Maastricht iv/ Florence Consensus Report
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1a A The use of high-dose (twice a day) PPI increases the efficacy of triple therapy 1b A Extending the duration of PPI-clarithromycin-containing triple treatment from 7 to 10e14 days improves the eradication success by approximately 5% and may be considered 1a A
1a A Certain probiotics and prebiotics show promising results as an adjuvant treatment in reducing side effects 5 D PPI-clarithromycin-containing treatments do not need to be adapted to patient factors except for dosing 5 D After failure of a PPI-clarithromycin containing therapy, either a bismuth containing quadruple therapy of Levofloxacin containing triple therapy are recommended. 1a A Rising rates of Levofloxacin resistance should be taken into account 2b B After failure of second-line treatment, treatment should be guided by antimicrobial susceptibility testing whenever possible 4 A The urea breath test or a laboratory based validated monoclonal stool test are both recommended as non-invasive tests for determining the success of eradication treatment. There is no role for serology 1a A
651 Guidelines Statement 9: The use of high-dose (twice a day) PPI increases the efficacy of triple therapy.
Evidence level: 1b Grade of recommendation: A There is indirect and direct evidence that high-dose PPI can improve the cure rates of H pylori treatment. Indirect evidence comes from old multiple studies showing that high-dose PPI was necessary for the ef ficacy of dual thera- pies and the meta-analysis showing that twice-a-day PPI was better than a single daily dose in triple therapy. 120
In addition, cure rates of standard triple therapy depend on the availability of PPI, which itself depends on the CYP2C19 and MDR poly- morphisms. A meta-analysis showed that extensive PPI metab- olisers had lower eradication rates, while the difference was only seen with omeprazole. 121 A lower eradication rate was also obtained when the MDR T/T genotype was present compared with the T/C and C/C genotypes. 122 Direct evidence comes from a meta-analysis showing that high-dose PPIs increase cure rates by around 6e10% in comparison with standard doses. 123 A subanalysis of these data showed that the maximal effect was seen in the studies comparing high doses of the more potent second-generation PPIsdnamely, 40 mg of esomeprazole twice a day, with a stan- dard dose of a first-line PPI also twice a day. 123
The rationale for this
finding is that the difference in the degree of gastric secre- tion between arms is more important when using double doses of more potent PPIs. According to the data of this last suba- nalysis, increasing the dose of PPI from, for example, 20 mg omeprazole twice daily to 40 mg of esomeprazole or rabeprazole twice daily may increase cure rates by 8e12%. < Increase the length of treatment. Statement 10: Extending the duration of PPI-clarithromycin-containing triple therapies from 7 to 10e14 days improves the eradication success by about 5% and may be considered. Evidence level: 1a Grade of recommendation: A Four meta-analyses have been carried out and yielded very similar results, that is, a 10-day treatment improves the eradica- tion rate by 4% and a 14-day treatment improves the eradication rate by 5-6%, in comparison to a 7-day treatment. 124e127
There was no difference regarding the rate of side effects. While the difference in ef ficacy is statistically significant, they may be considered relevant or not, according to other factors such as cost.
use metronidazole instead of amoxicillin as the second antibiotic. Statement 11: PPI-clarithromycin-metronidazole (PCM) and PPI-clarithromycin- amoxicillin (PCA) regimens are equivalent. Evidence level: 1a Grade of recommendation: A The meta-analysis of Gisbert et al 128 was updated for the Maastricht IV conference. A subanalysis was performed on the trials using the same high dose of clarithromycin (500 mg) in both arms, showing an eradication of 71% for PCM and 65% for PCA, but the difference did not reach statistical signi ficance (OR
¼0.82 (95% CI 0.58 to 1.16)). When the PCM and PCA regimens were compared in patients with clarithromycin-resistant strains, a statistically signi ficant
difference was seen (p <0.001), but this difference may be due to the heterogeneity of the studies. The few comparative studies analysed could not ascertain whether the differences observed were truly due to an effect of treatment or to confounders. < Adding an adjuvant treatment. Statement 12: Certain probiotics and prebiotics show promising results as an adjuvant treatment in reducing side effects. Evidence level: 5 Grade of recommendation: D Lactoferrin has been used to improve H pylori treatment. Two meta-analyses obtained the same results and showed that lactoferrin increases the ef
containing triple therapies. 129 130
However, the poor quality of many trials and the limited number of centres involved should be emphasised and preclude giving a positive recommendation. Meta-analyses on the studies where Lactobacilli were used are heterogeneous as they mix different species and strains. Addi- tional work needs to be performed to determine the strain, dose and administration to be used. 131 131a
A meta-analysis on the use of Saccharomyces boulardii as adjuvant to triple therapy showed promising results (OR ¼0.46 (95% CI 0.3 to 0.7)). 132 All these treatments are most likely to lead to a decrease of adverse events, especially diarrhoea and indirectly may help to improve the eradication rate. More studies need to be performed. < Other factors. Statement 13: PPI-clarithromycin-containing treatments do not need to be adapted to patient factors except for dosing. Evidence level: 5 Grade of recommendation: D Besides the CYP2C19 and MDR1 polymorphisms, which affect the availability of the PPI administered, and the inter- leukin (IL)-1 b polymorphisms, which affect the intragastric acidity present in the stomach in the case of H pylori infection, other factors have been considered: type of disease, BMI and smoking status. Treating patients with peptic ulcer disease shows a consis- tently better outcome than treating patients with FD. Several studies have shown an association between clarithromycin resistance and FD status of the patients 133
without pinpointing the causes. In patients with high BMI, especially obese people, the distribution volume of the drugs being higher, it is most likely that the concentration at the gastric mucosal level will be lower and the risk of failure higher. 134 In contrast, Asian patients who usually have a lower BMI will have a better outcome. Smoking is also a risk factor for failure. The summary OR for eradication failure among smokers versus non-smokers was 1.95 (95% CI 1.55 to 2.45) corresponding to a mean difference of 8.4% in eradication rate in a meta-analysis. 135
The reason may be a reduction of antibiotic delivery due to a decreased gastric blood flow, a decrease in intragastric pH in cases of smoking, and nicotine could potentiate the vacuolating toxin activity of H pylori in gastric cells. It may also be a marker of poor compliance. Second-line treatment. Statement 14: (1) After failure of a PPI-clarithromycin-containing treatment, either a bismuth-containing quadruple therapy or levofloxacin-containing triple therapy is recommended. Evidence level: 1a Grade of recommendation: A (2) Rising rates of levofloxacin resistance should be taken into account. Evidence level: 2b Grade of recommendation: B 652 Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 Guidelines The rationale is to abandon clarithromycin in an empirical second-line-treatment because there is a likelihood that selection of a clarithromycin-resistant strain occurred. Three pragmatic studies have evaluated the Maastricht 3 guidelinesdthat is, the sequence of triple therapy followed by quadruple therapy, in routine clinical practice. 136e138 The three studies show that a high rate of eradication success can be achieved with the Maastricht 3 approach. Studies from Asia suggest that quadruple therapy is also effective as a second-line treatment in Asia.
139 A recent meta-analysis of quadruple therapy showed that metronidazole resistance had limited effect on the outcome when adequate dosages and durations are used. This meta- analysis also showed that compliance with quadruple therapy is high.
116 140 Recent studies of quadruple therapy using a single capsule preparation have shown good ef ficacy
114e116 This
treatment meets the proposed criteria for a second-line treat- ment
136 : it does not contain the key antibiotic of the original regimen (clarithromycin), 137
the treatment is not affected by clarithromycin resistance, 139 metronidazole resistance in vitro does not affect the outcome of quadruple therapy signi fi- cantly, 140 compliance with the regimen is high 115 and the
regimen is effective in most parts of the world. Use of 10-day PPI-levo floxacin-amoxicillin is the other alter- native second-line treatment based on the results obtained in recent years. 141 142
However, the rapid acquisition of resistance may jeopardise its future ef ficacy. It is strongly advised that levo
floxacin should not be used in a patient with chronic infectious bronchopneumopathy who may have received fluo- roquinolones. Whenever possible it is recommended to test levo floxacin susceptibility before to prescribe it. Third-line treatment. Statement 15: After failure of second-line treatment, treatment should be guided by antimicrobial susceptibility testing whenever possible. Evidence level: 4 Grade of recommendation: A After two treatment failures, it appears recommendable to empirically prescribe antibiotics not previously used but, whenever possible, to obtain gastric biopsy specimens to culture H pylori and perform susceptibility testing. 143 144
It will enable the best choice to be made among the various antibiotics that can be used and to which H pylori may develop resistance. Besides clarithromycin and levo floxacin already mentioned, rifabutin is another candidate that may be used. 138 145 146 Regions or populations of high clarithromycin resistance First-line treatment. Statement 16: In areas of high clarithromycin resistance, bismuth-containing quadruple therapies are recommended for first-line empirical treatment. If this regimen is not available, sequential treatment or a non-bismuth quadruple therapy is recommended. Evidence level: 1a Grade of recommendation: A In regions of high clarithromycin resistance, bismuth-containing quadruple therapies are the first choice. It appears mandatory to avoid clarithromycin use in the standard regimen under such circumstances if this antibiotic cannot be tested. The treatment recommended contains bismuth salts for which no resistance has been described, tetracycline for which resistance is seldom found in Europe and metronidazole for which in vitro resistance is common but can be overcome by increasing the length of treatment. Several studies have shown good results with such regimens. Furthermore, despite the number of pills, the compliance was satisfactory and the bismuth-containing regimens do not lead to more adverse events than the standard clarithromycin- containing triple therapy. 147
However, bismuth drugs may not be available in some areas. It is then necessary to prescribe sequential treatment. While not ideal because it contains clarithromycin, it has been shown that clarithromycin resistance could be overcome in a number of cases. Indeed, the success rate with clarithromycin-resistant strains was 75%. 110 Non-bismuth quadruple therapy (the so called ‘concomitant’ treatment) is also an option. Second line therapy. Statement 17: (1) In areas of high clarithromycin resistance after failure of bismuth- containing quadruple therapy, levofloxacin containing triple therapy is recommended. Evidence level: 5 Grade of recommendation: D (2) Rising rates of levofloxacin resistance should be taken into account. Evidence level: 2b Grade of recommendation: B After failure of the second-line treatment (with bismuth- containing quadruple regimen), it is recommended to use the PPI-containing levo floxacin regimen. 141 142 However, given the rise in resistance to this antibiotic, the prevalence must be taken into account. Third-line therapy. Statement 18: After failure of second-line therapy, treatment should be guided by antimicrobial susceptibility testing, whenever possible. Evidence level: 4 Grade of recommendation: A The recommendation is the same as in areas of low clari- thromycin resistance. Treatment options in patients with penicillin allergy Statement 19: In patients with penicillin allergy, in areas of low clarithromycin resistance, for a first-line treatment, a PPI-clarithromycin-metronidazole combination may be prescribed and in areas of high clarithromycin resistance, the bismuth- containing quadruple therapy should be preferred. As a rescue regimen, in areas of low fluoroquinolone resistance, a levofloxacin- containing regimen (together with a PPI and clarithromycin) represents a second-line alternative in the presence of penicillin allergy. Evidence level: 2c Grade of recommendation: B In this relatively common subgroup of patients, a triple therapy including a PPI, clarithromycin and metronidazole represents one of the most frequently recommended regimens in areas of low clarithromycin resistance. 148
A PPI, tetracycline, metroni- dazole regiment 149 is a better alternative in areas with high clarithromycin resistance, as well as the bismuth-containing quadruple therapy. As a rescue treatment, levo floxacin is a good alternative 150 but its
ef ficacy might be jeopardised by high resistance rates in some areas. Follow-up after H. pylori treatment Statement 20: The UBT or a laboratory-based validated monoclonal stool test are both recommended as non-invasive tests for determining the success of eradication treatment. There is no role for serology. Evidence level: 1a Grade of recommendation: A Statement 21: The time for testing the success of H pylori eradication after the end of treatment should be at least 4 weeks. Evidence level: 2b Grade of recommendation: B In special cases where a gastric ulcer or gastric MALT lymphoma has been diagnosed, follow-up is necessary with upper digestive endoscopy and then biopsy-based tests can be performed for Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 653
Guidelines con firmation of H pylori eradication. In other situations, a non-invasive test is used. There is now overwhelming evidence that UBT is an excellent test for follow-up after H pylori eradication. 76 The discussion concerns the timing after the end of eradication treatment. The relapse rate seen in the 6 months or the year after H pylori eradi- cation is mainly related to recurrence of the same infection rather than a true reinfection. The proposed period of 4 weeks has there- fore been questioned and proposals have been made to extend it to 6 or 8 weeks. However, recent data do not support this proposal. Statement 22: (1) In uncomplicated duodenal ulcer (DU), prolonging acid inhibition with PPI is not recommended after H pylori treatment. Level: 1a Grade of recommendation: A (2) In gastric ulcers (GUs) and complicated DUs, prolonging PPI is recommended. Level: 1b Grade of recommendation: A H pylori is the key factor in peptic ulcer development and eradication is recommended for both DUs and GUs, as it has been shown that H pylori eradication effectively achieves ulcer healing rates of >90%.
151 152 Moreover, prolonged acid inhibi- tion with PPI is not required after successful H pylori eradication in uncomplicated DU. 153 154 On the other hand, data on the need to prolong PPI for GU healing after successful eradication are controversial. 154e156
GU requires longer acid inhibition for healing than DU and endoscopic follow-up is needed to ensure complete GU healing. H pylori eradication should be confirmed in GU. However, prolonged PPI is also bene ficial for improving healing when eradication has failed. Similarly, studies on complicated DU and GU also recommend prolonged PPI treatment after eradica- tion.
157 158 Therefore, PPI treatment should be continued after eradication treatment in GU until complete healing is achieved and in complicated DU until H pylori eradication is confirmed. Statement 23: H pylori eradication treatment should be started at reintroduction of oral feeding in cases of bleeding ulcer. Evidence level: 1b Grade of recommendation: A Bleeding is a common and severe complication of peptic ulcer disease. It is well established that H pylori eradication can effectively prevent bleeding recurrence in infected patients. 3 159
As the effect of PPI in preventing recurrent bleeding seems to be greater in H pylori-positive patients, the possibility of leaving H pylori infection untreated until the ulcer is completely healed has been hypothesised. 160 However, it has been shown that H pylori infection/eradication has no effect on early rebleeding rate in patients with peptic ulcer bleeding after endoscopic haemo- stasis. 161 162
On the other hand, delaying treatment to after discharge leads to reduced compliance or loss to follow-up without receiving treatment. 163
Based on a decision analytic model, it has been recently proposed that empirical treatment of H pylori infection in patients with bleeding peptic ulcer, imme- diately after feeding is restarted, is the most cost-effective strategy for preventing recurrent haemorrhage. 164
The most in fluential variable in this analysis was the prevalence of H pylori infection in patients with peptic ulcer bleeding. In patients with peptic ulcer bleeding the prevalence of H pylori infection appears to be lower than in patients with uncomplicated peptic ulcer disease, varying, in recent European studies, from 43% to 56%, possibly explained by NSAID use. 165
In areas of low H pylori infection, instead of an empirical treatment, a test-and-treat strategy should be considered. In the setting of peptic ulcer bleeding, histology and rapid urease test maintain a high speci ficity, but are affected by a low sensitivity, possibly leading to undertreatment. 166 167 Serology seems not to be in fluenced by upper gastrointestinal (GI) bleeding and has been recommended in this setting by previous Maastricht consensus reports. The accuracy of the UBT remains very high in these patients, despite PPI treatment. 168
Current consensus in upper
gastrointestinal bleeding
recommends performing a delayed test, 4d8 weeks after the bleeding episode. 169
Table 3 Treatment of Helicobacter pylori-positive peptic ulcer diseases Statement Level of
evidence Grade of
recommendation In uncomplicated DU, prolonging acid inhibition with PPI is not recommended after Helicobacter pylori treatment 1a A
is recommended 1b A H pylori eradication treatment should be started at reintroduction of oral feeding in cases of bleeding ulcer 1b A DU, duodenal ulcer; GU, gastric ulcer; PPI, proton pump inhibitor. Figure 1
Treatment regimen should be selected according to areas of low and high clarithromycin resistance (Clari-R). Low prevalence of Clari- R if
treatment, second-line treatment is selected without resistance testing, whereas with further failure, third-line treatment should be chosen based on Helicobacter pylori cultures and antibiotic susceptibility testing. PPI, proton pump inhibitor. 654
Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084 Guidelines |