Consensus statement the Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults
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marginally improved ITT eradication rates overall (87.5% [95% CI, 78.5% –93.1%] vs 82.7% [95% CI, 73%–89.4%]; P ¼ .39), but eradication rates were much higher among levo floxacin-resistant strains (70.6% vs 37.5%). 52 After
prior treatment failure (including both standard triple and nonbismuth quadruple therapies), BPAL had an ITT eradi- cation success rate of 90% (95% CI, 86% –94%) in a pro- spective cohort study. 108
Decisions. The consensus group agreed that for pa- tients who have previously failed to respond to H pylori eradication therapy, levo floxacin-containing therapy (usually PAL) is an option. However, in light of evidence of higher eradication rates with longer treatment durations, 106 the
consensus group recommended a 14-day regimen. Statement 10. In patients who have previously failed to respond to clarithromycin-containing H py-
lori eradication therapy, we recommend against the use of clarithromycin-containing regimens as sub- sequent therapy. GRADE: Strong recommendation; quality of evidence low. Vote: strongly agree, 100%. Key evidence ( Supplementary Table 10 ). As discussed with statements 2 and 5, the ef ficacy of clarithromycin- containing regimens is highly affected by clarithromycin resistance. 19,22,46,52 –55 More importantly, the prevalence of secondary resistance is very high (up to 70% in some series).
20,40 Decisions. As a result of resistance concerns, the consensus group recommended against reuse of clari- thromycin in patients who have already failed to respond to a clarithromycin-containing regimen. Statement 11. In patients who have previously failed to respond to a levo floxacin-containing H py- lori eradication therapy, we recommend against the use of levo floxacin-containing regimens as subse- quent therapy. GRADE: Strong recommendation; quality of evidence low. Vote: strongly agree, 62.5%; agree, 37.5%. Key evidence ( Supplementary Table 11 ). As discussed in statement 6, the ef ficacy of levofloxacin-containing regi- mens is highly affected by levo floxacin resistance. 52,81 Studies have shown that the prevalence of secondary levo- floxacin resistance is very high (up to 63% in some series).
83,84 Decisions. As a result of resistance concerns, the consensus group recommended against reusing levo floxacin
in patients who have already failed to respond to a levo
floxacin-containing regimen. Previous quinolone use is also associated with levo floxacin-resistant H pylori and would be expected to reduce the therapeutic success of this agent. Statement 12. In patients who have previously failed to respond to H pylori eradication therapy, we recommend against the use of sequential non- bismuth quadruple therapy (PA followed by PMC) as an option for subsequent therapy. GRADE: Strong recommendation; quality of evidence very low. Vote: strongly agree, 50%; agree, 50%. Key evidence ( Supplementary Table 12 ). Cohort data have suggested that sequential nonbismuth quadruple therapy can be effective after failure of previous eradication therapy, but data are from a small number of patients (42 patients in total) and low quality. 109,110 As discussed in statement 7, eradication success rates with this regimen were low ( <80%) and inferior to concomitant administra- tion when used in the first-line setting ( Figure 2
). 69 In addition, this strategy was associated with very low eradi- cation of clarithromycin and dual clarithromycin and metronidazole resistant strains (62% and 47%). 69 Decisions. The consensus group recommended that sequential nonbismuth quadruple therapy not be used as rescue therapy, because it is less ef ficacious than other therapies. Statement 13. We recommend restricting the use of rifabutin-containing regimens to cases in which at least 3 recommended options have failed. GRADE: Strong recommendation; quality of evidence very low. Vote: strongly agree, 62.5%; agree, 37.5%. Key evidence ( Supplementary Table 13 ). A systematic review of 21 studies assessing rescue therapy with rifabutin-containing regimens found that the overall ITT eradication success rate was 73% (95% CI, 67% –79%).
111 The success rate was 79% for second-line regimens and 66% to 70% for third-line or greater regimens. The preva- lence of resistance was low at 1.3%. Rifabutin triple therapy for 10 days was shown to be effective in approximately one- half of patients when used as fourth-line rescue therapy in a cohort of 190 patients, with an ITT eradication rate of 52% (95% CI, 45% –59%). 112,113
Other issues and discussion. The most commonly stud- ied rifabutin-containing regimen is PPI þ amoxicillin þ rifabutin [PAR]; current evidence suggests that 10 days may be more effective than 7 days, but no additional bene fit has
been shown with 14 days, which may increase the side ef- fect burden. 111,114 For this reason, this is the only regimen for which a duration of therapy of 10 days may be sug- gested; however, this suggestion is based on a small number of patients who were treated. Rifabutin-containing regimens should be reserved for patients with multiple treatment failures. Because eradication in the rescue setting is low, there are concerns about adverse events, especially myelotoxicity, and cost is also an issue. In addition, although the prevalence of resistance is low, there are theoretical concerns that overuse may increase the prevalence of rifabutin-resistant mycobacteria in the com- munity, for which this agent is currently very important. 111
Decisions. The consensus group agreed that rifabutin- containing regimens may be useful in the rescue setting but appear to be less safe than other regimens and should be reserved for patients with multiple previous failures (eg, PBMT, PAMC, and PAL). Other
statements/comments. PAMC as rescue therapy. The consensus group concluded that there was insuf
ficient evidence to support or refute the efficacy of PAMC as a second-line option and thus was unable to recommend for or against this regimen as a rescue therapy. In a small Japanese study, the ITT eradication rate with PAMC after failure of PAC triple therapy was 88.5%, compared with 82.7% with PAM. 115 No data were found assessing the use of this regimen after failure of bismuth quadruple therapy. July 2016 Toronto Consensus for H pylori Treatment 61
The role of acid suppression. Acid suppression plays an important role in eradication of H pylori infection. Successful eradication has been shown to be closely related to the degree of acid inhibition, with a cohort study using triple therapy (PAC) showing a signi ficantly higher mean gastric pH in patients with versus without successful eradication (6.4 vs 5.2; P ¼ .013). 116
It has been suggested that achieving more potent acid inhibition can improve treatment success. Meta-analyses of RCTs have shown higher eradication rates with triple therapy using a standard-dose PPI twice daily versus once daily (13 studies; 83.9% vs 77.7%; P
117
and with a high-dose (eg, esomeprazole 40 mg twice daily) versus standard-dose PPI (eg, esomeprazole 20 mg twice daily) (6 studies; 82% vs 74%; P ¼ .03). 118
In addition, a meta-analysis of 35 studies showed higher eradication rates with esomeprazole (82.3% vs 77.6%; odds ratio, 1.32; 95% CI, 1.01 –1.73) and rabeprazole (80.5% vs 76.2%; odds ratio, 1.21; 95% CI, 1.02 –1.42) compared with first-generation PPIs (omeprazole, lanso- prazole, pantoprazole). 119 Another potential method to improve acid inhibition would be to use newer, more potent antisecretory agents. Potassium-competitive acid blockers inhibit gastric H þ /
þ –adenosine triphosphatase in a K þ competitive but reversible manner and thus do not require prior proton pump activation to achieve their antisecretory effect. 120,121 One of these agents, vonoprazan, was recently approved in Japan for a number of gastrointestinal diseases, including eradication of H pylori infection. 121 Data suggest that the pH 4 holding time with this drug is equivalent to esome- prazole 20 mg 4 times daily. 122,123 Superior clinical ef ficacy of this more potent acid suppressant in triple therapy regimens has been shown in first-line and second-line settings. 124
For example, vonoprazan-based triple therapy with amoxicillin and clarithromycin had greater eradication success rates (92.6% vs 75.9%; P
lansoprazole-based treatment due to the difference in eradication of clarithromycin-resistant cases (82.0% vs 40.0%; P
< .0001), although treatment success in the presence of clarithromycin resistance is still far from desirable. 124
High-dose dual therapy. Further evidence for increased ef ficacy with greater acid suppression comes from a study of high-dose PPI dual therapy. 50 Despite the recognized inadequacy of standard-dose PPI dual therapy, 125
a large RCT reported signi ficantly higher ITT eradication rates with high-dose PPI dual therapy (amoxicillin 750 mg 4 times a day and rabeprazole 20 mg 4 times a day for 14 days; 95.3%) as first-line treatment compared with either 10-day sequential (85.3%) or 7-day standard triple ther- apy (80.7%) and as second-line treatment (89.3%) compared with sequential (51.8%) but not levo floxacin- based triple therapy (78.6%). 50 It is unknown how this regimen would compare with PBMT. This regimen may prove to be advantageous given the low prevalence of amoxicillin resistance, but the consensus group felt that more evidence was needed (eg, compared with 14-day PBMT or PAMC first-line therapy, compared with PBMT in rescue therapy and in other countries) before a state- ment on this therapy could be developed. However, high- dose dual PPI therapy for 14 days may be an option when both dual metronidazole/clarithromycin resistance and levo floxacin resistance are suspected, such as in a patient with multiple previous failures to respond to therapy.
Supplemental Therapy Statement 14. In patients with H pylori infection, we recommend against routinely adding probiotics to eradication therapy for the purpose of reducing adverse events. GRADE: Strong recommendation; quality of evidence very low. Vote: strongly agree, 87.5%; agree, 12.5%.
Statement 15. In patients with H pylori infection, we recommend against adding probiotics to eradi- cation therapy for the purpose of increasing eradi- cation rates. GRADE: Strong recommendation; quality of evidence very low. Vote: strongly agree, 62.5%; agree, 37.5%. Key evidence ( Supplementary Table 14 ). A meta- analysis
of 10 trials concluded that
Lactobacillus- containing and Bi
probiotic preparations during H pylori eradication therapy may have bene ficial effects on eradication rate and incidence of total side effects. 126
However, this analysis was rated low-quality evidence due to serious limitations, inconsistency, and indirectness (the majority of trials assessed the impact of probiotic supplementation when added to triple rather than quadruple therapy). Two RCTs have reported no improvement in eradication rates with the addition of probiotics to quadruple therapy in adults. 127,128 When added to sequential nonbismuth quadruple therapy, there was no signi ficant impact on eradication rates; however, side effects and compliance were improved compared with placebo. 127 When added to bismuth quadruple therapy, a multi-strain probiotic com- pound showed no bene ficial effects on efficacy (ITT eradi- cation rate, 76.6% vs 81.1%; P ¼ .029) or overall tolerability (P ¼ .851) compared with placebo. 128 There was a signi fi- cant reduction in diarrhea but an increase in abdominal pain. Other issues and discussion. Although some studies suggest possible bene ficial effects, these results are incon- sistent across studies and there are a number of concerns with use of probiotics. 129 Formulations are not standardized and contain different bacterial strains in different combi- nations and at different concentrations; therefore, studies are needed to determine which, if any, speci fic formulations may actually have bene ficial effects. Use of probiotics also increases the cost and complexity of an already complex treatment regimen. Decisions. The consensus group concluded that the ev- idence does not convincingly show that probiotics will in- crease the ef ficacy of the recommended eradication therapies and they should not be used for this purpose. In contrast, although not recommended routinely for the pre- vention of adverse events, they may be potentially useful, and unlikely harmful, in certain high-risk cases to prevent diarrhea or Clostridium dif ficile infection. 62 Fallone et al Gastroenterology Vol. 151, No. 1 Future Directions The lack of availability of data on local susceptibility patterns and eradication success rates was identi fied as a
knowledge gap that has a major impact on the choice of therapy and hence best management. Periodic susceptibility testing should be considered by health authorities, and cli- nicians should be encouraged to record their successes. These data should be published or presented at conferences to help monitor susceptibility on an ongoing basis. There is a need for well-conducted, head-to-head RCTs on the ef ficacy of concomitant nonbismuth therapy versus PBMT as
first-line treatment, as well as studies on 10-day versus 14-day regimens. In addition, more data are needed on the ef ficacy of rescue therapies after failure of concomitant or PBMT first-line treatment. As discussed in statement 8, there continues to be a need to determine the optimal doses of drugs included in the recommended regimens, including the effects of various doses of metronidazole (500 mg 3 times daily vs 500 mg 4 times a day) for PBMT. The role of more potent acid sup- pression through higher or more frequent doses, or the use of newer antisecretory agents such as vonoprazan, requires further study. The increasing prevalence of resistance and increasing rates of failure of current therapies emphasize the need to continue developing and evaluating new regimens. Moxi floxacin-containing triple therapies have been studied in some parts of the world. 130
–133 Several meta-analyses of RCTs have reported that this regimen is better tolerated than bismuth quadruple therapy and is as effective in the first-line setting 130
and more effective in the second-line setting.
130,131 However, moxi floxacin is affected by the same high prevalence of fluoroquinolone resistance as lev- o floxacin (see statement 6). Bismuth quadruple therapy with a PPI, amoxicillin, and clarithromycin (PBAC) 134
–137 or levo floxacin (BPAL; see statement 9) may be an effective alternative to PBMT. 52,108 Eradication success rates with PBAC have been widely variable, ranging from 55% to 96% in RCTs.
134 –137
In addition, this regimen will likely be affected by clarithromycin resistance. Further study on high-dose PPI dual therapy (amoxicillin 750 mg 4 times a day and rabeprazole 20 mg 4 times a day for 14 days) 50 and other high-dose dual regimens is required before they can be recommended. In certain countries, some agents are not available; therefore, alternative regimens may be required for treat- ment failure. For example, if bismuth and levo floxacin are not available, high-dose PPI dual therapy or PAM can be considered. Further studies on these and other alternatives are required for those who fail to respond to treatment. Limitations of the Consensus There are some limitations of this consensus that should be mentioned. It would have been ideal if the consensus panel also included primary care physicians, patients, or other stakeholders, although their potential viewpoints were discussed at the face-to-face meeting before every vote. In addition, it was decided not to search for data before 2008 to avoid confounding of data from earlier studies that had higher eradication success rates likely as a result of lower antibiotic resistance. However, this cutoff can be viewed as a shortcoming, especially in the rare instance when no new data were available. Older studies and meta-analyses were used as a discussion point when presenting newer studies and newer meta-analyses, because we did not want to completely ignore older data. The older data were only used in decision making if newer data did not exist for that particular statement. We believe this approach was valid because it puts more emphasis on more recent data while not ignoring data published before 2008. Finally, the systematic evaluation of evidence relied on studies in which the populations had variable percentages of antibiotic resistance. This would affect the success rates of the different regimens and conclusions may not be gener- alizable
to speci
fic practice populations. 57 Similarly, different studies may have used different doses, dosing in- tervals, and relationships to meals that are not taken into account when combining results from different studies. Some of these factors may also play a role in determining outcome and have not been addressed by this consensus. Summary
Based on evidence of higher eradication rates with regi- mens of longer duration and increasing failure of shorter treatment durations, the consensus group strongly recom- mended that all H pylori eradication regimens be given for 14 days. Recommended first-line strategies include Figure 3. Algorithm for eradication therapies for first-line and rescue treatments. *Some members of the consensus group advocated against the repeat use of PBMT, whereas others suggested it may be useful to reserve rifabutin for fourth-line use (see statement 8). Optimized refers to using a higher dose of PPI or metronidazole. See Tables 1
and 2 for more details on regimens and dosing. July 2016 Toronto Consensus for H pylori Treatment 63
traditional quadruple bismuth therapy (PBMT), concomitant nonbismuth quadruple therapy (PAMC), and the restricted use of PPI triple therapy (PAC or PMC) to regions with known low clarithromycin resistance or high eradication success rates ( Table 1
and Figure 3
). Levo floxacin triple therapy (PAL) and sequential nonbismuth quadruple ther- apy (PA followed by PMC) were not recommended for first- line treatment. Potential strategies for subsequent therapy for patients who fail to respond treatment are shown in Figure 3 . The
choice of second-line treatment depends on previous anti- biotic exposure. If there is no previous metronidazole exposure, PBMT and levo floxacin-containing therapies are both options. If the patient was previously exposed to metronidazole, PAL is the preferred second-line option. If PAL has failed, then PBMT is the next option even if previ- ously exposed to metronidazole. An optimized PBMT with higher-dose PPI and metronidazole 500 mg 4 times a day could be considered an option if the patient has previously failed to respond to regular PBMT and PAL, especially if one wanted to avoid rifabutin. However, there is not a large body of evidence for this, and some members of the group argued that repeating PBMT would not be useful. The use of rifabutin-containing regimens should be restricted to pa- tients who have failed to respond to at least 3 prior options. Regarding nonbismuth quadruple therapy, there were insuf
ficient data to make a recommendation regarding concomitant PAMC as rescue therapy, but sequential ther- apy (PA followed by PMC) was not recommended. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at Yüklə 0,75 Mb. Dostları ilə paylaş:
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