Meta-Analysis Open Access
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2014; 20(40): 14973-14985
Published online Oct 28, 2014. doi: 10.3748/wjg.v20.i40.14973
Standard triple therapy for Helicobacter pylori infection in China: A meta-analysis
Ben Wang, Zhi-Fa Lv, You-Hua Wang, Hui Wang, Xiao-Qun Liu, Yong Xie, Xiao-Jiang Zhou, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330000, Jiangxi Province, China
Author contributions: Wang B and Lv ZF contributed equally to this work; Wang B and Lv ZF designed the study, analyzed the data and wrote the manuscript; Wang B, Lv ZF and Wang YH designed the research; Wang B, Lv ZF, Wang YH, Wang H and Liu XQ performed the research; Xie Y and Zhou XJ designed the study and edited the manuscript as corresponding author.
Supported by National Science and Technology Major Projects for “Major New Drugs Innovation and Development” of China, No. 2011ZX09302-007-03
Correspondence to: Yong Xie, MD, PhD, Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, No. 17 Yongzhengwai Street, Donghu District, Nanchang 330000, Jiangxi Province, China. xieyong_med@163.com
Telephone: +86-791-88692507 Fax: +86-791-88623153
Received: February 28, 2014
Revised: May 8, 2014
Accepted: May 25, 2014
Published online: October 28, 2014

Abstract

AIM: To assess the efficacy and safety of standard triple therapy compared with other pre-existing and new therapies in China.

METHODS: Literature searches were conducted in the following databases: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the VIP database, the China National Knowledge Infrastructure database, and the Chinese Biomedical Database. A meta-analysis of all randomized controlled trials (RCTs) comparing standard triple therapy for the eradication of Helicobacter pylori with pre-existing and new therapies in China was performed using Comprehensive Meta-Analysis 2.0. There were 49 studies that met our criteria and the qualities of these studies were assessed using the Jadad scale. The Mantel-Haenszel method was used for pooling dichotomous data. We also conducted subgroup analyses according to age, duration of treatment and drug type. Sensitivity analyses and a cumulative meta-analysis were also performed with CMA 2.0. Publication bias was evaluated using Egger’s test, Begg’s test or a funnel plot.

RESULTS: A total of 49 RCTs including 8332 patients were assessed. This meta-analysis showed that standard triple therapy with proton pump inhibitors (PPIs), amoxicillin (AMO) and clarithromycin (CLA) was inferior to sequential therapy [relative risk (RR) = 0.863; 95% confidence interval (CI): 0.824-0.904], but was not superior to quadruple therapy (RR = 1.073; 95%CI: 0.849-1.357) or other triple therapies (RR = 1.01; 95%CI: 0.936-1.089). The meta-analysis also suggested that standard triple therapy is slightly more effective than dual therapy (RR = 1.14; 95%CI: 0.99-1.31). However, the differences were not statistically significant. We removed the only trial with a regimen lasting 14 d by sensitivity analysis and found that 7-d standard triple therapy was superior to 7-d dual therapy (RR = 1.222; 95%CI: 1.021-1.461). Moreover, a sub-analysis based on the duration of quadruple therapy indicated that the 7-d and 10-d standard triple therapies were inferior to sequential therapy (RR = 0.790; 95%CI: 0.718-0.868; RR = 0.917; 95%CI: 0.839-1.002, respectively). Additionally, there were no significant differences in cure rate or adverse events among standard triple therapy, quadruple therapy, and other triple therapies (RR = 0.940; 95%CI: 0.825-1.072; RR = 1.081; 95%CI: 0.848-1.378, respectively). Standard triple therapy had a higher occurrence of side effects than sequential therapy (RR = 1.283; 95%CI: 1.066-1.544).

CONCLUSION: The eradication rates with a standard triple therapy consisting of PPI, AMO, and CLA are suboptimal in China, and new treatment agents need to be developed.

Key Words: Helicobacter pylori, Eradication, Combination drug therapy, Amoxicillin, Clarithromycin, Adverse effects, Meta-analysis

Core tip: This study compared the efficiency of standard triple therapy with other pre-existing and new therapies on the Chinese mainland and examined the eradication rates for Helicobacter pylori in China. The results showed that the standard triple therapy including proton pump inhibitors, amoxicillin and clarithromycin might not be suitable for first-line therapy.



INTRODUCTION

Helicobacter pylori (H. pylori) infection is currently very common[1], and infection plays an important role in some gastrointestinal diseases, such as peptic ulcers, chronic gastritis, gastric cancer, and gastric malignant disease[2]. Eliminating H. pylori can reduce the recurrence of peptic ulcers and prevent gastric cancer[2]. Standard triple therapy with a proton pump inhibitor (PPI), amoxicillin (AMO) and clarithromycin (CLA) has been extensively employed around the world, and contributed to an eradication success rate of over 90% in the 1990s[3]. However, because of the wide application in H. pylori infection, eradication rates have declined to less than 60%[4,5]. The primary reason for this decline is the resistance of H. pylori to antibiotics, particularly CLA and metronidazole[5].

The standard triple therapy with PPI, AMO and CLA is still recommended as one of the first line anti-H. pylori treatments when the resistance rate of H. pylori to CLA is less than 15%-20%[6-8]. This therapy has encountered some challenges, and although the eradication rate is decreasing[4], the resistance of H. pylori to CLA has increased[9]. One recent study suggested that the therapy could not achieve an acceptable eradication rate[10].

The efficacy of triple therapy consisting of PPI, AMO and CLA has been demonstrated by several studies during the past decade in China. However, the use of antibiotics for other diseases without rigorous supervision has caused a rapid increase in the prevalence of antibiotic-resistant H. pylori in China. A recent study showed that the resistance of H. pylori to CLA is more than 80% and another study suggested that the primary resistance of H. pylori to CLA is 17.2%[11,12]. These data indicate that the current effectiveness of standard triple therapy consisting of PPI, AMO and CLA may be diminished in some areas[13-15]. Furthermore, one study indicated that standard triple therapy was not superior to sequential therapy[16]. Despite the development of resistance, experts consider standard triple therapy effective in areas where H. pylori resistance rates to CLA are less than 15%[7].

Whether the standard triple therapy is suitable as a first-line therapy for H. pylori infection in China remains controversial. The changes in eradication rates of standard triple therapy containing PPI, AMO and CLA with time also remains uncertain in China. To further assess the efficacy and safety of standard triple therapy compared with other eradication treatments (other triple therapies, quadruple treatments and sequential treatments), we conducted this systemic review and meta-analysis. Furthermore, we also performed a cumulative meta-analysis to investigate the changes in the eradication rate of the standard triple regime over time in China.

MATERIALS AND METHODS
Data sources

We searched PubMed (to November 2013), EMBASE (to November 2013), the Cochrane Central Register of Controlled Trials (Issue 11, 2013), the VIP database, the China National Knowledge Infrastructure database (CNKI), and the Chinese Biomedical Database (CBM). The specific search algorithm used for each database was the following: PubMed - [(amoxicillin AND clarithromycin) AND triple] AND “Helicobacter pylori”[Mesh], Filters: Randomized Controlled Trial); Embase - “Helicobacter pylori”/expand “amoxicillin”/exp and “clarithromycin”/exp and triple and “human”/de and “randomized controlled trial”/de; the Cochrane Central Register of Controlled Trials - amoxicillin AND clarithromycin AND triple AND helicobacter pylori; the VIP database, CNKI database and CBM database - were searched with the following keywords: “Helicobacter pylori”, “amoxicillin”, “clarithromycin” and “triple”.

Selection criteria

The articles eligible for inclusion in the meta-analysis met the following inclusion criteria: (1) randomized controlled trial; (2) inclusion of at least 2 branches of treatment, including: (1) standard triple therapy (PPI, AMO, CLA), (2) dual therapy (PPI, a type of antibiotic), quadruple therapy, sequential therapy or other triple therapy; (3) an H. pylori diagnosis by urea breath test (UBT), rapid urease test, histology, and/or fecal antigen testing; (4) eradication testing with UBT and/or histology at least 4 wk after completion of therapy; (5) an available eradication rate; (6) no restrictions in age or sex; (7) a study population composed of subjects who had never been treated for H. pylori; (8) inclusion of mainland Chinese residents; and (9) studies published in Chinese must have been published in core journals (Peking University Library Chinese Core Periodical Catalog, 2012).

Exclusion criteria

The following were exclusion criteria: (1) articles and/or abstracts not reporting tests used to diagnose infection and/or follow-up infection; (2) articles and/or abstracts not conducted on the Chinese mainland; and (3) articles with inappropriate treatments in the control group or standard triple group, including the use of traditional Chinese medicine or probiotics.

Outcome assessment

The primary study outcomes for the meta-analysis included the following: (1) the efficacy of standard triple therapy compared with established and new therapies in eradicating H. pylori infection; and (2) the incidence of adverse events in standard triple therapy vs other therapies.

Data extraction and quality assessment

Two independent reviewers (Wang B and Lv ZF) extracted the data from the selected studies using standardized data extraction forms. Any disagreement was resolved by consensus.

The following data were extracted: study design, number of patients in each treatment arm, testing used to confirm persistent infection prior to study enrollment and eradication after the completion of treatment, drug regimen, duration of treatment, eradication rates by intention to treat (ITT) analysis, percentage of adverse effects and severe adverse effects. The study quality was assessed using the Jadad scale.

Statistical analysis

The data analysis was performed using the Mantel-Haenszel method by meta-analysis software Comprehensive Meta-Analysis 2.0 (Biostat, Englewood, NJ, United States). For each trial, we calculated the relative risk (RR) for the primary measure. The RRs were presented with 95% confidence intervals (CIs), with a P-value < 0.05 considered significant. The study endpoints were calculated by ITT. We estimated the degree of heterogeneity among the trial results using the χ2 statistic (with a P-value < 0.10 considered significant) and the I2 test (25%, 50%, and 75% represent low, moderate and high heterogeneity, respectively). Whenever significant heterogeneity (P < 0.1 or I2 > 50%) was achieved, we used the random effect model to combine the effect sizes of the included studies. If no significant heterogeneity was found, we selected a fixed effect to pool the data. The subgroup or sensitivity analyses were performed where appropriate. We assessed the presence of publication bias with Egger’s test and Begg’s test or a funnel plot if necessary.

RESULTS
Description of the studies

The bibliographical search yielded a total of 1283 studies. Of these studies, 1069 studies were from PubMed, Cochrane and EMBASE, while the other 214 studies published in Chinese were from CBM, VIP and CNKI. Among the studies that were found in PubMed, Cochrane and EMBASE, we excluded 553 duplicate studies and an additional 484 studies that were not conducted on the Chinese mainland. Therefore, we retrieved 32 potentially relevant articles for a more detailed assessment. After examining the titles and abstracts, we excluded 3 unrelated articles. After reviewing the full-text articles we excluded 13 articles with inappropriate treatments in the control group or standard triple group, 4 non-randomized controlled trials (RCTs) and 3 articles that were published in non-core journals. Finally, 9 English language RCTs met the inclusion criteria. For the Chinese articles, we excluded 57 duplicates and 1 study that was not conducted on the Chinese mainland. We also excluded 7 unrelated articles, 61 articles with inappropriate treatments in the control group or standard triple group, 28 non-RCTs and 20 articles that were published in non-core journals after examining all titles, abstracts and full texts. Finally, we identified 40 Chinese RCTs that met the inclusion criteria. In conclusion, 49 RCTs[14-62] met the inclusion criteria. The flowchart of reviews showed the detailed process of selection (Figure 1). The characteristics and quality score of the 49 trials included in the meta-analysis are summarized in Table 1.

Table 1 Characteristics of studies included in systematic review and meta-analysis.
Ref.AgeStandard triple therapyControl group therapyH. pylori infection initial diagnosis ⁄ re-checkingEradication rate by ITT (standard triple therapy/control group therapy)Side effectsJadad scores
Geng et al[17], 2003AdultP A CO ARUT/RUT86.6% (71/82)/71.3% (57/80)4 /71
Wu et al[18], 2004ChildO A CO CH or C/UBT93.3% (56/60)/76.0% (38/50)-1
Gao et al[19], 2006AdultR A CR ARUT UBT/RUT UBT93.8% (45/48)/91.5% (43/47)4/51
Huang et al[15], 2013ChildO A CST-10 (O A/O C M)H, RUT ST/ H, RUT ST64.87% (157/242)/81.4% (96/118)61/322
Yan et al[16], 2011AdultE A CST-10 (E A/E C T)H RUT/UBT H75.10% (220/341)/75.20% (185/281)-2
Liu et al[22], 2011ChildO A CST-10 (O A/O C M)UBT/UBT60.61% (20/33)/91.18% (31/34)3
OAM group: O A M69.70% (23/33)
Jia et al[41], 2012AdultE A CST-10 (E A/E C L)RUT UBT/RUT UBT76.0% (38/50)/94.0% (47/50)3/41
Zhang et al[42], 2012AdultR A CST-9 (RA/RCOrn)UBT RUT/UBT80.2% (89/111)/90.2% (101/112)10/62
R A C B91.1% (102/112)7
Li et al[43], 2012ChildO A CST-10 (O A/O C F)UBT RUT/UBT69.7% (23/33)/91.2% (31/34)5/42
Zhou et al[44], 2011AdultO A CST-10 (O A/O C L )RUT H/RUT H79.60% (35/44)/88.9% (40/45)-2
Wu et al[45], 2011AdultE A CST-10 (E A/E C T)UBT H RUT/UBT H RUT90.20% (46/51)/90.40% (47/52)18/122
Zhu et al[46], 2010ChildO A CST-10 (R A/R C T)UBT S/UBT S70.73% (29/41)/92.68% (76/82)7/51
Zhang et al[47], 2010AdultP A CST-10 (P A/P C T)UBT/UBT73.0% (61/74)/92.3% (36/39)12/63
Lu et al[48], 2010ChildO A CST-10 (O A/O C T)S UBT RUT/UBT82.43% (26/36)/90% (36/40)6/72
Hu et al[49], 2009AdultE A CST-10 (E A/E C T)RUT H/UBT77.50% (31/40)/94.87% (37/39)8/72
Pang et al[50], 2009AdultO A CST-10 (O A/O C T)RUT H UBT/RUT UBT89.60% (60/67)/91.90% (63/69)19/102
Wang et al[51], 2009AdultE A CST-10 (E A/E C T)RUT H/UBT76.92% (40/52)/92.00% (46/50)12/101
Zhao et al[52], 2009AdultP A CST-10 (P A/P C )H/UBT67.24% (39/58)/83.87% (52/62)6/52
Huang et al[53], 2009AdultO A CST-10 (O A/O C T)UBT/UBT69.2% (36/52)/92.5% (49/53)-1
Ma et al[54], 2008AdultO A CST-10 (O A/O C T)RUT UBT/RUT UBT65.1% (41/63)/83.6% (56/67)12/113
Huang et al[55], 2012AdultE A CST-10 (E A/E C M)RUT H/RUT H78.4% (40/51)/80.0% (40/50)9/103
Gao et al[56], 2010AdultO A CRAB L;RUT H/UBT80.56% (58/71)/83.33% (60/72)11/62
ST-10 (O A/O C T)88.89% (64/72)14
Huang et al[61], 2012ChildO A CST-10 (O A/O C M)B C/UBT78.8% (109/160)/85.2% (46/54)26/62
Zheng et al[60], 2005AdultE A C1d-E A M BRUT H/UBT80.50% (33/41)/38.50% (15/39)2/12
Dai et al[37], 2012AdultE A CE A F BUBT/UBT78.12% (25/35)/88.57% (31/35)4/82
Xu et al[38], 2011AdultE A CE A C BUBT/UBT73.02% (46/69)/88.71% (55/67)7/83
Liu et al[39], 2010AdultR A CR A C BUBT/UBT62.90% (39/62)/88.70% (55/62)4/51
Hu et al[13], 2012AdultLan A CLan A C BRUT H UBT/UBT70.00% (70/100)/88.10% (89/101)1/23
Jing et al[40], 2004AdultO/R A CO/R A C FUBT/UBT85.83% (103/120)/86.7% (40/60)4/52
Zhang et al[62], 2006AdultLan A CLan A C MUBT/UBT69.59% (103/157)/26.78% (64/239)148/2292
Luo et al[20], 2012AdultE A CE A LUBT RUT/UBT75.8% (91/120)/80.0% (96/120)21/192
Chen et al[21], 2011AdultR A CR A DUBT/UBT61.25% (49/80)/88.75% (71/80)-1
Xu et al[23], 2010AdultE A CE L FH UBT RUT/UBT RUT75.51% (37/49)/93.87% (46/49)6/51
Dai et al[24], 2010AdultE A CE A LUBT RUT/UBT82.10% (23/28)/88.90% (26/30)2/22
Xu et al[25], 2009AdultLan A CLan C MRUT UBT H/UBT83.87% (26/31)/60.00% (21/35)4/51
Wang et al[26], 2008AdultE A CA C BRUT H/UBT80.0% (16/20)/85.00% (17/20)10/102
Hu et al[27], 2008AdultO A CO A LRUT UBT/UBT85.70% (36/45)/90.20% (37/45)2/22
Su et al[28], 2005ChildO A CA M BRUT H UBT/UBT92.5% (74/80)/74.19% (92/124)16/242
Mou et al[29], 2004AdultO A CO C GmC H RUT/RUT H UBT84.20% (16/19)/80.00% (20/25)9/121
Chen et al[30], 2002AdultO A CL B FRUT H/RUT H88.20% (97/110)/86.70% (92/106)4/01
Chen et al[31], 1996AdultO A CA M BRUT H/RUT H89.6% (43/48)/83.87% (78/93)50/592
Cheng et al[32], 2010AdultLan A CLan A LUBT RUT/UBT74.50% (111/149)/82.99% (122/148)5/93
Zeng et al[33], 2007AdultO A CO A LUBT/UBT68.30% (28/41)/86.50% (32/37)6/51
Gao et al[34], 2005AdultO A CA C BH/H83.33% (25/30)/86.67% (26/30)0/22
Chen et al[35], 2004AdultO A CO A AmUBT/H93.33% (42/45)/92.72% (51/55)8/32
Chen et al[36], 2005AdultO A CO A AmUBT H/UBT H88.50% (23/26)/86.70% (26/30)2/21
He et al[58], 2004AdultR A CR C MC/UBT85.90% (55/64)/54.70% (35/64)-2
Guo et al[58], 2004AdultO A CO F C/O M C /O F ARUT S H/UBT84.90% (28/33)/73.74% (73/99)9/192
Sun et al[59], 2005AdultO A CO A MB /RUT H86.20% (50/58)/82.20% (37/45)6/52
Figure 1
Figure 1 Flow diagram of studies identified and selected. RCT: Randomized controlled trials; CNKI: China National Knowledge Infrastructure database; CBM: Chinese Biomedical Database.
Meta-analysis

Standard triple therapy vs dual therapy: Three studies[17-19] compared standard triple therapy with dual therapy. As shown in Figure 2, the pooled RR was 1.14 (95%CI: 0.99-1.31, P = 0.066). We found evidence of heterogeneity (I2 = 63%, P = 0.07) with funnel plot asymmetry (Egger’s test coefficient 2.75 to 10.28, P = 0.03) (Table 2).

Table 2 Results of meta-analysis.
Meta-analyses/subgroup analysesEradication rate with control groupRR (95%CI)I2
Standard triple therapy vs dual therapy78.00%1.140 (0.992–1.310)62.596%
7-d subgroup73.08%1.221 (1.084 –1.374)0.000%
Adverse events0.651 (0.276–1.539)0.000%
Standard triple therapy vs sequential therapy84.00%0.863 (0.824–0.904)37.400%
Adult subgroup82.90%0.899 (0.861–0.939)25.942%
Child subgroup87.29%0.779 (0.722–0.840)0.000%
7-d subgroup87.52%0.800 (0.752–0.851)0.000%
10-d subgroup80.17%0.849 (0.789–0.913)42.355%
14-d subgroup89.72%0.980 (0.916–1.048)0.000%
Omeprazole subgroup87.37%0.832 (0.772–0.898)47.049%
Esomeprazole subgroup77.01%0.932 (0.871–0.998)40.061%
Pantoprazole subgroup87.13%0.846 (0.746–0.960)0.000%
Rabeprazole subgroup91.24%0.847 (0.766–0.936)41.871%
Tinidazole subgroup81.43%0.889 (0.837–0.944)38.688%
Metronidazole subgroup83.20%0.810 (0.745–0.882)43.630%
Adverse events1.176 (0.975–1.419)0.000%
Standard triple therapy vs quadruple therapy64.90%1.073 (0.849–1.357)93.204%
1-d subgroup28.42%2.367 (1.923–2.914)0.000%
3-d subgroup66.67%1.288 (1.061–1.562)100.000%
7-d subgroup86.79%0.790 (0.718–0.868)0.000%
10-d subgroup88.04%0.917 (0.839–1.002)22.259%
Omeprazole subgroup66.67%1.250 (1.012–1.545)100.000%
Esomeprazole subgroup73.76%1.098 (0.699–1.725)88.852%
Lansoprazole subgroup45.00%1.391 (0.404–4.790)98.719%
Rabeprazole subgroup83.99%0.948 (0.771–1.166)84.733%
Adverse events0.940 (0.825–1.072)0.000%
Standard triple therapy with other triple therapies79.90%1.010 (0.936–1.089)72.233%
Adult subgroup80.92%0.999 (0.925–1.078)69.085%
Child subgroup73.25%1.079 (0.748–1.557)74.810%
7-d subgroup80.32%1.022 (0.949–1.100)60.674%
10-d subgroup77.78%0.933 (0.821–1.060)0.000%
14-d subgroup78.40%1.050 (0.712–1.549)93.921%
Omeprazole subgroup80.30%1.048 (0.976–1.125)49.506%
Esomeprazole subgroup84.47%0.911 (0.831–0.999)0.000%
Levofloxacin subgroup82.37%0.917 (0.852–0.987)0.000%
Furazolidone subgroup85.22%0.963 (0.762–1.216)73.898%
Metronidazole subgroup68.84%1.119 (0.882–1.420)80.863%
Adverse events1.081 (0.848–1.378)0.000%
Eradication rate with standard triple therapy74.5%
Figure 2
Figure 2 Forest plot of standard triple therapy vs dual therapy by random effect model.

The pooled eradication rate of dual therapy was 78.0% based on this meta-analysis. Due to the heterogeneity, we also performed sensitivity analyses and the difference became significant when the study of Gao et al[19] was removed (RR = 1.222, 95%CI: 1.021-1.461).

Data on adverse events were available for 2 trials. The pooled RR was 0.651 (0.276-1.539), which indicated no significant difference and no evidence of heterogeneity (I2 = 0%, P = 0.699).

Standard triple therapy vs sequential therapy: We identified 20 studies[15,16,22,41-56,61] comparing standard triple therapy with sequential therapy. As shown in Figure 3, the pooled RR was 0.863 (95%CI: 0.824-0.904, P < 0.001). We found evidence of heterogeneity (I2 = 37.4%, P = 0.047) with funnel plot asymmetry (Egger’s test coefficient -4.86 to -1.57, P < 0.001). The pooled eradication rate of sequential therapy was 84.0% based on this meta-analysis.

Figure 3
Figure 3 Forest plot of standard triple therapy vs sequential therapy by random effect model.

In addition, we performed a cumulative meta-analysis as shown in Figure 4. The pooled RRs for the years 2008, 2009, 2010, 2011, 2012, and 2013 were 0.779, 0.846, 0.852, 0.875, 0.876, and 0.870, respectively.

Figure 4
Figure 4 Cumulative meta-analysis of standard triple therapy vs sequential therapy by random effect model.

Due to the heterogeneity we also performed subgroup analyses according to age, duration of standard triple therapy (7-d, 10-d and 14-d), different PPIs in the standard triple therapy and for the different drugs used in the control group (the sequential therapy group).

In the subgroup analysis by age, the summary RRs in the adult and the child subgroups were 0.899 (95%CI: 0.861-0.939) and 0.779 (95%CI: 0.722-0.840), respectively. The pooled eradication rates of sequential treatments in the adult and the child subgroups were 82.90% and 87.29%.

For the duration of the standard triple therapy subgroup analysis, the pooled RRs in the 7-d, 10-d, and 14-d subgroups were 0.800 (95%CI: 0.752-0.851), 0.849 (95%CI: 0.789-0.913) and 0.980 (95%CI: 0.916-1.048), respectively. The pooled eradication rates of sequential treatments in the 7-d, 10-d, and 14-d subgroups were 87.52%, 80.17%, and 89.72%, respectively.

In the PPIs subanalyses, the pooled RRs in the omeprazole, esomeprazole, pantoprazole and rabeprazole subgroups were 0.832 (95%CI: 0.772-0.898), 0.932 (95%CI: 0.871-0.998), 0.846 (95%CI: 0.746-0.960), and 0.847 (95%CI: 0.766-0.936), respectively. The pooled eradication rates of sequential treatments in the omeprazole, esomeprazole, pantoprazole and rabeprazole subgroups were 87.37%, 77.01%, 87.13%, and 91.24%, respectively.

The examination of the different drugs used in the control group subanalysis showed the pooled RRs in the tinidazole and metronidazole subgroups were 0.889 (95%CI: 0.837-0.944) and 0.810 (95%CI: 0.745-0.882), respectively. The pooled eradication rates of sequential treatments in the tinidazole and metronidazole subgroups were 81.43% and 83.20%, respectively.

We also performed sensitivity analyses and found the pooled RRs were unchanged.

Data on adverse events were available for 16 trials. The pooled RR was 1.176 (95%CI: 0.975-1.419), which indicated no significant difference and no evidence of heterogeneity (I2 = 0%, P = 0.827).

Standard triple therapy vs quadruple therapy: There were 9 studies[13,37-40,42,56,60,62] comparing standard triple therapy with quadruple therapy. As shown in Figure 5, the pooled RR was 1.073 (95%CI: 0.849-1.357), P = 0.555. We found evidence of heterogeneity (I2 = 93%, P < 0.00001) with funnel plot asymmetry (Egger’s test coefficient -2.58 to 13.51, P = 0.15). The pooled eradication rate of quadruple therapy was 64.9% based on this meta-analysis.

Figure 5
Figure 5 Forest plot of standard triple therapy vs quadruple therapy by random effect model.

We performed a cumulative meta-analysis and the pooled RRs varied little with time. We also performed sensitivity analyses and found the pooled RRs were unchanged.

Due to the heterogeneity, we performed subgroup analyses according to the course of the quadruple therapy and different PPIs in the standard triple therapy.

The pooled RRs in the 1-d, 3-d, 7-d and 10-d duration of quadruple therapy subanalysis were 2.367 (95%CI: 1.923-2.914), 1.288 (95%CI: 1.061-1.562), 0.790 (95%CI: 0.718-0.868), and 0.917 (95%CI: 0.839-1.002), respectively. The pooled eradication rates of quadruple treatments in the 1-d, 3-d, 7-d and 10-d subgroups were 28.42%, 66.67%, 86.79%, and 88.04%, respectively.

For the subanalysis of PPIs, the pooled RRs in the omeprazole, esomeprazole, lansoprazole and rabeprazole subgroups were 1.250 (95%CI: 1.012-1.545), 1.098 (95%CI: 0.699-1.725), 1.391 (95%CI: 0.404-4.790), and 0.948 (95%CI: 0.771-1.166), respectively. The pooled eradication rates of quadruple treatments in the omeprazole, esomeprazole, lansoprazole and rabeprazole subgroups were 66.67%, 73.76%, 45.00%, and 83.99%, respectively.

Data on adverse events were available for 7 trials. The RR was 0.940 (95%CI: 0.825-1.072), which indicated no significant difference with no evidence of heterogeneity (I2 = 0%, P = 0.56).

Standard triple therapy vs other triple therapies: There were 20 studies[20-36,57-59] comparing standard triple therapy with other triple therapies. As shown in Figure 6, the pooled RR was 1.01 (95%CI: 0.936-1.089, P = 0.807). We found evidence of heterogeneity (I2 = 72%, P < 0.00001) but no funnel plot asymmetry (Egger’s test coefficient -2.35 to 3.51, P = 0.68). The pooled eradication rate of other triple therapy was 79.9% based on this meta-analysis.

Figure 6
Figure 6 Forest plot of standard triple therapy vs other triple therapy by random effect model.

As shown in Figure 7, we performed a cumulative meta-analyses and the pooled RRs varied little with time. We also performed sensitivity analyses and found the pooled RRs were unchanged.

Figure 7
Figure 7 Cumulative meta-analysis of standard triple therapy vs other triple therapy by random effect model.

Due to the heterogeneity, we performed subgroup analyses according to age, duration of standard triple therapy, different PPIs in standard triple therapy, and different drugs used in the control group (other triple therapy group).

The subanalysis by age showed that the summary RRs in the adult and the child subgroups were 0.999 (95%CI: 0.925-1.078) and 1.079 (95%CI: 0.748-1.557), respectively. The pooled eradication rates of other triple therapies in the adult and the child subgroups were 80.92% and 73.25%.

For the subanalysis of duration of standard triple therapy, the pooled RRs in the 7-d, 10-d and 14-d subgroups were 1.022 (95%CI: 0.949-1.100), 0.933 (95%CI: 0.821-1.060) and 1.050 (95%CI: 0.712-1.549), respectively. The pooled eradication rates of other triple therapies in the 7-d, 10-d, and 14-d subgroups were 80.32%, 77.78%, and 78.40%, respectively.

The PPI subanalysis indicated the pooled RRs in the omeprazole subgroup and the esomeprazole subgroup were 1.048 (95%CI: 0.976-1.125) and 0.911 (95%CI: 0.831-0.999), respectively.

To examine the different drugs used in the control group subanalysis, the pooled RRs for the levofloxacin, furazolidone, and metronidazole subgroups were 0.917 (95%CI: 0.852-0.987), 0.963 (95%CI: 0.762-1.216), and 1.119 (95%CI: 0.882-1.420), respectively. The pooled eradication rates of other triple therapies in the levofloxacin, furazolidone, and metronidazole subgroups were 82.37%, 85.22%, and 68.84%, respectively.

Data on adverse events were available for 16 trials. The pooled RR was 1.081 (95%CI: 0.848-1.378), indicating no significant difference and no evidence of heterogeneity (I2 = 0%, P = 0.79).

DISCUSSION

Graham et al[63] stratified the effectiveness of the treatment regimens for H. pylori infection into the following grades based on PP analysis: excellent regimen, if the eradication rate was more than 95%; good regimen, if a 91%-95% eradication rate was achieved; borderline, if the eradication rate was 85%-89%; and unacceptable if the eradication rate was less than 85%.

The standard triple treatment includes a PPI, CLA, and AMO or metronidazole to treat H. pylori infection. This treatment has become universal since all of the consensus conferences and guidelines worldwide recommend this treatment.

The following are the primary mechanisms of standard triple therapy: (1) AMO can impede the synthesis of the cell walls of H. pylori and can increase the concentration of CLA in H. pylori infection. Thus, the combination of the two can exert synergism; and (2) PPIs that modify the pH of gastric juice can inhibit the growth of H. pylori and diminish the activity of urease. Furthermore, PPIs can improve the concentration of CLA and AMO in the stomach by raising the pH of the gastric juice.

However, this triple regimen was used worldwide and the prevalence of H. pylori resistant to CLA has increased[7,8]. Drug resistance represents the major reason for the low eradication rate of the standard triple regimen consisting of PPIs, AMO and CLA[5]. One study conducted by the H. pylori Study Group of Digestive Diseases Division of the Chinese Medical Association demonstrated that the resistance rates of H. pylori to metronidazole, CLA, and AMO were 75.6%, 27.6%, and 2.7%, respectively[64].

The Maastricht consensus report IV indicates that triple therapy with AMO and CLA is not suitable for first-line therapy when the resistance rate of H. pylori to CLA is greater than 15%-20%. However, when the resistance rate of H. pylori is lower than 15% the regimen is still recommended as the preferred first-line regimen for H. pylori infection. The standard triple therapy shows a better eradication rate in CLA-sensitive strains than in CLA-resistant strains (88% vs 18%)[65].

Our meta-analysis and systematic review showed that the standard triple therapy might not be suitable for first-line therapy in China because the pooled eradication rate is 74.5%.

According to our meta-analysis comparing the standard triple therapy with dual treatments, the eradication rate of the standard triple therapy with PPIs, AMO, and CLA was slightly higher than for dual treatments (RR = 1.14, 95%CI: 0.99-1.31). However, when the study of Gao et al[19] was removed, the difference became significant. This result may be associated with the following causes: (1) the number of studies included in this meta-analysis was insufficient. Only 3 RCTs compared the standard triple therapy with dual treatment; and (2) the quality of the studies was low. More high quality RCTs are required to determine the actual difference between the standard triple therapies and dual treatments.

In the meta-analysis comparing standard triple therapy with sequential treatments, the outcomes demonstrated that standard triple therapy was inferior to sequential treatments (RR = 0.863; 95%CI: 0.824-0.904). The subgroup analyses showed no statistical significance among those treatments. Additionally, a recent study showed sequential treatment could achieve an 89.7% eradication rate by per protocol analysis in China[15]. Thus, although the guidelines of China do not recommended sequential treatment as a first-line therapy, we suggest that it is worth further study to identify the effectiveness of sequential therapy in China. Our subgroup analyses also showed that 14-d treatments were superior to 7-d treatment. These results indicate that a longer duration might be more effective when used for H. pylori infection. The cumulative meta-analysis showed that the RRs were stable.

Our meta-analysis comparing the standard triple vs quadruple treatments showed that the eradication rate of the standard triple treatment was similar to quadruple treatments. This finding conflicts with most of the pre-existing consensus. The results of subgroup analyses showed that the 7-d quadruple treatments were superior to the standard triple treatment (RR = 0.790, 95%CI: 0.718-0.868) and that the 1-d and 3-d quadruple treatments were inferior to the standard triple treatment (RR = 2.367, 95%CI: 1.923-2.914; RR = 1.288, 95%CI: 1.061-1.562, respectively). It was interesting that the effectiveness of the 10-d standard triple treatment was equivalent to that of the 10-d quadruple treatments (RR = 0.917, 95%CI: 0.839-1.002). Although we performed subgroup analyses based on the duration, age, and PPI used in the standard triple groups, the significant heterogeneity in this meta-analysis may also affect its reliability.

Based on our meta-analysis comparing standard triple treatments with other triple treatments, the eradication rate of the standard triple treatments was similar to that of other triple treatments. This result suggested that the standard triple treatment was not inferior to other triple treatments. The eradication rates of both standard triple treatments and other triple treatments were less than 80%. We also performed subgroup analyses based on different PPIs, durations, and treatments in the control group. The results showed that the treatments containing levofloxacin were able to provide higher eradication rates than standard triple therapy and is consistent with other studies[66,67]. Interestingly, the effectiveness of the esomeprazole subgroup was inferior to the control group. There was no statistical significance in other subgroups. To determine the variations in the eradication rate of standard triple treatments compared with other triple treatments against time, we performed a cumulative meta-analysis of the chronological order of the studies’ publication dates. We found that the effectiveness of the standard triple treatment with PPI, AMO and CLA gradually reduced with time. This may be related to the increasing resistance rate of H. pylori to CLA.

Strengths and limitations

To diminish bias there were 2 reviewers who performed the study selection, data extraction and the evaluation of study quality. We comprehensively analyzed the efficacy of the standard triple therapy with PPI, AMO and CLA in anti-H. pylori treatment. The subgroup analyses and sensitivity analyses made the outcomes of our meta-analyses reliable.

There were several limitations to our meta-analysis. First, most of the studies included in our meta-analysis had problems with concealing the allocation and blinding, which might have affected our results. However, we performed sensitivity analyses to determine the reliability of our results. Second, there was heterogeneity in the meta-analysis and we conducted subgroup analyses and sensitivity analyses to decrease these effects. Third, the quality of the studies included in the meta-analysis might also affect our result. Fourth, the available published languages might have exerted a bias. Thus, it is likely that our meta-analysis does not reflect all outcomes. Finally, we asked authors for unpublished data, but their lack of response may have introduced further bias.

In conclusion, the effectiveness of the standard triple therapy with PPIs, AMO, and CLA is inferior to sequential treatments and is similar to other triple treatments, but is not superior to quadruple therapy. The standard triple treatment achieves a low eradication rate for H. pylori infection and is not suitable as a first-line therapy for treatment of H. pylori infection in China.

COMMENTS
Background

The standard triple regimen with proton pump inhibitors (PPIs), amoxicillin (AMO) and clarithromycin (CLA) is still recommended as a first-line regimen for treatment of Helicobacter pylori infection by several groups. However, the eradication rate is decreasing and the resistance of Helicobacter pylori (H. pylori) to CLA is increasing.

Research frontiers

In China, the efficacy of the standard triple therapy consisting of PPI, AMO and CLA, has been shown by some studies to be considerable over the past decade. However, the prevalence of antibiotic-resistant H. pylori is increasing rapidly. It is unclear if the standard triple therapy is suitable for treatment of H. pylori infection in China.

Innovations and breakthroughs

This was the first meta-analysis comparing the efficiency of standard triple therapy with other pre-existing and new therapies on the Chinese mainland. Furthermore, this meta-analysis also examined the eradication rates for H. pylori and the changes in the eradication rate of the standard triple therapy with time on the Chinese mainland.

Applications

The results indicated that standard triple therapy of PPI, AMO, and CLA might not be suitable for first-line therapy on the Chinese mainland and new agents for treatment need to be developed.

Peer review

This meta-analysis study is well structured and has a great scientific merit. It provides an important contribution to H. pylori therapeutics in China.

Footnotes

P- Reviewer: Cavalini LT, Rotta I S- Editor: Nan J L- Editor: Cant MR E- Editor: Wang CH

References
1.  Tonkic A, Tonkic M, Lehours P, Mégraud F. Epidemiology and diagnosis of Helicobacter pylori infection. Helicobacter. 2012;17 Suppl 1:1-8.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 90]  [Article Influence: 7.5]  [Reference Citation Analysis (1)]
2.  McColl KE. Clinical practice. Helicobacter pylori infection. N Engl J Med. 2010;362:1597-1604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 529]  [Cited by in F6Publishing: 525]  [Article Influence: 37.5]  [Reference Citation Analysis (0)]
3.  Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. European Helicobacter Pylori Study Group. Gut. 1997;41:8-13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 679]  [Cited by in F6Publishing: 712]  [Article Influence: 26.4]  [Reference Citation Analysis (1)]
4.  Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K, Giguère M, Rivière M, Mégraud F. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011;377:905-913.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 350]  [Cited by in F6Publishing: 349]  [Article Influence: 26.8]  [Reference Citation Analysis (0)]
5.  Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59:1143-1153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 652]  [Cited by in F6Publishing: 694]  [Article Influence: 49.6]  [Reference Citation Analysis (0)]
6.  Malfertheiner P, Megraud F, O’Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56:772-781.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1348]  [Cited by in F6Publishing: 1295]  [Article Influence: 76.2]  [Reference Citation Analysis (0)]
7.  Malfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, Gensini GF, Gisbert JP, Graham DY, Rokkas T. Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. Gut. 2012;61:646-664.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1541]  [Cited by in F6Publishing: 1503]  [Article Influence: 125.3]  [Reference Citation Analysis (4)]
8.  Fock KM, Katelaris P, Sugano K, Ang TL, Hunt R, Talley NJ, Lam SK, Xiao SD, Tan HJ, Wu CY. Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol. 2009;24:1587-1600.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 384]  [Cited by in F6Publishing: 405]  [Article Influence: 27.0]  [Reference Citation Analysis (1)]
9.  Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M, Hirschl AM, Andersen LP, Goossens H, Glupczynski Y. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2013;62:34-42.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 588]  [Cited by in F6Publishing: 610]  [Article Influence: 55.5]  [Reference Citation Analysis (2)]
10.  O’Connor A, Molina-Infante J, Gisbert JP, O’Morain C. Treatment of Helicobacter pylori infection 2013. Helicobacter. 2013;18 Suppl 1:58-65.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 41]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
11.  Vakil N, Vaira D. Treatment for H. pylori infection: new challenges with antimicrobial resistance. J Clin Gastroenterol. 2013;47:383-388.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 41]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
12.  De Francesco V, Giorgio F, Hassan C, Manes G, Vannella L, Panella C, Ierardi E, Zullo A. Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis. 2010;19:409-414.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Hu FL, Cheng H, Zhang XZ, An HJ, Sheng JQ, Lü NH, Xie Y, Chen ZS, Xu JM, Hu NZ. [Jinghuaweikang capsules combined with triple therapy in the treatment of Helicobacter pylori associated gastritis and duodenal ulcer and analysis of antibiotic resistance: a multicenter, randomized, controlled, clinical study]. Zhonghua Yixue Zazhi. 2012;92:679-684.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
14.  Zhou YQ, Xu L, Wang BF, Fan XM, Wu JY, Wang CY, Guo CY, Xu XF. Modified Sequential Therapy Regimen versus Conventional Triple Therapy for Helicobacter Pylori Eradication in Duodenal Ulcer Patients in China: A Multicenter Clinical Comparative Study. Gastroenterol Res Pract. 2012;2012:405425.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 10]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
15.  Huang J, Zhou L, Geng L, Yang M, Xu XW, Ding ZL, Mao M, Wang ZL, Li ZL, Li DY. Randomised controlled trial: sequential vs. standard triple therapy for Helicobacter pylori infection in Chinese children-a multicentre, open-labelled study. Aliment Pharmacol Ther. 2013;38:1230-1235.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 19]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
16.  Yan X, Zhou L, Song Z, Xue Y, Wang Y, Bai P, Hou X, Xu S, Chen M, Xiong L. Sequential therapy for helicobacter pylori eradication in adults compared with triple therapy in China: A multiple center, prospective, randomized, controlled trial. Helicobacter. 2011;16:77-143.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.1]  [Reference Citation Analysis (0)]
17.  Geng HP, Zhou QD. Combined with pantoprazole, clarithromycin and amoxicillin in treatment of Helicobacter pylori infection. Zhongguo Yiyuan Yaoxue Zazhi. 2003;23:101.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Wu TF, Huang AF. Curative effect observation of Anqi piece added on therapy in children with Helicobacter pylori infection. Shiyong Erke Linchuang Zazhi. 2004;19:782-783.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Gao J, Li X, Wu X, Shen W, He L. Triple therapy with Rabeprazole, and Sucralfate for eradication of Helicobacter pylori in duodenal ulcer disease. Huaxi Yaoxue Zazhi. 2006;21:213-214.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Luo LL, Zhang L, Xu JM, Hu YM, Lu CY, Wang ZH. Comparison of 7-d levofloxacin triple regimen with 10-d standard triple regimen for the first-line eradication of Helicobacter pylori. Anhui Yike Daxue Xuebao. 2012;47:845-848.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Chen EP, Lian ZF, Chen LF. The Efficacy of combiantion of amoxicillin-clavulanate potassium and doxycycline for Helicobacter pylori infection in elderly. Zhongguo Laonianxue Zazhi. 2011;31:3049-3050.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Liu FL, Zhen LN, Zhao Y, Xia ZW, Situ AM, Zhang SH. The efficacy of sequential therapy and standard triple therapy for eradication of Helicobacter pylori infection in children. Linchuang Erke Zazhi. 2011;29:925-928.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Xu PR, Huang J, Zhou F. The efficacy of triple regimen with esomeiprazole levofloxacin and furazolidone for Helicobacter pylori eradication treatment. Zhonghua Yiyuan Ganranxue Zazhi. 2010;20:857-859.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Dai XS, Zhang XX, Chen HP, Li LP, Han SX. Clinical study of levofloxacin triple regimen for Helicobacter pylori eradication. Huaxi Yaoxue Zazhi. 2010;25:222-223.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Xu MH, Tang YB, Zhang GY, Chen FY, Tang LA, Leng AM, Liu JS. Random control study on eradicating of Helicobacter pylori with lansoprazole-based triple therap. Zhongguo Xiandai Yixue Zazhi. 2009;19:267-269.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Wang PW, Jiang HQ, Jing DD. Ranitidine bismuth citrate based triple therapy eradication of Helicobacter pylori: a randomized control study. Zhongguo Xinyao Zazhi. 2008;17:515-517.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Hu JH, Wu JS, Chen LG. Omeprazole, levofloxacin and amoxicillin triple therapy for Helicobacter pylori infection. Shiyong Yixue Zazhi. 2008;24:1621-1623.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Su L, Xu CD, Chen SN. Curative effects of triple therapy in children with Helicobacter pylori infection. Shiyong Erke Linchuang Zazhi. 2005;20:847-849.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Mou FH, Wei H, Hu FL. A clinical trial of swibec-based triple regimens for Helicobacter pylori eradication. Zhongguo Xinyao Zazhi. 2004;13:1036-1039.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Chen Y, Chen YP, Tao RF. Levofloxacin triple therapy for eradication of Helicobacter pylori infection in 106 cases. Zhongguo Xinyao Yu Linchuang Zazhi. 2002;21:437-439.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Chen SP, Chen ZQ, Bei L, Wen SH. Omeprazole, clarithromycin and amoxicillin therapy for Helicobacter pylori infection. Zhonghua Neike Zazhi. 1996;35:8-11.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Cheng H, Hu FL, Zhang GX, Shi RH, Du YQ, Li ZS, Han W, Li YQ, Wu QD, Qian KD. [Levofloxacin-based triple therapy for first-line Helicobacter pylori eradication treatment: a multi-central, randomized, controlled clinical study]. Zhonghua Yixue Zazhi. 2010;90:79-82.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
33.  Zeng YM, Zhu MJ. Comparison of omeprazole, amoxicillin and clarithromycin or levofloxacin 1 week triple therapy for Helicobacter pylori eradication. Chongqing Yixue. 2007;36:1317-1318.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Gao G, Li H, Cao J. Observation of ranitidine bismuth citrate treatment of Helicobacter pylori related peptic ulcer. Shiyong Yixue Zazhi. 2005;21:2600.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Chen H, Li BT, Zhou HM. The efficacy of azithromycin, amoxicillin and omeprazole triple therapy for Helicobacter pylori eradication. Zhongguo Quanke Yixue. 2004;7:1858-1859.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Chen YZ, Guo J, Chen D. Comparison of efficacy of azithromycin triple and clarithromycin triple therapy for eradication of Helicobacter pylori. Chongqing Yixue. 2005;34:1403-1404.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Dai XS, Zhang L, Xie DL, Chen HP, Li LP, Han SX. Clinical efficacy of quadruple therapy including furazolidone on Helicobacter pylori infection. Huaxi Yaoxue Zazhi. 2012;27:595-596.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Xu MH, Zhang GY, Li CJ. Efficacy of bismuth-based quadruple therapy as first-line treatment for helicobacter pylori infection. Zhejiang Daxue Xuebao (Yi Xue Ban). 2011;40:327-331.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
39.  Liu BT, Liu PF, Zhao FJ. Clinical observation of compound bismuth aluminate granules combined with ray Bella, clarithromycin, amoxicillin in the treatment of Helicobacter pylori associated ulcer. Jiangsu Yiyao. 2010;36:2821-2822.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Jing DD, Wang P, Chen J, Zhou Y, Wang N, Wang X. Rabeprazole-based short term triple or quadruple regimens for Helicobacter pylori eradication: a randomized control study. Zhonghua Xiaohua Zazhi. 2004;24:250-251.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Jia DQ. Efficacy and safety of eradication of Helicobacter pylori infection with levofloxacin sequential therapy of patients with duodenal ulcer. Zhongguo Neijing Zazhi. 2012;18:1304-1306.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Zhang J, Yang J, Wang HT, Liu YL, Duan HL. Efficacy of sequential therapy for Helicobacter pylori eradication. Tanjin Yiyao. 2012;40:79-80.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Li L, Lin QH. Clinical Analysis of 10 Day Sequential therapy for Helicobacter pylori infection children. Xiandai Yufang Yixue. 2012;39:2440-2441.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Zhou W. Comparison of the efficacy of ten-day sequential therapy with conventional triple therapy for Helicobacter pylori eradication. Xiandai Yufang Yixue. 2011;38:3834-3835.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Wu GL, Lan Y, Zhang XJ. Sequential therapy versus standard triple therapy for Helicobacter pylori eradication. Shijie Huaren Xiaohua Zazhi. 2011;19:3100-3109.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Zhu LM. The efficacy and safety of amoxicillin-clavulanate potassium and rebeprazole for Helicobacter pylori infection in children. Zhongguo Shiyong Erke Zazhi. 2010;25:545-548.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Zhang FY, Huang XX. Sequential treatment for Helicobacter pylori eradication in peptic ulcer patients. Zhongguo Quanke Yixue. 2010;13:3813-3814.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Lu JH, Xu MY, Shen Y, Yang WX. Comparison of the efficacy of 10 day sequential therapy and conventional triple therapy for Helicobacter pylori infection in children. Zhongguo Dangdai Erke Zazhi. 2010;12:988-990.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Hu SQ, Zhang M. A 10-day sequential therapy for Helicobacter pylori-infected patients: an analysis of 39 cases. Shijie Huaren Xiaohua Zazhi. 2009;17:1693-1695.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Pang SZ, Zhao WX, Ren Y. The comparison of 10 day sequential therapy and 14 day triple therapy for eradication Helicobacter pylori. Shiyong Yixue Zazhi. 2009;25:3058-3060.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Wang RX, Qin J. Comparison of 10-day sequential therapy with standard therapy for Helicobacter pylori. Chongqing Yixue. 2009;38:2322-2323.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Zhao QX, Huang DY. Efficacy of tinidazole-containing sequential therapy in the eradication of Helicobacter pylori infection. Shijie Huaren Xiaohua Zazhi. 2009;17:3666-3669.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Huang CT. The comparison of 10 day sequential therapy and standard triple therapy for eradication of Helicobacter pylori. Guangdong Yixue. 2009;30:1657.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Ma CX, Peng GL, Zhao YK, Ma XY, Zhan LY. Treatment outcomes of functional dyspepsia patients with Helicobacter pylori infection: a comparison between sequential treatment regimen and conventional triple therapy. Dier Junyi Daxue Xuebao. 2008;29:908-911.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Huang XX, Xiong LS, Ma S, Bai P, Dong Y, Yang X, Gao X, Liang L, Zhou L, Chen M. Efficacy of triple therapy and sequential therapy in the eradication of Helicobacter pylori in patients receiving long-term non-steroidal anti-inflammatory drugs treatment. Zhonghua Xiaohua Zazhi. 2012;32:814-817.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  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;16:4357-4362.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 48]  [Cited by in F6Publishing: 50]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
57.  He XX, Zhao YH, Hao YT. [Effect of CYP2C19 genetic polymorphism on treatment efficacy of Helicobacter pylori infection with rabeprazole-based triple therapy in Chinese]. Zhonghua Neike Zazhi. 2004;43:13-15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
58.  Guo CY, Wu YB, Liu HL, Wu JY, Zhong MZ. Clinical evaluation of four one-week triple therapy regimens in eradicating Helicobacter pylori infection. World J Gastroenterol. 2004;10:747-749.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Sun WH, Ou XL, Cao DZ, Yu Q, Yu T, Hu JM, Zhu F, Sun YL, Fu XL, Su H. Efficacy of omeprazole and amoxicillin with either clarithromycin or metronidazole on eradication of Helicobacter pylori in Chinese peptic ulcer patients. World J Gastroenterol. 2005;11:2477-2481.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Zheng Q, Pan Y, Zhang L, Xiao SD. Comparison of the efficacy of 1-day high-dose quadruple therapy versus 7-day triple therapy for treatment of Helicobacter pylori infection. Chin J Dig Dis. 2005;6:202-205.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
61.  Huang J, Gong ST, Ou WJ, Pan RF, Geng LL, Huang H, He WE, Chen PY, Liu LY, Zhou LY. [A 10-day sequential therapy for eradication of Helicobacter pylori infection in children]. Zhonghua Erke Zazhi. 2012;50:563-567.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
62.  Zhang L, Shen L, Ma JL, Pan KF, Liu WD, Li J, Xiao SD, Lin SR, Classen M, You WC. Eradication of H pylori infection in a rural population: one-day quadruple therapy versus 7-day triple therapy. World J Gastroenterol. 2006;12:3915-3918.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence-based medicine rather than medicine-based evidence. Clin Gastroenterol Hepatol. 2014;12:177-186.e3; Discussion e12-13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 10]  [Reference Citation Analysis (0)]
64.  Chinese Helicobacter pylori Research Group, Chinese Society of Gastroenterology, Cheng H, Hu FL, Xie Y, Hu PJ, Wang JY, Lv NH, Zhang JZ, Zhang GY, Zhou Zf, Wu KL, Zhang LX, Peng XW, Dai N, Tang GD, Jiang K, Li Y, Hou XH, Bai WY, Wang MY, Wang MC, Ye HJ, Liu YL, Xu L. Prevalence of Helicobacter pylori resistance to antibiotics and its influence on the treatment outcome in China: A multicenter clinical study. Weichang Bing Xue. 2007;12:525-530.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Mégraud F. H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004;53:1374-1384.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 607]  [Cited by in F6Publishing: 655]  [Article Influence: 32.8]  [Reference Citation Analysis (1)]
66.  Gisbert JP, Pajares R, Pajares JM. Evolution of Helicobacter pylori therapy from a meta-analytical perspective. Helicobacter. 2007;12 Suppl 2:50-58.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 53]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
67.  Zhang ZF, Zhao G, Liu LN. [Effectiveness and safety of proton pump inhibitor and levofloxacin based first-line triple therapy in the eradication of Helicobacter pylori: a meta-analysis]. Zhonghua Yixue Zazhi. 2008;88:2722-2725.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]