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HIGHLIGHTS FROM GASTRO UPDATE EUROPE —
Prague, April 29-30, 2016 Review by Guido N. J. Tytgat
These highlights summarize a selection of the most important gastrointestinal discoveries of high clinical relevance presented at the recent Gastro update Europe in prague. the selected topics are indicative of what the faculty considered to be essential to be communicated to the astute busy gastroenterologist in clinical practice, who wants to stay abreast of clinically important developments. Whenever appropriate a personal note or comment is included to further raise the educational level of these highlights. gastro update europe, a truly intense educational enterprise, presented and discussed by top opinion leaders in gastroenterology and hepatology, is a unique teaching format of yearly rising scientific quality.
DISORDERS OF THE PROXIMAL DIGESTIVE TRACT
Peter Malfertheiner Lecture — Gastro Update Europe 2016 Review by Guido N. J. Tytgat
Prague
Prof. Peter Malfertheiner from Germany reviewed the most salient recent achievements in the upper intestinal tract.
Gastroesophageal reflux disease (GERD) continues to be one of the leading diagnoses in ambulatory care both in the USA and in Europe. Proton pump inhibitors (PPI) remain by far the first drug class for the initial therapy for symptomatic GERD, with a trend to increase the dose and the frequency of dosing. Even stronger inhibition of acid secretion is possible with a so-called potassium competitive acid blocker (p-cab) such as vonoprazan. Vonoprazan binds immediately and selectively to both active and resting pumps in the parietal cell; the slow dissociation from the pump explains the long-lasting acid inhibition. Moreover, the drug is not influenced by Cyp2C19 genotype. Vonoprazan shows impressive prolonged acid secretory inhibition, so far with few if any adverse effects (in contrast to previous p-cab attempts). It is to be expected that the spectacular Japanese results will be confirmed in the West and that the drug ultimately will become available in Europe. What the proper indications and mode of administration of this superior acid suppressant will be in clinical practice will require detailed study in view of the non-negligible consequences of prolonged profound acid suppression.
The use of PPIs, even very long-term, is generally considered as rather safe. Yet clinicians should remain vigilant for possible adverse effects (magnesium,.vitamin B12 etc).
Earlier studies pointed to a potentially enhanced risk of PPI-related community-acquired respiratory tract infection, but in a recent retrospective analysis of over 14 000 patients, there was no causal association
between esomeprazole versus placebo in the occurrence of community-acquired respiratory tract infection and pneumonia, which is certainly reassuring.
The PPI-clopidogrel controversy is fading away; indeed an updated meta-analysis was presented regarding the incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without PPIs. The myocardial infarction rate and the overall mortality were indistinguishable between the 2 groups, which again is reassuring.
More annoying is perhaps the relationship between PPI use and chronic kidney disease. In a study of the risk for atherosclerosis in 10.000 community participants, PPI use (which was more common in Caucasians, the obese and users of antihypertensives) was associated with chronic kidney disease, especially with twice-daily dosing. This finding contrasts with the detailed analysis of the long-term comparison of anti-reflux surgery versus prolonged PPI therapy where essentially no laboratory abnormalities were discovered between the 2 groups. One can only speculate why some participants in the atherosclerosis study were at risk for chronic kidney disease (pre-existent latent kidney disease, pharmacological interactions, confounders, etc). Anyhow, significant laboratory anomalies are not to be expected in reflux patients on PPI monotherapy.
Intriguing was a recent pharmacoepidemiologic study showing an increased risk of dementia in PPI users. Obviously a prospective randomised clinical trial is mandatory to establish a direct cause and effect relationship between PPI use and incident dementia in the elderly. Such a study will be extremely difficult to carry out, but of high clinical relevance in view of the rising
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dementia and PPI use in the elderly, often as a gastric mucosal protectant.
Several studies analysed the (major) effects of long-term PPI use on the colonic microbiota, and especially on the rising risk of lostridium difficile infection.
There is a significantly lower abundance in gut commensals, and a lower microbial diversity in PPI users, with a significant increase in oral and upper gastrointestinal tract commensals together with increased numbers of enterococ, streptococ, staphylococ and potentially pathogenic Escherichia coli. The observed changes may well result from the removal of the low pH gastric barrier (the so-called acid sterilizer).
Alginate / antacids such as Gaviscon double action, which particularly in the area of the acid pocket in the upper stomach are usually used as add-on therapy for insufficiently controlled or break-through symptoms during PPI therapy for reflux control. A recent large Chinese study showed that Gaviscon (2 tablets 4 x daily) as monotherapy could successfully relieve symptoms in mild to moderate GERD. It seems somewhat doubtful whether such results could be confirmed in the west and whether it would change the PPI dominance as first-line therapy for GERD.
Esophageal columnar metaplasia or Barrett esophagus, present in 1-2% of the general population and some 10% of GERD patients, continues to generate major attention largely because of the 30-40% increased risk of esophageal adenocarcinoma. Remember that the majority of Barrett patients will not progress to cancer and that only some 5% of adenocarcinoma patients have been identified as Barrett carriers before cancer diagnosis. Is it possible to reduce the cancer risk? The overall risk of neoplastic progression can be reduced by some 30% with aspirin / NSAID therapy, by some 48% with statin therapy and by some 67% with PPI. Based on these data, many clinicians prescribe prolonged PPI therapy also in asymptomatic carriers of columnar metaplasia.
Solid information upon which to base guidelines for endoscopic / bioptic surveillance (a hotly debated topic) do not exist. There is some consensus that surveillance of non-dysplastic Barrett, to decrease the risk of cancer death, should only be considered and targeted to high-risk groups: age > 50y, Caucasian, male gender, the obese, symptomatic. Also, the length of the Barrett segment is relevant. Of over 1.000 T1 adenocarcinomas, 56% occurred in long segment (>3cm) Barrett esophagus. The estimated annual cancer transition in long segment was 0.22%.
Few would now disagree that patients with high-grade dysplasia should be amenable to preferentially endoscopic therapy (resection with radiofrequency ablation).
A new American trial confirmed that patients with well established low-grade dysplasia should also be amenable to radiofrequency ablation. The annual rates of progression to high-grade dysplasia / early adenocarcinoma in that study were 6.6% in the surveillance arm compared to 0.77% in the radiofrequency arm.
Eosinophilic esophagitis remains the most intriguing novel esophageal disorder. The rising frequency, at least in the West, is genuine. A large Danish study showed that the increased incidence and prevalence outpaces the changes in endoscopy and biopsy practice. The rise of the disease remains largely enigmatic. Insufficient microbial / parasitic allergen exposure early in life may well contribute to a predominance of a Th2- type immune response pattern later in life. A simplified pathophysio-logic scheme is shown below.
In the traditional definition, eosinophilic esophagitis does not respond to acid suppression. Yet many patients with eosinophilic inflammation do seem to respond to PPI therapy, the so-called PPI-responsive esophageal eosinophilia, leading to the concept that PPI-REE was a separate entity. However, sufficient data have been presented to show that eosinophilic esophagitis and PPI-REE are almost indistinguishable also from a genetic point of view. It would appear that in the initial and mild phases of the disease, symptoms may respond to acid inhibition. PPIs have anti-inflammatory effects, but PPI-responsiveness may gradually disappear as the fibrotic remodelling ofthe disease progresses. Therefore the first therapeutic approach is PPI therapy. Should PPI therapy fail, topically active corticosteroids should be tried. In a large multicenter trial budesonide effervescebt tablets (twice 1 or 2 mg) or viscous suspension (twice 2 mg) were compared versus placebo, and both showed high histological remission rates.
Gastrointestinal bleeding remains a major life-threatening emergency, especially in the elderly and is of major current interest in view of the rising use of the novel non-vitamin K antagonist anticoagulants (noacs). In a large population-based cohort study, the hazard ratio of gastrointestinal bleeding with dabigatran was 2.29, with rivaroxaban 2.84, and with warfarin 2.87. In patients with atrial fibrillation, the risk of bleeding with dabigatran was less compared with warfarin, except for patients older than 75 years. This was confirmed
D'Alessandro A et al. Pathological mechanisms underlying therapy of EoE. World J Gastrointest Pathophysiol 2015;6:150
disorders of the proximal digestive tract |
in a meta-analysis of 23 studies comparing the risk of major gastrointestinal bleeding with non-vitamin K oral anticoagulants (noac) versus warfarin, showing that the bleeding risk in atrial fibrillation was not different between noacs and vitamin K antagonists. Fortunately the risk of dabigatran-related gastrointestinal bleeding can be reduced by gastroprotective agents as shown in a population-based study where the bleeding risk was 2.5% and was lowered to about half with gastroprotec-tive agents.
Detailed analysis of 10 randomized controlled trials regarding the use of PPI in the prevention of low-dose aspirin-associated upper gastrointestinal injury led to the following conclusions: PPIs decrease the risk of low-dose aspirin-associated upper gastrointestinal ulcers with 84% and of bleeding with 73%; for patients treated with dual anti-platelet therapy of low-dose aspirin and clopidogrel, PPIs prevent bleeding in 64% without increasing the risk of major adverse cardiovascular events. Moreover, PPIs were markedly superior to H2RAs in ulcer and bleeding prevention.
Protection was also shown in a nation-wide Scandinavian study which showed that the use of PPI was associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDS.
The overall age-standardised incidence of gastric cancer (8.8 per 100,000) and cardiac cancer (3.3 per 100,000) remains high with 5-year survival rates of less than 25%. H. pylori infection, especially with virulent strains, remains the leading cause through pre-neoplas- 1st line tic remodelling of the gastric mucosa. Ideally, H. pylori should be eradicated before the development of irreversible 2ndline pre-neoplastic lesions. The risk of cancer increases from gastritis, atrophic gastritis, intestinal metaplasia and dysplasia. The Olga system is increasingly used to monitor the changes in the gastric mucosa and to estimate the cancer risk. Arguments have been presented to take an additional biopsy of the angulus next to the standard antrum and corpus biopsies as this raises the detection of atrophy and intestinal metaplasia.
Since the quality of the endoscopic equipment is continuously improving, there is a trend to move away from non-targeted to targeted biopsies, directed to areas of minor abnormality, only detectable with high-definition endoscopes, with or without supplementary technologies (chromo, NBI etc). The demand for high-quality equipment such as high-definition is supported by a sobering British retrospective analysis, revealing that 8.3% of patients with gastric cancer had their malignancy missed at endoscopy carried out within the 3 previous years.
Screening of high-risk individuals and subjects in high-risk areas should ideally be conducted with the so-called gastropanel (measuring gastrin17, pepsinogen I, II, and ratio, and anti-H. pylori antibodies). As already stated, ideally H. pylori eradication should occur before gastric mucosal neoplastic remodelling, but even after endoscopic resection of gastric neoplasia, eradication
may be indicated to prevent metachronous lesions in approximately 60%, as shown in a recent meta-analysis.
There is a manifest revival of bismuth-based therapy for H. pylori eradication. The Maastricht V-2016 edition recommends for areas with high (>15%) clarithromycin resistance, bismuth quadruple or non-bismuth quadruple therapy (PPI, amoxicilline, clarithromycin, no-troimidazol).In areas of high dual claqrithromycin and metronidazole resistance, bismuth quadruple therapy is the recommended first line treatment. Apparently concomitant non-bismuth quadruple therapy is superior to sequential therapy.
Bismuth appears to act, not by direct interaction with urease or the urea channel in the inner bacterial membrane, but by impeding proton entry in the organism. The diminished fall in cytoplamic pH with acidification in the surrounding medium favors upregulation of the genes involved in growth, which allows augmented efficacy of the growth-dependent antimicrobials.
Amoxicillin can be used instead of tetracycline in firstline bismuth quadruple therapy as shown in a large important Chinese study comparing 14 d therapy with bismuth, lanzoprazole, amoxicillin, and metronidazole (cure rates 94 and 93% for metronidsazole sensitive vs resistant) and bismuth, lanzoprazole, amoxicillin, and clarithromycin (cure rates 99 and 77% for clarithromycin sensitive vs resistant).
Based on susceptibility testing only
Overall recommendations in case of eradication failure are summarised below:
Novel eradication schemes have been attempted in case of eradication failure with non-bismuth quadruple therapy such as:
• bismuth, esomeprazole, amoxicillin, levofloxacin (cure rate 74% in highly resistant patients: amoxicillin 8%; clarithromycin 56%; metrnidazole 74%; levofloxacin 36%)
• bismuth quadruple; omeprazole and pylora (=bismuth subcitrate, tetracycline, metronidazole) for 10 d (cure 83% in patients with resistance to metronidazole, clarithromycin and fluoroquinolone or with multiple prior treatment failures).
• adding rifabutin to pantoprazol and amoxicillin or rifabutin to pantoprazol, amoxicillin, and bismuth. More intensified acid suppression with the novel p-
cab vonoprazan was shown to improve the eradication rates from 76% [lanzoprazole, amoxicillin, clarithromycin] to 93% [vonoprazan, amoxicillin, clarithromycin] in over 600 gastroduodenal ulcer patients.
PPI-Clari-Amoxicillm/metronidazole
1st line
Bismuth Quadruple or
PPI-Levofloxacin/Amoxicillin
£
Malfertheiner et al., GUT 2012 May; 61 (5):646-64; GUT 2016 subm
