American Journal of Therapeutics 23, e880–e893 (2016)

Sequential Therapy or Standard Triple Therapy for Helicobacter pylori Infection: An Updated Systematic Review Li Feng, MD,1 Mao-Yao Wen, MD,1 Yong-Jun Zhu, MD,2 Ruo-Ting Men, PhD,1 and Li Yang, MD1*

The effectiveness of standard triple therapy (STT) for the eradication of Helicobacter pylori has decreased recently. Sequential therapy (SQT) is a new regimen proposed to address this problem. The aim of this study was to compare the efficacy of SQT versus STT for H. pylori eradication. We searched The Cochrane Library, MEDLINE, Web of Science, and EMBASE databases up to July 2014. The risk ratios (RRs) of eradication rate were pooled, with a 95% confidence interval (CI). Thirty-six randomized clinical trials including a total of 10,316 patients met the inclusion criteria. The RR for eradication of H. pylori with SQT compared with STT was 1.14 (95% CI: 1.09–1.17), the eradication rates were 84.1% and 75.1%, respectively. There was significant heterogeneity between trial results (I2 5 73%; P , 0.00001). Subgroup analyses showed that SQT was superior to both 7- and 10-day STT, but not significantly better than 14-day STT. This superiority existed when patients were treated with either metronidazole or tinidazole. Patients with single clarithromycin-resistant strain showed a greater benefit of SQT over STT (eradication rates 80.9% vs. 40.7%), RR 5 1.98 (95% CI: 1.33–2.94). There was no significant difference between groups in terms of the risk of adverse effects. In conclusion, SQT is more efficacious than STT (7 days and 10 days) in the eradication of HP, but the pooled rate seemed suboptimal. Further research is needed to develop more effective therapeutic approaches. Surveillance of resistance rates should be performed to guide treatment. Keywords: eradication, Helicobacter pylori, meta-analysis, standard triple therapy, sequential therapy

INTRODUCTION Standard triple therapy (STT) consisting of a proton pump inhibitor (PPI) and 2 antibiotics, amoxicillin and clarithromycin, twice daily for 7–14 days,1–3 has become the most widely recommended first-line

1

Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu, Sichuan, China; and 2Department of Gastroenterology, The Second People’s Hospital of Chengdu, Sichuan, China. Supported by grants from Science and Technology Department of Sichuan Province of China (No. 2013FZ0085 and No.2014FZ0002), Chengdu City Science, and Technology Bureau of Sichuan Province of China (13PPYB994SF-014). The authors have no conflicts of interest to declare. *Address for correspondence: Department of Gastroenterology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, China. E-mail: [email protected]

eradication therapy for Helicobacter pylori for a long time. However, recent data show that the efficacy of STT is constantly decreasing worldwide, largely due to an increase in drug resistance of bacterial.4–7 Several strategies have been proposed to improve the eradication rate, one of which was sequential therapy (SQT). Zullo et al8 first introduced this therapy in Italy in 2000, reporting that eradication rate rised considerably [intention to treat (ITT): 98%; 95% CI: 94.3–100]. This regimen is a simple dual therapy including a PPI and amoxicillin for the first 5 days, followed by a PPI plus clarithromycin and metronidazole (or tinidazole) for a second 5 days. SQT has been shown to be more effective than STT in multiple randomized controlled trials and several meta-analyses, although several studies have also demonstrated conflicting results. The purpose of this systematic review was to update evidence on SQT compared with STT for H. pylori eradication.

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SQT or STT for Helicobacter pylori Infection

METHODS This systematic review was performed according to the guideline of PRISMA.9,10 Search strategy Electronic searches were performed in Embase, MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trial in The Cochrane Library (January 2000 to July 2014). Separate computer-assisted searches were performed with “Helicobacter pylori,” “H. pylori,” “sequential,” “triple,” “treatment,” and “therapy” as medical subjects. The search was limited to (1) English language, (2) randomized clinical trials (RCTs), and (3) humans. Eligibility assessment was performed independently in an unblended standardized manner by 2 reviewers. Disagreements between reviewers were resolved by consensus. After eligible studies were identified, we added studies selected from conference meeting abstracts and previous meta-analytic studies. Inclusion and exclusion criteria We included literature that met the following PICOS approaches: (1) Participants: adult patients with HP infection receiving de novo eradication regimen. The status of H. pylori must be measured by at least one of the following methods: rapid urease test, H. pylori

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stool antigen test (HpSA), histology or culture of an endoscopic biopsy sample, or urea breath test (UBT) before treatment. (2) Intervention: original 10-day SQT (PPIs and amoxicillin 1 g for the first 5 days, followed by PPIs, clarithromycin 500 mg, and metronidazole or tinidazole for the remaining 5 days; all drugs are given twice daily). (3) Comparison: STT consisted of PPIs (20/40 mg twice a day), amoxicillin (1 g twice a day), and clarithromycin (0.5 g twice a day) with different durations (7 days, 10 days, or 14 days). (4) Outcome measures: primary outcome is defined as the eradication of H. pylori, which had to be confirmed by a negative 13C-UBT or other generally accepted methods at least 4 weeks after treatment was finished; secondary outcomes are compliance and the frequency of adverse events. We excluded (1) nonrandomized studies, (2) retreatment after eradication failure, and (3) studies in children. Data extraction Data were extracted from all selected publications separately by 2 investigators, and if these investigators could not reach an agreement, the final decision was made by means of consensus with a third investigator. Data were extracted from each study including (1) baseline characteristics of the participants, (2) methods of diagnosing infection and confirming eradication details of interventions, and (3) types of

FIGURE 1. Flowchart of the meta-analysis. www.americantherapeutics.com

American Journal of Therapeutics (2016) 23(3)

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Studies

Intervention

Location

Total no. patients SQT/STT

SQT

STT

Participants

Type of publication

Centers

Italy Italy Italy Italy Italy Italy Italy Italy South Korea China China Iran China Italy Spain Latin American South Korea Italy China China South Korea South Korea South Korea South Korea Taiwan India South Korea Morocco Taiwan Canada India Morocco

94/93 174/184 522/527 45/52 116/231 89/90 72/141 150/150 77/81 67/63 62/58 107/107 72/71 90/90 115/115 486/488 205/205 131/108 52/51 281/341 79/80 115/345 116/130 162/164 84/79 138/134 77/81 104/115 300/300 51/53 111/120 140/141

OA5; OCM5 EA5; ECT5 RA5; RCT5 RA5; RCT5 RA5; RCT5 RA5; RCT5 EA5; ECT5 PA5; PCT5 OA5; OCM5 OA5; OCT5 PA5; PCT5 OA5; OCM5 OA5; OCT5 EA5; ECT5 OA5; OCM5 LA5; LCM5 PA5; PCM5 EA5; ECT5 EA5; ECT5 EA5; ECT5 LA5; LCM5 RA5; RCT5 RA5; RCM5 RA5; RCM5 PA5; PCM5 PA5; PCT5 OA5; OCM5 PA5; PCM5 LA5; LCM5 RA5; RCM5 PA5; PCT5 OA5; OCT5

7OAC 7EAC 7RAC 10RAC 7/10RAC 7RAC 7/10EAC 10PAC 7OAC 7OAC 7PAC 10OAC 7OAC 7EAC 10OAC 14LAC 14PAC 7EAC 14EAC 10EAC 10LAC 7/10/14RAC 7RAC 7RAC 7PAC 10PAC 7OAC 7PAC 14LAC 10RAC 14PAC 7OAC

PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD NUD PUD + NUD PUD + NUD NUD PUD + NUD NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD PUD + NUD

Abstract Abstract Full text Full text Full text Full text Full text Full text Full text Full text Full text Full text Full text Full text Full text Full text Full text Abstract Full text Abstract Full text Full text Full text Full text Abstract Full text Abstract Full text Full text Full text Full text Full text

1 1 8 3 2 3 2 2 1 1 1 1 1 1 1 7 1 1 1 4 1 1 1 6 1 1 1 1 6 1 1 1

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Focareta et al13 Focareta et al14 Zullo et al15 De Francesco et al (a)16 De Francesco et al (b)17 Zullo et al18 Scaccianoce et al19 Vaira et al20 Choi et al21 Ma et al22 Zhao et al23 Aminian et al24 Gao et al25 Paoluzi et al26 Molina-Infante et al27 Greenberg et al28 Kim et al29 Gatta et al30 Wu et al31 Yan et al32 Chung et al33 Choi et al34 Oh et al35 Park et al36 Hsu et al37 Javid et al38 Jeon et al39 Lahbabi et al40 Liou et al41 Morse et al42 Nasa et al43 Seddik et al44

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Table 1. Main characteristics of included studies.

131/149

131/135 50/50 140/140

Peru

Singapore Brazil China

Yep-Gamarra et al45 Song et al46 Eisig et al47 Zhou et al48

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*Type of PPI was not mentioned. A, amoxicillin; C, clarithromycin; E, esomeprazole; L, lansoprazole; M, metronidazole; NR, not reported; NUD, non-ulcer dyspepsia; O, omeprazole; P, pantoprazole; PUD, peptic ulcer disease; R, rabeprazole; SQT, sequential therapy; STT, standard triple therapy; T, tinidazole.

1 1 4 Abstract Abstract Full text 10*AC 10LAC 10EAC *A5; *CM5 LA5; LCT5 EA5; ECT5

PUD + NUD NUD PUD + NUD

1 Abstract 10OAC OA5; OCT5

PUD + NUD

Centers STT Location Studies

Total no. patients SQT/STT

Table 1. (Continued) Main characteristics of included studies.

Intervention SQT

Participants

Type of publication

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outcome measures, such as H. pylori eradication, compliance, and incidence of side effects. We contacted authors for any incomplete outcome data from included trails. If outcome data were still not available, participants were considered as eradication failures for the primary outcome (“worst-case” scenario). Risk of bias in individual studies To ascertain the validity of eligible randomized trials, pairs of experienced reviewers working independently determined the adequacy of randomization and concealment of allocation, blinding methods, reports of withdrawal and dropouts, selective reporting, and other sources of bias. The quality of the included studies was assessed by using the modified Jadad scale, and a score of .3 was considered as high quality.11 We did not consider blinding to be crucial since the outcome (eradication) was assessed by objective means (usually 13C-UBT). To check the robustness of the pooled estimate of primary outcome, sensitivity analyses were performed by calculating the pooled risk ratio (RR), excluding studies with abstract only or with modified Jadad score no more than 3, respectively. Funnel plot was created to assess the risk of publication bias. To assess the asymmetry of funnel plot, we carried out Begg rank correlation test and Egger regression intercept test. Statistical analysis We used the Cochrane Review Manager 5.2 software (RevMan 2012) and Stata Version 11.0 (College Station, TX) for meta-analyses. Pooled results were derived by using the fixed-effect model, unless significant heterogeneity was present. The dichotomous outcomes, the results from individual studies, and pooled statistics are reported as the RR and the risk difference (RD) between the experimental and control groups with 95% CI. The numbers needed to treat (NNTs) were calculated from the reciprocal of the pooled RD. Heterogeneity between studies was quantified using the x2 test with a P value ,0.1 set as the cutoff, if existed. The values of 25%, 50%, and 75% as edge limits for low, moderate, and high heterogeneity were used.12 If the heterogeneity was more than 50% but it was still considered appropriate to pool the data, all analyses were based on a random-effect model. Meta-regression and subgroup analysis were also performed to explore the possible source of heterogeneity. Further subgroup analyses according to duration of comparative treatment (7 days, 10 days, and 14 days), kind of nitroimidazole derivatives in SQT (tinidazole or metronidazole) were preplanned. American Journal of Therapeutics (2016) 23(3)

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Studies

Report the reasons of dropouts and withdrawals

Discontinue therapy due to AE SQT/STT

Losses and exclusions SQT/STT

Jadad score

0 0 0/1 0

0/0 0/0 16/20 1/1

2 2 5 5

Randomization

Allocation

Blinding

Not clear Not clear Adequate Adequate

Not clear Not clear Adequate Adequate

No No No No

Clear Clear Clear Clear

Adequate

Adequate

No

Clear report

0

1/4

5

Adequate Adequate

Adequate Adequate

No No

Clear report Clear report

3 2/4

2/3 2/4

5 5

Adequate Adequate Adequate Not clear Adequate Adequate Adequate Adequate

Adequate Not clear Not clear Not clear Adequate Adequate Adequate Adequate

Double No No No No No No No

Clear report Clear report Clear report Clear report Not report Clear report Clear report Clear report

0/1 0 0 0 0 0 3/2 5

7/4 7/5 6/4 4/4 1/0 0/0 3/12 5/2

7 3 4 2 4 5 5 5

Adequate Adequate Not clear Adequate Not clear Adequate Adequate Adequate Adequate Not clear Adequate Not clear Adequate

Adequate Adequate Not clear Not clear Not clear Adequate Adequate Not clear Adequate Not clear Adequate Not clear Adequate

No Single No No No No No No No No No No No

Clear report Clear report Clear report Not report Not report Clear report Clear report Clear report Clear report Not report Clear report Not report Clear report

0 0 0 0 NR 3/3 8 0 2/2 0 0/1 NR 0/5

18/13 15/24 0/1 NR NR 11/12 9/24 5/3 30/39 1/1 14/11 7/5 6/9

5 6 2 3 1 5 5 4 5 1 5 1 5

report report report report

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Focareta et al13 Focareta et al14 Zullo et al15 De Francesco et al (a)16 De Francesco et al (b)17 Zullo et al18 Scaccianoce et al19 Vaira et al20 Choi et al21 Ma et al22 Zhao et al23 Aminian et al24 Gao et al25 Paoluzi et al26 Molina-Infante et al27 Greenberg et al28 Kim et al29 Gatta et al30 Wu et al31 Yan et al32 Chung et al33 Choi et al34 Oh et al35 Park et al36 Hsu et al37 Javid et al38 Jeon et al39 Lahbabi et al40

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Table 2. Methodological assessment of included trials.

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RESULTS

5 5 5 5 3 1 4 5

Jadad score

SQT or STT for Helicobacter pylori Infection

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Number of losses and exclusions include those lost to follow-up and poor compliant in both of the experimental and control groups. AE, adverse effect; NR, not reported.

15/21 11/4 5/4 11/10 8/11 2/8 2/1 8/12 6/13 0 0 1/2 4/8 NR NR 0 Clear report Clear report Clear report Clear report Clear report Not report Not report Clear report No No No No No No Double No Adequate Adequate Adequate Adequate Not clear Not clear Not clear Adequate Adequate Adequate Adequate Adequate Not clear Not clear Not clear Adequate Liou et al41 Morse et al42 Nasa et al43 Seddik et al44 Yep-Gamarra et al45 Song et al46 Eisig et al47 Zhou et al48

Allocation Studies

Randomization

Blinding

Losses and exclusions SQT/STT Discontinue therapy due to AE SQT/STT Report the reasons of dropouts and withdrawals Table 2. (Continued) Methodological assessment of included trials.

Study characteristics In according to our search strategy, 36 RCTs13–48 (27 full-text articles and 9 abstracts) were included in our study. The flowchart for selection of studies is shown in Figure 1. A total of 10,316 participants (4901 for SQT and 5415 for STT) were enrolled in the included studies. Characteristics of these studies are shown in Table 1. In 1 RCT, there were 2 arms in the intervention group41 (10-day and 14-day SQT), and we compared only 10-day SQT with STT. In addition, 3 other RCTs compared SQT to 3 different durations of STT (7, 10, and 14 days),17,19,34 we combined all of the STT arms into a single group to analyze the pooled RR. And then the corresponding subgroup meta-analyze was followed. Risk of bias in included studies The methodology assessment and risk of bias were presented in Table 2. The number of cases followed up and the reasons for the failures at follow-up were reported in most of the trials. All the trials did not report a baseline difference between the 2 groups and said they were randomized. Only 22 trials described how to generate the allocation sequence. Most studies were open-label randomized controlled trials; there were just 2 trials applying double-blinded design.20,47 The aforementioned scarcity in the report of the information about the discussed quality items may lead to selection and performance biases, which are a threat to the validity of the review. Overall H. pylori eradication rate The eradication rates with SQT and STT ranged from 54.9% to 95.7% and from 54.7% to 90.7% on an ITT basis, respectively. On ITT analysis, pooled eradication rate was 84.1% (4122 of 4901 patients) for SQT versus 75.1% (4066 of 5415 patients) for STT. The RR was 1.13 (95% CI: 1.09–1.17), which demonstrated superiority of the SQT over STT (Figure 2). RD was 10% (95% CI: 7–13), giving an NNT of 10 favoring SQT. There was significant heterogeneity between trial results (I2 5 73%; P , 0.00001). Subgroup analyses based on the duration of STT Nineteen, 15, and 6 studies were assessed, respectively, for 7-day, 10-day, and 14-day STT versus 10day SQT (Figure 3). The eradication rate in studies for SQT and 7-day STT was 88.3% and 72.8%, respectively, based on ITT analysis, with an RD of 15% (95% CI: 13–18) yielding an NNT of 7. The pooled RR with a fixed-effect model was 1.21 (95% CI: American Journal of Therapeutics (2016) 23(3)

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FIGURE 2. Forest plot based on overall H. pylori eradication rates for ITT analysis.

1.18–1.25; P , 0.00001), favoring SQT. There was no significant heterogeneity (P 5 0.37; I2 5 7%). Fifteen studies compared SQT with STT regimen of 10 days, random-effect model was chosen due to significant heterogeneity (P 5 0.004; I2 5 57%). The eradication rate in studies was 79.8% and 74.0% for SQT and 10-day STT, respectively, based on ITT analysis, the pooled RR was 1.08 (95% CI: 1.03–1.14; P 5 0.004), and the RD was 6% (95% CI: 2–10) yielding an NNT of 17. Six studies compared SQT with STT regimen of 14 days; random-effect model was chosen due to significant heterogeneity (P 5 0.003; I2 5 72%). The eradication rates of SQT and 14-day STT were 82.0% and 80.8% by ITT analysis, respectively. The pooled RR was 1.03 (95% CI: 0.96–1.11; P 5 0.39) indicating no statistically significant difference. American Journal of Therapeutics (2016) 23(3)

Subgroup analyses based on the type of nitroimidazole Fifteen RCTs adopted metronidazole in their SQT regimen and 21 RCTs used tinidazole (Figure 4). The subgroup analysis showed that SQT was significantly better than STT when patients were treated with either metronidazole or tinidazole. The eradication rate in studies comparing metronidazole-based SQT (M-SQT) with STT was 81.7% and 76.3% based on ITT analysis, the pooled RR was 1.09 (95% CI: 1.03–1.16, P 5 0.004), and the RD was 7%(95% CI: 2–12) yielding an NNT of 15 favoring M-SQT. The eradication rate for tinidazole-based SQT (T-SQT) and STT was 86.0% and 75.1% based on ITT analysis, respectively. The pooled RR was 1.15 (95% CI: 1.11–1.20; P , 0.00001), and the www.americantherapeutics.com

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FIGURE 3. Forest plots of Helicobacter eradication rates based on the duration of triple therapy for ITT analysis.

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FIGURE 4. Forest plots of Helicobacter eradication rate based on the type of nitroimidazole for ITT analysis.

RD was 12% (95% CI: 9–15) yielding an NNT of 9 favoring T-SQT. Subgroup analyses based on antibiotic resistance Antibiotic resistance is one of the major factors responsible for the treatment failure of STT. In this review, we also pooled all available data about clarithromycin resistance and metronidazole resistance. Among American Journal of Therapeutics (2016) 23(3)

the included studies, 6 conducted H. pylori culture,15,20,30,33,41,42 4 provided data on the efficacy of HP eradication in patients with clarithromycin resistance, 4 for metronidazole resistance, and 3 for dual clarithromycin and nitroimidazole resistance (Figure 5). Patients with clarithromycin-resistant strains benefitted from SQT rather than STT (eradication rate: 80.9% vs. 40.7%), and the pooled RR between www.americantherapeutics.com

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SQT or STT for Helicobacter pylori Infection

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FIGURE 5. Forest plots of eradication rate based on antibiotic resistance.

SQT and STT was 1.98 (95% CI: 1.33–2.94; P 5 0.0007). Patients with nitroimidazole-resistant strains showed no significant difference between regimens, but patients could benefit more from SQT (85.8%) than from STT (83.9%); the pooled RR was 1.02 (95% CI: 0.87– 1.20; P 5 0.77). Patients with both clarithromycin and nitroimidazole resistance did not report significant difference between SQT and STT; the eradication rates (48.3% vs.48%, respectively) were unsatisfactory. Compliance and adverse events Compliance to the therapy is another major factor influencing curative effect. Generally, consumption of more than 90% of the prescribed drugs is considered to be a good compliance. Full data on the patient compliance were assessed in 29 trials comparing the SQT with STT. Overall, similar compliance rates were reported among the 29 studies except for 2 RCTs36,42: www.americantherapeutics.com

Park et al in 2012 and Morse et al in 2013 (81.5% and 78.4% with SQT; 76.2% and 92.5% with STT, respectively). Data regarding therapy-related adverse effects were available from 26 of the included trials. Adverse events occurred in 649 of 3410 patients (19.0%) treated with SQT versus 705 of 3874 patients (18.2%) treated with the STT (Figure 6). The RR was 1.01 (95% CI: 0.91– 1.13), which demonstrated no significant difference between SQT and STT in terms of adverse events. Common adverse events included diarrhea, abdominal pain, nausea/vomiting, metallic taste, abdominal distention, pruritus, and glossitis. Most adverse events were mild or moderate. Publication bias and sensitivity analysis For H. pylori eradication rates with SQT versus STT, the symmetric funnel plot indicated that no evidence American Journal of Therapeutics (2016) 23(3)

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FIGURE 6. Forest plot for adverse events.

of publication bias was observed (Figure 7). In addition, the result of Begg test (P 5 0.892) and Egger test (P 5 0.281) also provided no statistical evidence for publication bias. In the sensitivity analysis, we

excluded 11 studies with no more than 3 of modified Jadad score as well as 9 studies of abstract form and a community-based participatory research.42 The eradication rates were not significantly affected. Also, the

FIGURE 7. Funnel plot to assess publication bias. American Journal of Therapeutics (2016) 23(3)

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SQT or STT for Helicobacter pylori Infection

recalculated pooled RR was not significantly different when each study estimate was individually omitted from the data set.

DISCUSSION STT consisting of a PPI and 2 antibiotics is the first-line eradication therapy for H. pylori. However, the efficacy of STT is constantly decreasing worldwide recently. Two meta-analyses including more than 53,000 patients have shown that the ITT cure rate is less than. 80%.49,50 The most important explanation for the decrease in efficacy of the STT is the increase in H. pylori resistance to antibiotics, especially clarithromycin. The clarithromycin resistance rate in an European survey performed at 10-year intervals increased from 9% in 199851 to 17.6% in 2008,52 approximately by 1% per year. Novel and more effective therapeutic approaches to eradicate H. pylori are still urgently needed. Several strategies have been proposed to address this problem, including bismuth-containing quadruple therapy, concomitant therapy, and SQT. Some studies suggested that SQT was not affected by bacterial and host factors, which have predicted the outcome of STT treatments, such as the presence of the CagA gene,16,41 smoking,6,35,36 or endoscopic finding (PUD or NUD)13,14,16,17,29,36,41; thus, it could achieve better efficiency than STT, although several studies have also demonstrated conflicting results. Systematic review including newly published studies is necessary for more convincing evidence. The results of our meta-analysis arrive at the following conclusions: (1) SQT is superior to STT in the eradication of H. pylori, RR 5 1.13 (95% CI: 1.09–1.17; P , 0.00001). There was significant heterogeneity between included trials (I2 5 73%; P , 0.00001); subgroup analyses and random-effect model were chosen for pooled analyses. The possible reasons for heterogeneity include the reliability of randomization, different duration of treatment therapy (STT), different type of nitroimidazole. (2) Further subgroup analyses based on the duration of STT (7 days, 10 days, or 14 days) and the type of nitroimidazole derivatives in SQT (tinidazole or metronidazole) were conducted. SQT was superior to both 7-day (RR 5 1.21; 95% CI: 1.18–1.25; P , 0.00001) and 10-day (RR 5 1.08; 95% CI: 1.03–1.14; P 50.004) STT; the eradication rates between SQT and 14-day STT were similar (RR 5 1.03; 95% CI: 0.96–1.11; P 5 0.39). Both SQT and extending the duration of STT from 7 to 10–14 days improved the eradication success. (3) SQT was significantly better than STT when patients were treated with either metronidazole or tinidazole. The effect size with tinidazole was higher than www.americantherapeutics.com

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with metronidazole (NNT 9 vs. 15), suggesting a benefit of this drug with SQT. (4) Six studies reported H. pylori culture patients with clarithromycin-resistant strains benefited from SQT more than from STT (RR 5 1.98; 95% CI: 1.33–2.94; P 5 0.0007), neither nitroimidazole resistance nor dual clarithromycin and nitroimidazole resistance showed significant difference in H. pylori eradication between SQT and STT. The Maastricht-IV Consensus suggested that PPI clarithromycin containing triple therapy without prior susceptibility testing should be abandoned in the region where the clarithromycin resistance rate is over 15%– 20%.53 (5) Despite SQT has a more complex posology, good compliance rates were reported among most studies comparing the SQT with STT. There was no significant difference between groups in terms of the risk of adverse effects. This information is very important for the selection of regimens. The potential limitations of this study include unclear or inadequate allocation concealment and no blinding in almost all of the trials. We also included 9 abstracts and 1 full text, which reported inadequate outcome data for the sake of completeness.13,14,30–32,37,39,45–47 In addition, most of the published studies did not have data regarding antibiotic resistance, which could significantly affect treatment outcomes.

CONCLUSIONS In conclusion, SQT is a reasonable alternative for initial therapy; however, the eradication rate (,90%) is not very satisfactory. Monitoring of resistance rates should be performed to guide treatment. Further studies are needed to assess the optimum algorithm for H. pylori treatment and develop more effective therapeutic approaches.

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American Journal of Therapeutics (2016) 23(3)

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Sequential Therapy or Standard Triple Therapy for Helicobacter pylori Infection: An Updated Systematic Review.

The effectiveness of standard triple therapy (STT) for the eradication of Helicobacter pylori has decreased recently. Sequential therapy (SQT) is a ne...
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