Consensus statement the Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults
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evaluations regarding the GRADE approach for the statements were also reviewed, and all panelists discussed the findings and other issues before finalization of the phrasing for individual statements. Any PICO components that are unequivocally implied were removed from the final statements to make the message clearer to the readers. Finally, participants were asked to vote on their level of agreement for each speci fic statement. A statement was accepted if >75% of participants voted 4 (agree) or 5 (strongly agree) on a scale of 1 to 5 (with 1, 2, and 3 representing disagree strongly, disagree, and uncertain, respectively). Once a statement was accepted, the participants then voted on the “strength” of the recommendation, which was accepted with a 51% vote. Per the GRADE system, the strength of each recommendation was assigned as strong ( “we recommend.”) or conditional ( “we suggest.”). The strength of the recom- mendation considers risk-bene fit balance, patients’ values and preferences, cost and resource allocation, and quality of the evidence. Therefore, it is possible for a recommendation to be classi
fied as strong despite having low-quality evidence to support it or conditional despite the existence of high-quality evidence to support it. 39 Based on the GRADE approach, a strong recommendation indicates the statement should be applied in most cases, while a conditional recommendation signi fies that clinicians “.should recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences. ” 39 The steering committee drafted the initial manuscript, which was revised by all members of the consensus group and all au- thors, after which it was made available to all members of CAG for comments before submission for publication. Per CAG policy, all participants provided written disclosure of relevant potential con
flicts of interest for the 24 months before the meeting, which were made available to the other group members. Role of the Funding Sources CAG administered all aspects of the meeting, which was cofunded by CAG and the Canadian Helicobacter Study Group with no external funding sources. Recommendation Statements The individual recommendation statements are pro- vided and include the quality of supporting evidence as assessed by the GRADE method and the voting results; a discussion of the evidence considered for the speci fic statement is also presented. The quality of evidence was determined to be low for some statements, largely because of high risk of bias (most often due to lack of adequate blinding). Acknowledging the importance of quality of evidence, the consensus group also considered other fac- tors in issuing strong rather than conditional recommen- dations for certain statements despite lower quality of evidence. The strength of these recommendations was driven by consequences of therapeutic failure, including the negative consequences of peptic ulcer disease, such as gastrointestinal bleeding, an increased risk of the devel- opment of gastric cancers, and an increased risk of the development of resistant strains. 20,40,41 In addition, erad- ication success is highest with initial therapy and decreases with subsequent rescue therapy attempts. 42,43 Hence, a treatment option may have been strongly rec- ommended even if the evidence was not high quality to avoid the negative consequences of failure. A summary of the recommendation statements is provided in Table 3 . The most important evidence for each of the statements is summarized in Supplementary Tables 1 to 14 . All Patients Statement 1. In patients with H pylori infection, we recommend a treatment duration of 14 days. GRADE: Strong recommendation; quality of evidence moder- ate for PAC and very low for PBMT, PAMC, and PAL. Vote: strongly agree, 87.5%; agree, 12.5%. Key evidence ( Supplementary Table 1 ). A Cochrane meta-analysis of RCTs found that a 14-day duration of PPI triple therapy was associated with a signi ficantly greater proportion of eradication compared with shorter durations (ITT: 45 studies, 14 vs 7 days, 82% vs 73%; 12 studies, 14 vs 10 days, 84% vs 79%). 28 A signi ficant effect was seen in 54 Fallone et al Gastroenterology Vol. 151, No. 1 the PAC subgroup (34 studies of 14 vs 7 days; relative risk of H pylori persistence, 0.65 [95% con fidence interval {CI}, 0.57
–0.75]; number needed to treat [NNT], 12 [95% CI, 9 –16]) as well as in the PPI, amoxicillin, and quinolone subgroup (2 studies of 14 vs 7 days; relative risk, 0.37 [95% CI, 0.16
–0.83]; NNT, 3 [95% CI, 2–10]) ( Table 4
). There was Table 3.Summary of Consensus Recommendations for the Treatment of H pylori Infection All patients 1. In patients with H pylori infection, we recommend a treatment duration of 14 days. GRADE: Strong recommendation; quality of evidence moderate for PAC and very low for PBMT, PAMC, and PAL. First-line therapy 2. In patients with H pylori infection, we recommend that the choice of first-line therapy consider regional antibiotic resistance patterns and eradication rates. GRADE: Strong recommendation; quality of evidence low. 3. In patients with H pylori infection, we recommend traditional bismuth quadruple therapy (PBMT) for 14 days as one of the options for first-line therapy. GRADE: Strong recommendation; quality of evidence moderate for efficacy and very low for duration. 4. In patients with H pylori infection, we recommend concomitant nonbismuth quadruple therapy (PAMC) for 14 days as one of the options for first-line therapy. GRADE: Strong recommendation; quality of evidence moderate for efficacy and very low for duration. 5. In patients with H pylori infection, we recommend restricting the use of PPI triple therapy (PAC or PMC for 14 days) to areas with known low clarithromycin resistance ( <15%) or proven high local eradication rates (>85%). GRADE: Strong recommendation; quality of evidence moderate for ef ficacy of PPI triple therapy for 14 days and low for restrictions. 6. In patients with H pylori infection, we recommend against the use of levo floxacin triple therapy (PAL) as a first-line therapy. GRADE: Strong recommendation; quality of evidence very low. 7. In patients with H pylori infection, we recommend against the use of sequential nonbismuth quadruple therapy (PA followed by PMC) as a first-line therapy. GRADE: Strong recommendation; quality of evidence moderate. Prior failure 8. In patients who have previously failed to respond to H pylori eradication therapy, we recommend traditional bismuth quadruple therapy (PBMT) for 14 days as an option for subsequent therapy. GRADE: Strong recommendation; quality of evidence low. 9. In patients who have previously failed to respond to H pylori eradication therapy, we suggest levo floxacin-containing therapy for 14 days as an option for subsequent therapy. GRADE: Conditional recommendation; quality of evidence low. 10. In patients who have previously failed to respond a clarithromycin-containing H pylori eradication therapy, we recommend against the use of clarithromycin-containing regimens as subsequent therapy. GRADE: Strong recommendation; quality of evidence low. 11. In patients who have previously failed to respond to a levo floxacin-containing H pylori eradication therapy, we recommend against the use of levo floxacin-containing regimens as subsequent therapy. GRADE: Strong recommendation; quality of evidence low. 12. In patients who have previously failed to respond to H pylori eradication therapy, we recommend against the use of sequential nonbismuth quadruple therapy (PA followed by PMC) as an option for subsequent therapy. GRADE: Strong recommendation; quality of evidence very low. 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. Supplemental therapy 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. 15. In patients with H pylori infection, we recommend against adding probiotics to eradication therapy for the purpose of increasing eradication rates. GRADE: Strong recommendation; quality of evidence very low. NOTE. 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. Similarly, the group concluded that there was insuf ficient evidence to make a recommendation on high-dose dual therapy with a PPI and amoxicillin. See Tables 1 and
2 for more details on regimens and dosing. Table 4.Relative risks for H pylori Persistence According to Duration of Regimen Studies (n ¼ 75) 14 vs 7 days 10 vs 7 days 14 vs 10 days PPI triple therapy (n ¼ 59)
0.66 (0.60 –0.74);
NNT, 11 (9 –14); (n ¼ 45) 0.80 (0.72 –0.89);
NNT, 21 (15 –38); (n ¼ 24) 0.72 (0.58 –0.90);
NNT, 17 (11 –46); (n ¼ 12) PAC (n ¼ 34)
0.65 (0.57 –0.75);
NNT, 12 (9 –16); (n ¼ 34) 0.80 (0.70 –0.91);
NNT, 21 (14 –48); (n ¼ 17) 0.69 (0.52 –0.91);
NNT, 16 (10 –54); (n ¼ 10) PMC (n ¼ 4)
0.87 (0.71 –1.07); (n ¼ 4) 0.99 (0.55 –1.79); (n ¼ 2) — PAQ (n
¼ 2) 0.37 (0.16 –0.83); NNT, 3 (2 –10); (n ¼ 2) 0.58 (0.36 –0.95); NNT, 7 (5 –59); (n ¼ 2) — PPI bismuth quadruple therapy (n ¼ 6)
0.71 (0.44 –1.15); (n ¼ 3) 0.70 (0.43 –1.14); (n ¼ 2) 1.13 (0.59 –2.18); (n ¼ 1) NOTE. Based on data from a meta-analysis by Yuan et al. 28 Values are relative risk for H pylori persistence (95% CI); NNT (95% CI); studies (n). PAQ, PPI
þ amoxicillin þ quinolone. July 2016 Toronto Consensus for H pylori Treatment 55
no increase in discontinuations due to adverse events with increasing duration of therapy. With regard to quadruple therapies, a systematic review of cohort studies found a trend toward greater treatment success with longer durations (from 3 to 10 days) of non- bismuth quadruple therapy (PAMC) (see statement 4). 44 A
eradication rates compared with standard 10-day PAMC (ITT, 93% vs. 87%; P < .01); however, the optimized regimen was not only of longer duration but also included an increased PPI dose. 45 Finally, for bismuth quadruple therapy, the Cochrane meta-analysis of RCTs did not find that duration has a sig- ni ficant effect on therapeutic success for first-line therapy ( Table 4
), 28 but there are very few studies with this com- parison and a trend was suggested (see statement 3). A meta-analysis performed for
the consensus meeting assessed the duration of this regimen for the treatment of those who previously failed to achieve eradication. Overall, 51 RCT and cohort studies were included (see statement 8), and meta-analysis showed that the ITT eradication rate was numerically but not statistically higher with the 14-day regimen versus the 10-day regimen (78.7% vs 75.6%; P
¼ .33). Other issues and discussion. The increasing prevalence of resistant strains of H pylori has led to increasing pro- portions of failure of traditional H pylori treatments. 18 –22
In a RCT of clarithromycin-containing triple therapies, the eradication success rate of resistant strains was 35% lower than that of sensitive strains. 46 The impact was greatest among regimens of the shortest duration; the eradication success rate of sensitive versus resistant strains was 42% higher in the 7-day group, 33% higher in the 10-day group, and 22% higher in the 14-day group. Therefore, indirect evidence supports increased ef ficacy with longer durations of therapy in resistant strains. The differences in ef ficacy
between therapies in the studies presented are likely underestimated, because many of the studies are older and the proportion of resistant strains has increased since they were conducted. Decisions. In light of the higher eradication rates with longer durations of therapy compared with regimens of shorter durations, the consensus group strongly recom- mended that all H pylori regimens (both first-line and rescue therapies) be administered for 14 days. This prolonged use of antibiotics for all patients is warranted because the increased failures with shorter regimens would result in resistant strains and less successful future treatments. It is best to achieve the maximum cure rates from the start. First-Line Therapy Statement 2. In patients with H pylori infection, we recommend that the choice of first-line therapy consider regional antibiotic resistance patterns and eradication rates. GRADE: Strong recommendation; qual- ity of evidence low. Vote: strongly agree, 100%. Key evidence ( Supplementary Table 2 ). Although no study directly examined the impact of tailoring first-line therapy
to local
antibiotic resistance patterns and
eradication rates, a meta-analysis of 5 RCTs (n ¼ 701) found that culture-guided triple therapy resulted in a signi ficantly
lower risk of treatment failure compared with empirical standard triple therapy (ITT relative risk, 0.84; 95% CI, 0.77 –0.90; P < .00001; eradication rate, 85.4% vs 71.5%). 47 Other issues and discussion. H pylori –resistant strains have become more prevalent over time. 19 Studies from the 1990s showed a low prevalence of clarithromycin resistance ranging from 1% to 8%, 18,19 which has risen to 16% to 24% in more recent studies from around the world. 48 –50 Primary resistance to metronidazole appears to have remained relatively stable over time at 20% to 40%. 4,18
–20,51 H pylori
resistance to amoxicillin generally remains low at approxi- mately 1% to 3%. 4,18,19,50,51 In addition, the prevalence of secondary resistance to clarithromycin and metronidazole is very high: up to 67% to 82%
for clarithromycin and 52%
to 77%
for metronidazole. 20,40,50 RCTs con
firm that the proportion of successful eradi- cation is signi ficantly lower in resistant compared with sensitive strains, especially with triple therapy 46,52 –55
and therapy of shorter duration. 46 The increasing prevalence of clarithromycin resistance is likely
the main
factor contributing to the increasing failure of non –culture-guided H pylori therapies over time, especially clarithromycin- based triple therapies. 21,22
A meta-analysis of 12 studies found that success of eradication with bismuth quadruple therapy remained stable at approximately 80% in studies from 2006 to 2011 compared with those from 2000 to 2005, but the ef ficacy of clarithromycin-based triple ther- apy decreased from approximately 80% in studies from 2000 to 2005 to only 62% in more recent studies (2006 –2011) (
Figure 1 ). 22 Bismuth quadruple therapy is unaffected by clari- thromycin resistance. 22,53 However, the eradication success Figure 1. Pooled successful eradication (ITT) in subgroup analysis according to year of study publication. Based on data from a meta-analysis by Venerito et al. 22 RDs are shown as proportions rather than percentages. 56 Fallone et al Gastroenterology Vol. 151, No. 1 rate with PBMT seems to be slightly lower in metronidazole- resistant versus metronidazole-sensitive strains (92% vs. 80%; P ¼ .06).
53,54 In one meta-analysis of triple and quadruple regimens, the successful eradication rate was found to decrease by 0.5% for every 1% increase in the prevalence of metronidazole resistance, suggesting that when metronidazole resistance is 30%, treatment ef ficacy decreases by 15%. 56 Similar effects of resistance have been seen with levo- floxacin triple therapy and bismuth quadruple levofloxacin- based therapy; among levo floxacin-susceptible strains, the eradication rate was 97% in both groups; however, among resistant strains, the proportion dropped to 71% with quadruple therapy and 38% with triple therapy. 52 If the susceptibility pro file of a patient’s infection or an estimate of it from the patient ’s population is known, the ef ficacy of a proposed regimen can be predicted. 57 –59
Un- fortunately, the resistance data required for these pre- dictions is not available in most areas. Pragmatically, a combination of local experience of treatment success with different regimens and the patient ’s pretreatment exposure to antibiotics can also aid in the identi fication of the regimen most likely to succeed. 60 Decisions. Evidence suggests that culture-guided therapy is associated with higher eradication success rates 47 and that both antibiotic-resistant H pylori 18,19,48
–50 and treatment failures 46,52
–55 are increasing. Therefore, it is important to encourage susceptibility testing to be made available locally and performed if the patient is undergoing endoscopy. However, it is not currently clinically practical or often possible to perform susceptibility testing in all patients. Therefore, the consensus group advised that local suscepti- bility patterns be used as a helpful surrogate when available. Studies to determine the local prevalence of primary antibi- otic resistance patterns are essential to assist clinicians in selecting the most appropriate first-line treatment for their practice. When available, the actual proportion of patients with successful eradication after receiving a speci fic treat- ment can be used to guide future treatment selection. As such, clinicians are encouraged to maintain records of the eradication rates they obtain locally with treatments. Statement 3. In patients with H pylori infection, we recommend traditional bismuth quadruple ther- apy (PBMT) for 14 days as one of the options for first-line therapy. GRADE: Strong recommendation; qual- ity of evidence moderate for ef ficacy and very low for dura- tion. Vote: strongly agree, 75%; agree, 25%. Key evidence ( Supplementary Table 3 ). Two systematic reviews of RCTs have evaluated the ef ficacy of first-line bismuth quadruple therapy (PBMT) compared with triple therapy (PAC). 21,22
The more recent meta-analysis of 12 RCTs found that the overall pooled eradication success rate was 77.6% with PBMT and 68.9% with PAC (risk difference [RD], 6%; 95% CI, À1% to 13%; note that the mathematical difference in the eradication success rate is not the same as the RD because the latter statistic is more appropriately weighted for the study effect size and precision of each estimate). 22 Although this analysis did not show a statisti- cally signi ficant difference, there was a trend toward greater eradication rates with PBMT. 22 The subgroup analysis of duration showed that 10-day quadruple therapy was more effective than 7-day triple therapy, but no differences were noted between the therapies when given for the same duration for either 7 days or 10 to 14 days. Speci fic analyses for 14-day PBMT were not performed. Only one study was found that directly compared 14-day durations in first-line therapy, which showed higher eradication success rates with bismuth quadruple therapy compared with triple therapy; however, this was signi ficant only in the per- protocol analysis and not the ITT analysis. 61 In addition, antimicrobial resistance has been shown to have less impact on the success of PBMT regimens (metronidazole-sensitive vs -resistant strains, 89.4% vs 80.6%) compared with PAC regimens (clarithromycin-sensitive vs -resistant strains, 90.2% vs 22.2%). 21 Other issues and discussion. As described in statements 1 and 8, a meta-analysis of observational data conducted for the meeting to evaluate the duration of bismuth quadruple Yüklə 0,75 Mb. Dostları ilə paylaş:
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