A Reappraisal of the Role of Alginate in GERD Management Edoardo V. Savarino MD, PhD Associate Professor of Gastroenterology University of Padova Italy Global Prevalence of GERD N=108 studies included in the meta-analysis Prevalence varied according to country (from 2.5% in China to 51.2% in Greece) In case of weekly heartburn/regurgitation was considered, pooled prevalence was 13.3% Risk factors: ≥50 years, smoking, NSAID/aspirin use and obesity Eusebi LH, et al. Gut 2018; 67:430–440 AllAll--Cause/CancerCause/Cancer--SpecificSpecific Mortality in GERD The HUNT study, a Norwegian population-based cohort study, was used to identify individuals with and without reflux in 1995– 997 and 2006–2008, with follow-up until 2014 All-cause mortality and cancer-specific mortality were assessed from the Norwegian Cause of Death Registry and Cancer Registry Ness-Jensen E, et al. Gut 2016;0:1–7. doi:10.1136/gutjnl-2016-312514 Clinical Manifestations of GERD Likely • Heartburn/Burning discomfort Due to Reflux • Regurgitation • Chest Pain (rule out heart disease!) • Dysphagia • Dental erosions • ENT/Cough/Asthma • Sleep disturbances • Dyspeptic symptoms: • EPS (epigastric pain and/or burning), • PDS (Bloating, Belching, Nausea, Vomiting, Early satiety, post-prandial fullness) Locke GR 3 rd et al. Gastroenterology 1997; 112(5):1448-56 Talley N. Aliment Pharmacol Ther 2004; 20 Suppl 5:27-37 Bardhan KD et al. Digestion 2004; 69(4):229-37 GERD: Therapy Proton pump inhibitors (PPIs) represent the mainstay of all acid-related diseases AGA Medical Position Statement on the Management of GERD. Gastroenterology 2008;135:1383–1391 Epidemiology of PPI Efficacy Boeckxstaens G, et al. Gut. 2014;63(7):1185-93. Partial Symptom--ResponseResponse to PPI in Patients with NERD or ERD • Post-hoc analysis of 4 RCTs (db, mc) – NERD (n=2,645) Armstrong et al, APT 2004 – Esophagitis (n=3,251) Labenz et al, APT 2005 NERD Esophagitis Symptoms ≥2 days 26.2% 19.3% Symptoms ≥3 days 19.9% 14.0% Partial symptom-response: ≥3 days with heartburn after 4 weeks and reduced heartburn frequency compared to baseline Bytzer P et al, Aliment Pharmacol Ther. 2012; 36(7):635-43 Impedance--pHpH Stratification of Patients with Typical Reflux Symptoms PUTATIVE MECHANISMS FOR PARTIAL /L ACK OF RESPONSE TO PPI T HERAPY : Poor Compliance and improper timing of PPI PPI administration Reduced PPI bioavailability, rapid metabolism PPI Residual acid reflux, NAB Eosinophilic esophagitis Weakly acidic reflux Duodeno-gastroesophageal/bile reflux Visceral hypersensitivity Delayed gastric emptying Psychological comorbidity PPI Functional Heartburn Concomitant functional gastric and/or bowel disorders PPI Savarino E, et al. Nat Rev Gastroenterol Hepatol. 2013;10(6):371-80 Moayyedi P and Talley NJ. Lancet 2006; 367:2086-100 Reported Adverse Events of PPIs Reimer C. et al. Best Pract Res Clin Gastroenterol 2013; 27:443–454 Savarino E, et al. Dig Liver Dis. 2016;48(8):851-9 Complications of PPI Therapy APPLICATION OF THE HILL CRITERIA TO SOME OF THE PROPOSED ASSOCIATIONS WITH LONG -TERM PPI T HERAPY Vaezi MF, et al .Gastroenterology 2017;153:35–48 Additional Treatments: What’s Now on the Shelf Lifestyle Modifications Proton Pump Inhibitors TLESR Reducers Promotility Drugs Alginates Sucralfate Visceral Pain Modulators Surgery Alternative Medicine (Hypnotherapy) Psychological Treatment Functional Gastrointestinal Disorders Treatment Origin of Alginate Alginates are products made ofof alginic acid, aachemicalchemical compound ofof natural origin that isis obtained from various algae ofof the genus Laminaria that grow inin the coastal areas ofof the Atlantic OceanOcean.. Laminaria hyperborea Demonstration of the Barrier Effect of Alginate in vitro Alginates Are Products Made by Alginic Acid→ Gel Barrier The addition of bicarbonate, interacting with the acid gastric juice, generates carbon dioxide which makes the gel floating → sort of "raft" viscose that floats on top of the gastric content by creating an obstacle to the gastro-oesophageal acid, food, pepsin and bile reflux Scarpignato C et al. Therapy Perspect 2011;16:1-37 Demonstration of the Barrier Effect of Alginate in vivo Zentilin P, et al. Aliment Pharmacol Ther 2005;21:29-34 Savarino E, et al. World J Gastroenterol. 2012;18(32):4371-8 Rohof WO et al, Clin Gastroenterol Hepatol. 2013 Dec;11(12):1585-91 Higher Efficacy of Sodium Alginate/Potassium Bicarbonate in Controlling Reflux Burden Rohof et al., Clin Gastroenterol Hepatol 2013 ;11: 1585-1591 An Evaluation of the Antireflux Properties of Sodium Alginate by Means of MIIMII--pHpH p<0,05 18,0 16,0 14,0 12,0 10,0 Basal After alginate intake 8,0 6,0 %%atat time time pHpH << (median(median 4 4 values) values) 4,0 p<0,05 p<0,05 2,0 0,0 Right lateral Supine Zentilin P et al, Aliment Pharmacol Ther. 2005;21(1):29-42005 An Alginate--AntacidAntacid Formulation Localizes to the Acid Pocket to Reduce AAcidcid Reflux Scintigraphic image of acid pocket (A) and 111mIn-labeled alginate-antacid (B) and the two recordings superimposed ©. It is demonstrated that the labeled alginate-antacid is present on top and co-localizes with the acid pocket in the proximal stomach. Rohof WO et al. Clin Gastroenterol Hepatol. 2013;11(12):1585-91 Superficial Esophageal Mucosal Afferent Nerves and Reflux Hypersensitivity in NERD A prospective study of 10 HVs. 13 NERD, 11 ERD, and 16 BE with proximal/distal biopsies Nerve fibers were searched with a labeled antibody against calcitonin gene-related peptide (CGRP), a marker of nociceptive sensory nerves. CGRP (green) and PGP (purple) co- localizing nerve fibers within the esophageal mucosal epithelium. The top panels demonstrate a superficial fiber in a patient with NERD. The lower panels demonstrate a deep fiber typical of BE, ERD, or HV. Woodland P, et al. Gastroenterology 2017;153:1230–1239 Savarino E, et al. Nat Rev Gastroenterol Hepatol. 2017 Nov;14(11):634-636 Topical Protection of Human Esophageal Mucosal Integrity Three distal esophageal biopsies from 22 patients with heartburn, and 22 control subjects. In mini-Ussing chambers, the change in TER of biopsies when exposed to neutral, weakly acidic, and acidic solutions The experiment was repeated in 10 patients after pretreatment of biopsies with sodium alginate, viscous control, or liquid control “protectant” solutions A fter Without pretreatment of biopsies pretreatment of biopsies Woodland P, et al. Am J Gastroenterol. 2013 Apr;108(4):535-43 Topical Protection of Human Esophageal Mucosal Integrity In vitro topical application of an alginate solution can protect mucosal biopsies against acid- induced changes in transepithelial electrical resistance (TER) Distal esophageal mucosal biopsies were (N=12) studied in Ussing chambers. Aim: to assess prolonged protection in a biopsy model In biopsies, 60 min after protection with alginate solution, the acidic exposure caused a 8.3 2.2% change in TER compared with 25.1 4.5% change after protection with the viscous control ( P 0.05). Labeled alginate could be seen coating the luminal surface in all cases. In vitro, alginate solutions can adhere to the esophageal mucosa for up to 1 h and exert a topical protectant effect. Woodland P, et al. Am J Physiol Gastrointest Liver Physiol. 2015;308(12):G975-80 Efficacy of Sodium AAlginatelginate Alone in Patients with GERD ––AARCT in Referral Centers Pouchain D et al., BMC Gastroenterol. 2012 Feb 23;12:18 Efficacy of Sodium AAlginatelginate Alone in Patients with NERD ––AARCT in Referral Centers Chiu et al., Aliment Pharmacol Ther 2013; 38: 1054-1064 Efficacy of Adding SSodiumodium AAlginatelginate to Omeprazole in Patients with NERD ––AARCT Omeprazole 20 od + Omeprazole 20 od + Na alginate/Na bicarbonate 30 ml qid Placebo 30 ml qid Manabe N et al., Diseases of the Esophagus 2012; 25:373–380 Efficacy of Adding SSodiumodium AAlginatelginate to Omeprazole in Patients with Regurgitation Coyle C et al, Aliment Pharmacol Ther. 2017 Jun;45(12):1524-1533 Relief of Dyspepsia Symptoms by An Acid PocketPocket--targetingtargeting Alginate--AntacidAntacid A double-blind, placebo-controlled, pilot study in GERD N= 110 with GERD received Gaviscon DA or placebo tablets for 7 consecutive days Thomas E et al., Aliment Pharmacol Ther. 2014;39(6):595-602 Effectiveness of Sodium Alginate + Sodium Bicarbonate in Controlling Symptoms of GERD in Pregnancy Coutesy of Carmelo Scarpignato The Role of An Alginate Suspension on Pepsin and Bile Acids Coutesy of Carmelo Scarpignato Strugala et al, J Pharma Pharmacol 2009; 61:1021-1028 The Value of a Liquid Alginate Suspension in the Management of laryngopharyngeal Reflux Reflux Symptom Index (RSI) Reflux Finding Score (RFS) 30 15 Base Base 25 20 10 15 * * 10 5 5 0 0 GavisconSodio Controlloplacebo GavisconSodio placeboControllo alginato/potassi alginato/potassi *P=00.008 vsbicarbonato controllo ** P=0.005 vs controllo bicarbonato McGlashan JA et al. Eur Arch Otorhinolaryngol. 2009 Feb;266(2):243-51 Alginate Therapy is Effective in GERD N=14 studies included in the meta-analysis (N=2095 subjects) Alginate-based therapies increased the odds of resolution of GERD symptoms when compared to placebo or antacids (OR: 4.42; 95% CI 2.45–7.97) , whereas they did not compare to PPIs or H2RAs (OR: 0.58; 95% CI 0.27–1.22). Leiman DA, et al. Dis Esophagus 2017;30(5):1-9 Are the Alginate--containingcontaining Formulations All Equal? Coutesy of Carmelo Scarpignato Another Useful and Interesting Indication…….. Deprescribing Proton Pump Inhibitors Alginate! OLDER ADULTS SHOULD BE PERIODICALLY EVALUATED FOR THE NEED