adverse events and thus compliance compared with ST. Likewise, switching of antibiotics also does not seem to affect compliance compared with CT. When compared head-to-head with 10 days of duration, CT tended to achieved slightly better eradication rates compared with ST without statistical significance. Because CT contains the same
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drugs as ST for a longer duration, it should always achieve equal or superior results. However, when given in the same duration, the CT regimen contains approximately twice the number of antibiotic pills compared with the ST regimen. It can be argued that by reducing the number of drugs, there may be a cost–benefit in using ST regimens. There are several limitations to our meta-analysis. First, the number of studies included in our analysis was small and the duration of regimens varied among the studies. The results might have been more convincing if statistical significance having additional number of studies were analyzed. A large amount of heterogeneity existed in the pooled OR eradication rates, which may have resulted from the different duration of the treatment regimens. Second, we were not able to examine antibiotic resistance and its association with eradication rates. Among the seven studies, only three reported data on antibiotic resistance. The results of these studies seem to confirm that CT is effective in dual resistant strains compared with ST. However, the sample size was too small in each group and thus we did not perform a subgroup analysis. Future studies investigating efficacy of each regimen in antibiotic-resistant strains are warranted. Third, we could not perform a cost-effective analysis. Whether the slight increase in eradication rates of CT over ST is worth the increased costs of the regimen could not be evaluated in this meta-analysis. In summary, CT failed to show higher eradication rates compared with ST. The adverse events and adherence to medications were not different between the two regimens. Further, high-quality RCTs are needed to reach a definite conclusion.
Acknowledgment The authors thank Na Jin Kim, MS, Medical Librarian, The Catholic University of Korea, for her aid during the literature search.
References 1 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. 2 Fock KM, Katelaris P, Sugano K et al. Second Asia-Pacific consensus guidelines for Helicobacter pylori infection. J. Gastroenterol. Hepatol. 2009; 24: 1587–600. 3 Chey WD, Wong BC, Practice Parameters Committee of the American College of G. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am. J. Gastroenterol. 2007; 102: 1808–25. 4 Coelho LG, Leon-Barua R, Quigley EM. Latin-American consensus conference on Helicobacter pylori infection. Latin-American national gastroenterological societies affiliated with the inter-American Association of Gastroenterology (AIGE). Am. J. Gastroenterol. 2000; 95: 2688–91. 5 Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter 2007; 12: 275–8. 6 Megraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut 2004; 53: 1374–84. 7 Zullo A, Rinaldi V, Winn S et al. A new highly effective short-term therapy schedule for Helicobacter pylori eradication. Aliment. Pharmacol. Ther. 2000; 14: 715–18. 8 De Francesco V, Margiotta M, Zullo A et al. Clarithromycin-resistant genotypes and eradication of Helicobacter pylori. Ann. Intern. Med. 2006; 144: 94–100.
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9 Gisbert JP, Calvet X, O’Connor A et al. Sequential therapy for Helicobacter pylori eradication: a critical review. J. Clin. Gastroenterol. 2010; 44: 313–25. 10 Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700. 11 Higgins JPT, Thompson SG, Deeks JJ et al. Cochrane Handbook for Systematic Reviews of Interventions 5.0.2. 2009. Available from URL: http://handbook.cochrange.org 12 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; 37: 647–50. 13 De Francesco V, Hassan C, Ridola L et al. Sequential, concomitant and hybrid first-line therapies for Helicobacter pylori eradication: a prospective randomized study. J. Med. Microbiol. 2014; 63: 748–52. 14 Wu DC, Hsu PI, Wu JY et al. Sequential and concomitant therapy with four drugs is equally effective for eradication of H. pylori infection. Clin. Gastroenterol. Hepatol. 2010; 8: 36–41.e1. 15 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. 16 Huang YK, Wu MC, Wang SS et al. Lansoprazole-based sequential and concomitant therapy for the first-line Helicobacter pylori eradication. J. Dig. Dis. 2012; 13: 232–8. 17 Lim JH, Lee DH, Choi C et al. Clinical outcomes of two-week sequential and concomitant therapies for Helicobacter pylori eradication: a randomized pilot study. Helicobacter 2013; 18: 180–6. 18 McNicholl AG, Marin AC, Molina-Infante J et al. Randomised clinical trial comparing sequential and concomitant therapies for Helicobacter pylori eradication in routine clinical practice. Gut 2014; 63: 244–9. 19 Hsu PI, Wu DC, Chen WC et al. Randomized controlled trial comparing 7-day triple, 10-day sequential, and 7-day concomitant therapies for Helicobacter pylori infection. Antimicrob. Agents Chemother. 2014; 58: 5936–42. 20 De Francesco V, Zullo A, Hassan C et al. Two new treatment regimens for Helicobacter pylori eradication: a randomised study. Dig. Liver Dis. 2001; 33: 676–9. 21 Zullo A, Gatta L, De Francesco V et al. High rate of Helicobacter pylori eradication with sequential therapy in elderly patients with peptic ulcer: a prospective controlled study. Aliment. Pharmacol. Ther. 2005; 21: 1419–24. 22 Zullo A, Vaira D, Vakil N et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment. Pharmacol. Ther. 2003; 17: 719–26. 23 Kim JS, Ji JS, Choi H et al. Sequential therapy or triple therapy for Helicobacter pylori infection in Asians: systematic review and meta-analysis. Clin. Res. Hepatol. Gastroenterol. 2014; 38: 118–25. 24 Kim JS, Kim BW, Ham JH et al. Sequential therapy for Helicobacter pylori infection in Korea: systematic review and meta-analysis. Gut Liver 2013; 7: 546–51. 25 Gatta L, Vakil N, Vaira D et al. Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. BMJ 2013; 347: f4587. 26 Dolapcioglu C, Koc-Yesiltoprak A, Ahishali E et al. Sequential therapy versus standard triple therapy in Helicobacter pylori eradication in a high clarithromycin resistance setting. Int. J. Clin. Exp. Med. 2014; 7: 2324–8.
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27 Kutluk G, Tutar E, Bayrak A et al. Sequential therapy versus standard triple therapy for Helicobacter pylori eradication in children: any advantage in clarithromycin-resistant strains? Eur. J. Gastroenterol. Hepatol. 2014; 26: 1202–8. 28 Zhou L, Zhang J, Chen M et al. A comparative study of sequential therapy and standard triple therapy for Helicobacter pylori infection: a randomized multicenter trial. Am. J. Gastroenterol. 2014; 109: 535–41. 29 Molina-Infante J, Gisbert JP. Optimizing clarithromycin-containing therapy for Helicobacter pylori in the era of antibiotic resistance. World J. Gastroenterol. 2014; 20: 10338–47.
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Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Eradication rates of each regimen in antibiotic resistant strains.
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