Effectiveness and Tolerance of Treatments for H pylori
Effectiveness and Tolerance of Treatments for H pylori
Through literature searches, 15,565 studies were identified, of which 15,281 were excluded after screening of the titles and abstracts. The full texts of 284 remaining studies were reviewed. Overall, 143 studies were eligible and were included (see study inclusion flowchart in Supplementary Appendix 1, Figure S1.1 http://www.bmj.com/content/351/bmj.h4052/related). These 143 studies covered 14 kinds of treatments ( Table 1 ). Of 91 possible comparisons between treatment regimens for the primary outcome, 34 were compared directly in the studies we identified. In total, 32,056 patients contributed to the efficacy analysis and 22,180 to the tolerance analysis. The average age of patients with H pylori was 47 years, and approximately 53% of participants were men. The baseline characteristics of the included studies are listed in Supplementary Appendix 1, Table S1.1 http://www.bmj.com/content/351/bmj.h4052/related, and the citation details are given in Supplementary Appendix 2 http://www.bmj.com/content/351/bmj.h4052/related. The risk of bias summary and figure for included studies are listed in Supplementary Appendix 3 http://www.bmj.com/content/351/bmj.h4052/related. Some studies did not present details for randomisation, allocation concealment, and blinding.
In total, the success of H pylori eradication was assessed for 14 treatments, presented in 143 studies, and data were available for 32,056 patients (intention to treat analysis). All commonly used treatments were assessed in at least one randomised controlled trial. Figure 1 graphically represents the network of eligible comparisons for the efficacy outcome of the network meta-analysis. For the efficacy outcome, the network meta-analysis estimations indicated that most treatments were better than the previously recommended seven days of standard triple treatment, the two exceptions being the seven days of levofloxacin based triple treatment and seven days of bismuth based quadruple treatment, which were comparable to the seven days of standard triple treatment ( Table 2 and Figure 2). In the comparisons between seven days and 10 or 14 days of treatments, longer treatments in most cases were better, and this was the case for standard triple treatments, levofloxacin based triple treatments, probiotic supplemented triple treatments, and bismuth based quadruple treatments. For the concomitant treatments and ranitidine bismuth citrate based triple treatments, the efficacy of the shorter treatments was comparable to that of the longer treatments (see Supplementary Appendix 4, Table S4.1 http://www.bmj.com/content/351/bmj.h4052/related).
(Enlarge Image)
Figure 1.
Network of eligible comparisons for treatment efficacy network meta-analysis. The width of lines is proportional to the number of studies compared in every pair of treatments, and the size of nodes is proportional to the total sample size of each treatment.
(Enlarge Image)
Figure 2.
Forest plot of network meta-analysis results for treatment efficacy outcomes compared with seven days of standard triple treatment.
In terms of eradication rates, all treatments, including the seven days of standard triple treatment, were still effective. Ranking on efficacy indicated that seven days of concomitant treatment was the highest, followed by 10 or 14 days of concomitant treatment, 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, 14 days of hybrid treatment, 10 or 14 days of sequential treatment, 10 or 14 days of ranitidine bismuth citrate based triple treatment, and 10 or 14 days of bismuth based quadruple treatment. Table 2 lists the eradicative effects of each treatment compared with the seven days of standard triple treatment and Supplementary Appendix 4, Table S4.1 http://www.bmj.com/content/351/bmj.h4052/related presents the results across all other treatment comparisons. Despite the seven days of concomitant treatment ranking the highest, data on this treatment method was provided by only three studies and in 504 participants.
Heterogeneity in pairwise meta-analysis was generally moderate (see Supplementary Appendix 4, Table S4.2 http://www.bmj.com/content/351/bmj.h4052/related). Similarly, no statistically significant inconsistency was indicated in most loops within the network for the efficacy outcome.
Treatment Comparison for Total Occurrence of Adverse Events. A total of 99 studies were included in the comparison of total occurrence rates of adverse events among the 14 treatments. Figure 3 graphically represents the network of eligible comparisons for the adverse event outcome of the network meta-analysis. Generally, the shorter the treatment time was, the lower the likelihood of adverse events. In our network meta-analysis comparisons, seven days of probiotic supplemented triple treatment and seven days of levofloxacin based triple treatment were significantly better than the seven days of standard triple treatment ( Table 3 and Figure 4). These two treatments ranked the best in terms of tolerance. Risks of any adverse event ranged from 14–34% in the different treatments. However, the results should be interpreted with caution because most network meta-analysis comparisons between the various treatments did not reach statistical significance. Table 3 lists the comparisons of adverse events for each treatment with the seven days of standard triple treatment. All other comparisons are shown in Supplementary Appendix 5, Table S5.1 http://www.bmj.com/content/351/bmj.h4052/related. The results of pairwise meta-analyses are also given in Supplementary Appendix 5, Table S5.2 http://www.bmj.com/content/351/bmj.h4052/related.
(Enlarge Image)
Figure 3.
Network of eligible comparisons for treatment tolerance network meta-analysis. The width of lines is proportional to the number of studies compared in every pair of treatments, and the size of nodes is proportional to the total sample size of each treatment.
(Enlarge Image)
Figure 4.
Forest plot of network meta-analysis results for treatment tolerance outcomes compared with seven days of standard triple treatment.
Treatment Comparison for Occurrence of Adverse Event Subtypes. In terms of the number of patients presenting with epigastric or abdominal pain, occurrence rates in the network meta-analysis revealed that ranitidine bismuth citrate based triple treatments and 10 or 14 days of probiotic supplemented triple treatment might be relatively optimal choices ( Table 4 ). The lowest rates of taste alteration were reported with seven days of levofloxacin based triple treatment and bismuth based quadruple treatments. Headaches with or without vomiting were experienced less frequently during probiotic supplemented triple treatments and 10 or 14 days of levofloxacin treatment. Patients taking the probiotic supplemented triple treatments and seven days of levofloxacin based triple treatment reported experiencing diarrhoea less often. Again, findings should be interpreted with caution since most comparisons did not reach statistical significance (see Supplementary Appendix 5, Tables S5.3, S5.5, S5.7, and S5.9 http://www.bmj.com/content/351/bmj.h4052/related). Credible intervals were not narrow in network meta-analysis comparisons and confidence intervals were wide in pairwise meta-analysis comparisons, reflecting the small number of studies available for these comparisons.
It was impossible to subdivide treatment groups further owing to the limited number of studies for each subgroup. However, we recognise that adverse events, particularly taste alteration, may differ by antibiotic choice. Clarithromycin may be one of the main contributors to risk of experiencing taste alteration: seven days of levofloxacin based triple treatment (proton pump inhibitor, levofloxacin, and amoxicillin) was compared with seven days of standard triple treatment (proton pump inhibitor, clarithromycin, and amoxicillin), and a lower risk for taste alteration was seen with levofloxacin instead of clarithromycin (data not shown).
Table 4 shows the occurrence rates and the relative ranks of treatments in terms of subtypes of adverse events. Supplementary Appendix 5, Tables S5.3-S5.10 http://www.bmj.com/content/351/bmj.h4052/related list all the results of network meta-analysis and pairwise meta-analysis.
Figure 5 presents all eradication treatments ordered by their relative ranks for efficacy, showing the separate contributions to the overall results of efficacy and tolerance. We found that 7, 10, or 14 days of concomitant treatment, 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, 14 days of hybrid treatment, and 10 or 14 days of sequential treatment were among the most effective treatments, whereas seven days of probiotic supplemented triple treatment and seven days of levofloxacin based triple treatment performed better in the tolerance analysis. In Figure 6, we ranked these eradication treatments according to both dimensions of efficacy and tolerance. Longer treatments in most cases were better for the efficacy outcomes and worse for adverse events, as most of these treatments lay in the upper left corner, whereas shorter treatments tended to have more optimal tolerance outcomes but lower efficacy as they appear mostly in the lower right corner of the figure.
(Enlarge Image)
Figure 5.
Efficacy and tolerance profile for all eradication treatments according to network meta-analyses (treatments are ordered based on efficacy ranking).
(Enlarge Image)
Figure 6.
Ranking for effectiveness and tolerance ofHelicobacter pylori treatments in network meta-analyses.
The meta-regression with efficacy outcomes indicated that mean or median age, sex ratio, Jadad score, and observation interval between the end of treatment and the time H pylori eradication was confirmed did not lead to significant changes in the results.
Sensitivity analyses of the publication year and the risks of bias of the included studies did not show any major change in the primary outcome (see Supplementary Appendix 4, table S4.1 http://www.bmj.com/content/351/bmj.h4052/related). However, if we excluded studies in which any comparison group had a sample size of fewer than 50 participants, most results were stable except for the seven days of concomitant treatment. The 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, and 10 or 14 days of concomitant treatment were among the most effective treatments compared with seven days of standard triple treatment, in this sensitivity analysis of studies with a minimum of 50 participants in each comparison group.
In the subgroup network meta-analysis, the efficacies of treatments differ by geographical locations. However, owing to the smaller sample sizes in each country, the credible intervals are wide and overlap for many treatments, and we cannot make a definitive conclusion about the superiority of one treatment over another. Supplementary Appendix 4, table S4.3 http://www.bmj.com/content/351/bmj.h4052/related presents the eradication rates of different countries calculated by network meta-analyses.
Visual inspection of funnel plots for the primary outcomes did not show distinct asymmetry (see Supplementary Appendix 4, fig S4.1 http://www.bmj.com/content/351/bmj.h4052/related).
Results
Study Characteristics and Quality Assessment
Through literature searches, 15,565 studies were identified, of which 15,281 were excluded after screening of the titles and abstracts. The full texts of 284 remaining studies were reviewed. Overall, 143 studies were eligible and were included (see study inclusion flowchart in Supplementary Appendix 1, Figure S1.1 http://www.bmj.com/content/351/bmj.h4052/related). These 143 studies covered 14 kinds of treatments ( Table 1 ). Of 91 possible comparisons between treatment regimens for the primary outcome, 34 were compared directly in the studies we identified. In total, 32,056 patients contributed to the efficacy analysis and 22,180 to the tolerance analysis. The average age of patients with H pylori was 47 years, and approximately 53% of participants were men. The baseline characteristics of the included studies are listed in Supplementary Appendix 1, Table S1.1 http://www.bmj.com/content/351/bmj.h4052/related, and the citation details are given in Supplementary Appendix 2 http://www.bmj.com/content/351/bmj.h4052/related. The risk of bias summary and figure for included studies are listed in Supplementary Appendix 3 http://www.bmj.com/content/351/bmj.h4052/related. Some studies did not present details for randomisation, allocation concealment, and blinding.
Treatment Efficacy
In total, the success of H pylori eradication was assessed for 14 treatments, presented in 143 studies, and data were available for 32,056 patients (intention to treat analysis). All commonly used treatments were assessed in at least one randomised controlled trial. Figure 1 graphically represents the network of eligible comparisons for the efficacy outcome of the network meta-analysis. For the efficacy outcome, the network meta-analysis estimations indicated that most treatments were better than the previously recommended seven days of standard triple treatment, the two exceptions being the seven days of levofloxacin based triple treatment and seven days of bismuth based quadruple treatment, which were comparable to the seven days of standard triple treatment ( Table 2 and Figure 2). In the comparisons between seven days and 10 or 14 days of treatments, longer treatments in most cases were better, and this was the case for standard triple treatments, levofloxacin based triple treatments, probiotic supplemented triple treatments, and bismuth based quadruple treatments. For the concomitant treatments and ranitidine bismuth citrate based triple treatments, the efficacy of the shorter treatments was comparable to that of the longer treatments (see Supplementary Appendix 4, Table S4.1 http://www.bmj.com/content/351/bmj.h4052/related).
(Enlarge Image)
Figure 1.
Network of eligible comparisons for treatment efficacy network meta-analysis. The width of lines is proportional to the number of studies compared in every pair of treatments, and the size of nodes is proportional to the total sample size of each treatment.
(Enlarge Image)
Figure 2.
Forest plot of network meta-analysis results for treatment efficacy outcomes compared with seven days of standard triple treatment.
In terms of eradication rates, all treatments, including the seven days of standard triple treatment, were still effective. Ranking on efficacy indicated that seven days of concomitant treatment was the highest, followed by 10 or 14 days of concomitant treatment, 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, 14 days of hybrid treatment, 10 or 14 days of sequential treatment, 10 or 14 days of ranitidine bismuth citrate based triple treatment, and 10 or 14 days of bismuth based quadruple treatment. Table 2 lists the eradicative effects of each treatment compared with the seven days of standard triple treatment and Supplementary Appendix 4, Table S4.1 http://www.bmj.com/content/351/bmj.h4052/related presents the results across all other treatment comparisons. Despite the seven days of concomitant treatment ranking the highest, data on this treatment method was provided by only three studies and in 504 participants.
Heterogeneity in pairwise meta-analysis was generally moderate (see Supplementary Appendix 4, Table S4.2 http://www.bmj.com/content/351/bmj.h4052/related). Similarly, no statistically significant inconsistency was indicated in most loops within the network for the efficacy outcome.
Tolerance of Treatments
Treatment Comparison for Total Occurrence of Adverse Events. A total of 99 studies were included in the comparison of total occurrence rates of adverse events among the 14 treatments. Figure 3 graphically represents the network of eligible comparisons for the adverse event outcome of the network meta-analysis. Generally, the shorter the treatment time was, the lower the likelihood of adverse events. In our network meta-analysis comparisons, seven days of probiotic supplemented triple treatment and seven days of levofloxacin based triple treatment were significantly better than the seven days of standard triple treatment ( Table 3 and Figure 4). These two treatments ranked the best in terms of tolerance. Risks of any adverse event ranged from 14–34% in the different treatments. However, the results should be interpreted with caution because most network meta-analysis comparisons between the various treatments did not reach statistical significance. Table 3 lists the comparisons of adverse events for each treatment with the seven days of standard triple treatment. All other comparisons are shown in Supplementary Appendix 5, Table S5.1 http://www.bmj.com/content/351/bmj.h4052/related. The results of pairwise meta-analyses are also given in Supplementary Appendix 5, Table S5.2 http://www.bmj.com/content/351/bmj.h4052/related.
(Enlarge Image)
Figure 3.
Network of eligible comparisons for treatment tolerance network meta-analysis. The width of lines is proportional to the number of studies compared in every pair of treatments, and the size of nodes is proportional to the total sample size of each treatment.
(Enlarge Image)
Figure 4.
Forest plot of network meta-analysis results for treatment tolerance outcomes compared with seven days of standard triple treatment.
Treatment Comparison for Occurrence of Adverse Event Subtypes. In terms of the number of patients presenting with epigastric or abdominal pain, occurrence rates in the network meta-analysis revealed that ranitidine bismuth citrate based triple treatments and 10 or 14 days of probiotic supplemented triple treatment might be relatively optimal choices ( Table 4 ). The lowest rates of taste alteration were reported with seven days of levofloxacin based triple treatment and bismuth based quadruple treatments. Headaches with or without vomiting were experienced less frequently during probiotic supplemented triple treatments and 10 or 14 days of levofloxacin treatment. Patients taking the probiotic supplemented triple treatments and seven days of levofloxacin based triple treatment reported experiencing diarrhoea less often. Again, findings should be interpreted with caution since most comparisons did not reach statistical significance (see Supplementary Appendix 5, Tables S5.3, S5.5, S5.7, and S5.9 http://www.bmj.com/content/351/bmj.h4052/related). Credible intervals were not narrow in network meta-analysis comparisons and confidence intervals were wide in pairwise meta-analysis comparisons, reflecting the small number of studies available for these comparisons.
It was impossible to subdivide treatment groups further owing to the limited number of studies for each subgroup. However, we recognise that adverse events, particularly taste alteration, may differ by antibiotic choice. Clarithromycin may be one of the main contributors to risk of experiencing taste alteration: seven days of levofloxacin based triple treatment (proton pump inhibitor, levofloxacin, and amoxicillin) was compared with seven days of standard triple treatment (proton pump inhibitor, clarithromycin, and amoxicillin), and a lower risk for taste alteration was seen with levofloxacin instead of clarithromycin (data not shown).
Table 4 shows the occurrence rates and the relative ranks of treatments in terms of subtypes of adverse events. Supplementary Appendix 5, Tables S5.3-S5.10 http://www.bmj.com/content/351/bmj.h4052/related list all the results of network meta-analysis and pairwise meta-analysis.
Effectiveness Versus Harms
Figure 5 presents all eradication treatments ordered by their relative ranks for efficacy, showing the separate contributions to the overall results of efficacy and tolerance. We found that 7, 10, or 14 days of concomitant treatment, 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, 14 days of hybrid treatment, and 10 or 14 days of sequential treatment were among the most effective treatments, whereas seven days of probiotic supplemented triple treatment and seven days of levofloxacin based triple treatment performed better in the tolerance analysis. In Figure 6, we ranked these eradication treatments according to both dimensions of efficacy and tolerance. Longer treatments in most cases were better for the efficacy outcomes and worse for adverse events, as most of these treatments lay in the upper left corner, whereas shorter treatments tended to have more optimal tolerance outcomes but lower efficacy as they appear mostly in the lower right corner of the figure.
(Enlarge Image)
Figure 5.
Efficacy and tolerance profile for all eradication treatments according to network meta-analyses (treatments are ordered based on efficacy ranking).
(Enlarge Image)
Figure 6.
Ranking for effectiveness and tolerance ofHelicobacter pylori treatments in network meta-analyses.
Network Assumptions, Sensitivity Analysis, and Publication Bias
The meta-regression with efficacy outcomes indicated that mean or median age, sex ratio, Jadad score, and observation interval between the end of treatment and the time H pylori eradication was confirmed did not lead to significant changes in the results.
Sensitivity analyses of the publication year and the risks of bias of the included studies did not show any major change in the primary outcome (see Supplementary Appendix 4, table S4.1 http://www.bmj.com/content/351/bmj.h4052/related). However, if we excluded studies in which any comparison group had a sample size of fewer than 50 participants, most results were stable except for the seven days of concomitant treatment. The 10 or 14 days of probiotic supplemented triple treatment, 10 or 14 days of levofloxacin based triple treatment, and 10 or 14 days of concomitant treatment were among the most effective treatments compared with seven days of standard triple treatment, in this sensitivity analysis of studies with a minimum of 50 participants in each comparison group.
In the subgroup network meta-analysis, the efficacies of treatments differ by geographical locations. However, owing to the smaller sample sizes in each country, the credible intervals are wide and overlap for many treatments, and we cannot make a definitive conclusion about the superiority of one treatment over another. Supplementary Appendix 4, table S4.3 http://www.bmj.com/content/351/bmj.h4052/related presents the eradication rates of different countries calculated by network meta-analyses.
Visual inspection of funnel plots for the primary outcomes did not show distinct asymmetry (see Supplementary Appendix 4, fig S4.1 http://www.bmj.com/content/351/bmj.h4052/related).
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