cde14617-e8b8-471f-95cd-09ee5b8b79d2.pptx

GErd

1. Managing GERD with Sodium alginate

2. Content 1. Current scenario of GERD Introduction Pathophysiology Epidemiology Diagnosis Management 2. Role of Sodium alginate in GERD management Introduction MOA- the alginate-antacid combination Place in therapy Clinical evidence 3. Efficacy in the pregnant women Global prevalence of heartburn in pregnancy Management guideline First-line agents used Benefits of alginate-antacid combination 4. Summary

3. Current scenario of GERD

4. Gastroesophageal reflux disease (GERD) This condition is defined by most of the international agencies as 1 - “A condition which develops when the reflux of gastric contents causes troublesome symptoms and/or complications” ………… Montreal consensus conference (GERD) is the most prevalent disease globally amongst the adult population. Herbella F, et al. World J Gastroenterol 2010;16(30):3745-3749.

5. Pathophysiology of GERD Role of TLESR Main mechanism involved in gastro- esophageal reflux (GER) both in healthy as well as GERD patients In GERD patients, TLESR along with acidic reflux events are increased. Straining and low LES pressure are other GER mechanisms seen in patients with severe esophagitis Role of delayed gastric emptying Delayed gastric emptying may provoke GER because the stomach is full for a longer time increasing the chances of GER Intra-gastric pressure when high over the resting LES pressure and increased gastric distension can trigger TLESR Delayed gastric emptying of the proximal stomach might increase GER, leading to postprandial and total acid exposure and to the number of reflux events per hour Impaired esophageal clearance Esophageal acid clearance has two steps: ( i ) involving primary (swallow-induced) and secondary peristalsis (distension-induced) and (ii) slow chemical clearance that neutralizes the acid by the bicarbonate present in the saliva Esophageal motility disorders are present in around 30% of the patients with GERD being ineffective esophageal motility Decreased salivation in GERD Deglutition of saliva promotes not only the primary peristalsis but also enhances the wash out by diluting and neutralizing acid reflux episodes mainly due to the presence of bicarbonate However, in GERD patients the saliva flow is decreased which could aggravate the symptoms Esophageal bile reflux Studies have shown that the total concentration of bile acids in esophageal aspirates is increased in GERD patients In addition to acid reflux, duodeno -gastro- esophageal reflux (DGER) is increased in severity across the GERD spectrum showing its possible relevance in the pathophysiology of GERD Farre R. Neurogastroenterol Motil 2013;25:783–799.

6. Global prevalence Fass , R., et al. Nat Rev Dis Primers 7, 55 (2021).

7. Indian prevalence Pune (25%) Trivandrum (22.2%) Ladakh (18.7%) Delhi (16.2%) Lucknow (11%) Vellore (8.2%) Chennai (28.5%) Pondicherry (5.02%) Rai, S, et al. Indian J Gastroenterol 40, 209–219 (2021).

8. Signs and symptoms GERD Atypical symptoms Typical symptoms Heartburn Acid regurgitation Dysphagia ENT Laryngitis/hoarseness Globus Sinusitis Otitis Postnasal drip Respiratory Asthma Chronic cough Pneumonia/bronchitis Cardiac Chest pain Sinus arrhythmia Lee AL, et al. Int J Chron Obstruct Pulmon Dis. 2015 Sep 14;10:1935-49.

9. Diagnosis Can be confirmed using the combination of symptom presentation objective testing with endoscopy ambulatory reflux monitoring response to antisecretory therapy In addition, GERD with delayed gastric emptying can be diagnosed using several invasive as well as non-invasive screening techniques. The presence of functional GI disorders should also be carefully assessed because they negatively impact on the treatment of reflux symptoms. Thus, patients with severe dyspeptic symptoms should be tested for gastroparesis. Diagnostic criteria Dyspepsia Heartburn Hoarse voice 24-h ambulatory esophageal pH monitoring showing abnormal acid reflux Mansour AE, et al. Egyptian Journal of Chest Diseases and Tuberculosis 2012;61:47–52. Katz PO et al. Am J Gastroenterol 2013;108:308–328.

10. Frequency scale for the symptoms of GERD (FSSG) score FSSG score ≥8 is considered to indicate probable GERD Kohata Y, et al. PLoS One. 2016 Mar 1;11(3):e0150554.

11. Diagnostic methods METHODS ADVANTAGES DISADVANTAGES PPI test Good in primary care for patients without alarm symptoms Positive in peptic ulcer disease and functional dyspepsia Specificity 24%–65% Endoscopy Enables diagnosis of esophagitis, Barrett esophagus, EoE and GERD complications Excellent specificity Poor sensitivity 70% patients have normal mucosa. High cost but most patients undergo testing as part of evaluation Biopsies Enables the diagnosis of microscopic esophagitis and rule out EoE Normal in functional heartburn 15% of normal individuals may have microscopic esophagitis Requires an experienced pathologist Catheter-based pH-metry Easy to perform Relatively non-invasive Enables detection of increased acid exposure and different locations along the esophagus and proximal stomach Accurate automatic analysis Unpleasant for patients, which might lead to behavior modification Day-to-day variability Sensitivity values below 71% in patients with normal findings from endoscopy Requires manometry Wireless pH-metry Enables prolonged monitoring (48–96 hrs.) Overcomes day-to-day variability and patients’ behavioral modification Better tolerated by patients Accurate automatic analysis Expensive Requires endoscopy Some patients have odynophagia requiring removal. Capsule may detach prematurely leading to inaccurate/suboptimal results Fass , R., et al. Nat Rev Dis Primers 7, 55 (2021).

12. Diagnostic methods pH–impedance Enables detection of nonacid reflux, aerophagia and supragastric belching Enables assessment of proximal reflux Best distinction between patients with GERD versus functional heartburn Unpleasant for patients Day-to-day variability Inaccurate automatic analysis (requires time-consuming manual editing) Requires manometry Unknown clinical relevance of non-acid reflux in the setting of aggressive acid suppression Salivary pepsin concentration Non-invasive Detected in high proportion of patients with GERD, and in high concentrations Moderate sensitivity and specificity Requires further validation Mucosal Impedance (MI) Decreased in esophagitis, NERD, Barrett esophagus and EoE Data acquired in short time period, eliminating the need for ambulatory tests Can measure MI values all along esophageal axis and radial distribution Normal in healthy individuals and functional heartburn Requires endoscopy but most patients will need endoscopy as part of work up Liquid and air esophagus may confound the results Cost unknown Undergoing validation studies Narrow-band imaging Distinguishes normal from NERD and reflux esophagitis Correlates with esophageal acid exposure Unclear effects for patient management and/or response to treatment Not readily available in all centers Fass , R., et al. Nat Rev Dis Primers 7, 55 (2021).

13. Treatment goals Relief of symptoms Prevention of symptom relapse Healing of erosive esophagitis Prevention of complications of esophagitis Jensen EN et al. Clin Gastroenterol Hepatol . 2016 Feb; 14(2): 175–182.e3

14. Lifestyle modifications Nutritional avoidance • Food that are acidic or otherwise irritative • Citrus fruits • Tomatoes • Onions • Carbonated beverages • Spicy foods • Foods that can cause gastric reflux • Fatty or fried foods • Coffee, tea, and caffeinated beverages • Chocolate • Mint Nutritional additions •Probiotics Smoking cessation Weight reduction for patients who are overweight (BMI 25.0 - 29.9) or obese (BMI > 30.0) or whose onset of symptoms was concurrent with weight gain within the normal range (BMI 18.5 - 24.9) Reduction in alcohol consumption Nighttime symptoms • Avoid eating within 3 hr before bedtime • Elevation of the head of the bed Postprandial symptoms • Consumption of smaller and more frequent meals • Avoid Lying down after a meal Abdominal obesity • Avoidance of tight garments Collebrusco , L, et al. Open Journal of Therapy and Rehabilitation, 5, 98-106.

15. Medical management Agents Advantages Disadvantages Antacids Rapid onset of action to provide symptomatic relief by acting within minutes to elevate intragastric pH above 3.5 Relatively short duration of action Action depends on contact neutralization of gastric acid Physiologic acid secretion and gastric emptying process limits the capacity of antacids to maintain an elevated pH H 2 RAs Effectively reduces heartburn symptoms and effectively controls gastric acid secretion They require systemic absorption for their action and hence may delay the onset of action Only reduces the volume of refluxate but doesn’t prevent reflux episode of weakly acidic gastric contents PPIs The profound and consistent acid suppressive effect of PPIs make them the mainstay of therapy for GERD Slow onset of action Long-term therapy could lead to serious adverse effects Few patients demonstrate a partial response (partial responders) or a complete absence of response (non-responders) to PPI therapy Alzubaidi M, Gabbard S. Cleve Clin J Med. 2015;82(10):685-92. Sandhu DS, Fass R. Gut Liver 2018; 12(1): 7-16. Mandel KG, et al. Aliment Pharmacol Ther . 2000 Jun;14(6):669-90.

16. Management algorithm of symptoms suspected because of GERD incompletely responsive to PPIs, previously empirically treated with PPI without objective workup Previously empirically treated with PPI without objective workup Optimize PPI Continue GERD treatment Discuss long-term GERD management options Diagnostic EGD (off PPI 2-4 weeks) Normal EGD Abnormal EGD Reflux monitoring (off PPI) Erosive esophagitis LA B/C/D Barrett's >3cm GERD confirmed No evidence of GERD look for other causes Other causes for symptoms identified treat mucosal disease Symptom relief Unsatisfactory symptom relief (-) (+) Katz PO et al. The American Journal of Gastroenterology 2022; 117(1):27-56. .

17. Management algorithm of symptoms suspected because of GERD incompletely responsive to PPIs in patients previously objectively defined as GERD. Previously objectively defined GERD Optimize PPI 2 to 4 week therapy Continue current treatment Discuss long-term GERD management options Perform impedance-pH monitoring on PPI BID Normal Abnormal Look for other causes Treat coexistent functional disease Consider surgical/endoscopic intervention Consider escalating medical therapy If primary symptoms regurgitation, consider MSA, TIF, or fundoplication in appropriate patient Symptom relief Unsatisfactory symptom relief Katz PO et al. The American Journal of Gastroenterology 2022; 117(1):27-56. .

18. Role of Sodium alginate in GERD management

19. Alginates in the treatment of GERD Alginates are natural polysaccharide polymers isolated from brown seaweed and often characterized as dietary fiber. Sodium alginates are sodium salt of alginic acid, which when coming in contact with the acidic environment of the stomach precipitates to form a low-density viscous gel. Additionally, alginates can form rafts both in vivo and in vitro , although, in vivo , alginates form a gel within seconds after exposure to gastric acid, whereas, in vitro , they begin to form a gel after a few minutes of administration. One of the most widely used alginate-based raft formulations contains sodium alginate, calcium carbonate, and sodium bicarbonate, and it develops a robust floating raft in the acidic environment of the stomach. These alginate-based formulations are often combined with other therapeutic classes such as antacids, H2RAs, and PPIs to increase the efficacy of raft formulations. Ali RR, et al. BMC Gastroenterology 2022;22:219.

20. Mechanism of action- Sodium alginate antacids Ali RR, et al. BMC Gastroenterology 2022;22:219.

21. Place in therapy Mild-moderate GERD Lifestyle measures (Avoid late evening meals, reduce alcohol intake and smoking, sleeping in a head elevated position) Alginates PPIs if symptoms persist Combination therapy with PPIs and alginates if partially responsive to PPIs Improvements in symptoms Alginates for intermittent/ PPIs when needed In the management of GERD First-line empirical treatment of mild-to-moderate GERD. Following the algorithm, PPIs are recommended for the treatment of patients with persistent symptoms of GERD. Alginates can be prescribed as an adjunctive therapy to PPIs in various circumstances such as during pregnancy or even in extra- esophageal GERD such as laryngopharyngitis or when patients are only partially responsive to PPIs Goh KL et al. JGH Open 2021; 5(8):855-863.

22. Place in therapy Nocturnal acid breakthrough (NAB) Despite the profound acid-suppressive effects of PPIs, they are unable to eliminate intragastric acidity, particularly during the night, due to their relatively shorter plasma half-life. PPIs dosed in the morning do not effectively suppress newly activated proton pumps. The lack of gravity-mediated drainage and salivary buffering due to infrequent swallows during night-time results in NAB and refractory GERD. Inclusion of an alginate-based formulation in the treatment regimen of patients receiving PPI therapy remarkably decreased reflux events at night, as observed in a multicentre , randomized, placebo-controlled study. Goh KL et al. JGH Open 2021; 5(8):855-863.

23. Evaluating the efficacy & safety of sodium alginate suspension compared to omeprazole in adult subjects with NERD ● 4-week, ● double-blind, ● parallel study NERD patients (N=195) Sodium alginate suspension 20 ml t.i.d (N=97) Omeprazole 20 mg once daily (N=98) Secondary efficacy endpoint: Percentage of patients achieving adequate heartburn or regurgitation relief at day 28 Primary efficacy endpoint: Percentage of patients achieving adequate heartburn or regurgitation relief Change from baseline of RDQ total score Patients’ overall satisfaction Chiu CT et al. Aliment Pharmacol Ther 2013;38:1054–1064.

24. Evaluating the efficacy & safety of sodium alginate suspension compared to omeprazole in adult subjects with NERD Non-inferiority of sodium alginate to omeprazole was demonstrated in the ITT population (Fig, p=0.175) Secondary efficacy endpoints were comparable between the two groups. The incidence of AEs was relatively low and there was no difference between the two groups (5.4% vs. 5.5% for sodium alginate vs. omeprazole). No severe adverse event was noted in the study. The study showed that sodium alginate was as effective as omeprazole for symptomatic relief in patients with non-erosive reflux disease Conclusion: Chiu CT et al. Aliment Pharmacol Ther 2013;38:1054–1064

25. Comparing efficacy of alginate - antacid liquid vs. antacid without alginate in controlling post-prandial acid reflux in GERD patients GERD patients (n=10) Alginate + antacid (DA) Antacid with equivalent neutralizing capacity Primary Outcome: Distal oesophageal acid exposure   Secondary Outcome : No. of reflux events Proximal extent of reflux Nadir pH of the refluxate Reflux mechanism & symptoms Table: Post-prandial acid exposure and reflux data Alginate + antacid antacid P value Distal acid exposure: Median % (IQR) 0.7 (0–28.2) 8.0 (0–7.2) 0.001 Number of acid reflux events: mean ± S.E.M. 8.7 ± 3.0 12.4 ± 2.7 0.06 Total reflux events: mean ± S.E.M. 22.5 ± 4.9 25.1 ± 7.3 0.54 Proximal reflux events: mean ± S.E.M. 8.7 ± 4.4 6.4 ± 3.7 0.29 Distal esophageal acid exposure was significantly less following the alginate-antacid combination compared to antacid alone Ruigh AD et al. Aliment Pharmacol Ther . 2014;40(5):531-7.

26. Comparing efficacy of alginate - antacid liquid vs. antacid without alginate in controlling post-prandial acid reflux in GERD patients Alginate Antacid After the first 30-min period the nadir pH was significantly less acidic in the alginate-antacid combination group and this effect persisted until 150 min post- prandially (p<0.05; paired t-test).   The decreased esophageal acid exposure observed during the alginate antacid treatment was related to the decreased acidity of the refluxate during these periods. ● Antacid ● Alginate-antacid The alginate-antacid liquid is more effective than an antacid without alginate in controlling post-prandial esophageal acid exposure. Conclusion: Ruigh AD et al. Aliment Pharmacol Ther . 2014;40(5):531-7.

27. Adding Alginate antacid to PPIs reduces breakthrough GERD symptoms 52 patients taking standard-dose of PPIs who had breakthrough symptoms were randomized to receive add-on therapy of Alginate antacid (n=26) Placebo (n=26) The study endpoint was a change in HRDQ score during treatment vs. placebo Mean HRDQ scores at baseline were similar in both treatment groups. Scores were significantly reduced from baseline to post-baseline in both treatment groups (P<.0001 for both), with the alginate-antacid group showing statistically significantly greater reductions compared with the placebo group ( P =.012). The percentage of responders patients was significantly greater for the alginate-antacid group than for the placebo group. (Figure) Adding alginate-antacid to PPI reduced breakthrough GERD. Response to intervention may vary according to whether symptoms are functional in origin. p = 0.005 Figure: Percentage of patients responding after 7 days of add-on alginate-antacid or placebo treatment. Responders were defined as those patients with a reduction of at least 3 days with HRDQ score (heartburn and regurgitation combined) >0.7 Coyle C et al. Aliment Pharmacol Ther . 2017;1–10.

28. Efficacy of alginate-antacid in post-supper suppression of the acid pocket and post-prandial reflux among obese participants. Randomized, controlled clinical trial 26 participants underwent 48 h wireless and probe-based pH- metry recording of the acid pocket and lower esophagus, respectively, and were randomized to a single post-supper dose of either Alginate antacid (n=13) Antacid (n=13) The median pH of the acid pocket was suppressed significantly with alginate-antacid vs antacid (all P < 0.04) Alginate antacid significantly reduced in % time pH < 4, symptom frequency and VAS on day 2 vs day 1 (all P < 0.05) Among obese individuals, the alginate-antacid liquid was superior to a non-alginate antacid in post-supper suppression of the acid pocket. Post-supper median pH values of the acid pocket on day 1 and day 2 were illustrated for (A) Alginate-antacid group and (B) the non-alginate antacid group. A B Conclusion: Deraman MA, et al. Aliment Pharmacol Ther . 2020 Jun;51(11):1014-1021.

29. Efficacy in the pregnant women

30. Heartburns in pregnancy Heartburn occurs in approximately 30% to 50% of pregnancies, reaching 80% in some populations. Approximately 17% of pregnant women experience heartburn and regurgitation simultaneously. The incidence of reflux symptoms across the 3 trimesters has recently been reported to be about 25% , with a steady increase in the severity of heartburn over the course of the pregnancy. Altuwaijri M. Medicine 2022;101:35(e30487)

31. Step-up approach towards management of GERD during pregnancy Pregnant women with typical GERD, heartburn and regurgitation Lifestyle and dietary modifications Antacids Sucralfate (1g,3 times daily) H2RA + Antacids PPI +Antacid Refer to gastroenterologists Alarm symptoms Symptom relief Symptom relief Symptom relief Symptom relief Symptom relief No response No response No response No response Altuwaijri M. Medicine 2022;101:35(e30487)

32. Drugs used in the heartburn and GERD in pregnancy First-line therapy – Antacids and mucosal protectant drugs Active ingredients Dose Notes Alginate/ antacid combination 10-20 ml po after meals Considered safe Aluminium hydroxide 5-10 ml as needed Considered safe, if patients has normal renal function. May cause constipation. Magnesium hydroxide 5 ml po 6 hourly Considered safe, not advised for chronic use. Aluminium /magnesium combinations 5-10 ml po after meals Considered safe, not advised for chronic use. Sucralfate 1 g po 6-hourly before meals. Considered safe, since minimal absorption. May interfere with the absorption of other medicines. Tondar LV, et al. S Afr Pharm J 2016;83(10):35-40

33. Safety and Efficacy of a Raft-Forming Alginate Reflux Suppressant for the Treatment of Heartburn during Pregnancy ● A multicentre, ● prospective, ● open-label, ● baseline-controlled study Alginate + antacid (liquid) 10-20 ml to a maximum of 80 ml/day, for 4 weeks Pregnant women with current symptoms of heartburn and/or reflux (N=144) Outcome: Resolution of symptoms Safety The efficacy of the study medication was rated by the investigator (primary endpoint) and the patient. Figure: frequency distribution for the ITT population of treatment of heartburn in pregnancy by alginate antacid liquid at study assessment. For the ITT population, the investigator deemed treatment to be a success (rated good or very good) in 91% of patients. Similarly, 90% of patients claimed treatment success with LG. Strugala V, et al. ISRN Obstet Gynecol. 2012;2012:481870. .

34. Safety and Efficacy of a Raft-Forming Alginate Reflux Suppressant for the Treatment of Heartburn during Pregnancy Figure: Severity of daytime and nocturnal heartburn experienced by pregnant women at baseline and after prn treatment with Liquid alginate-antacid for 4 weeks. (ITT). At baseline, 51% of women documented severe or very severe nocturnal heartburn and this was reduced to 32% after 4 weeks of treatment. A similar extent of improvement was seen with daytime heartburn with 32% experiencing severe or very severe symptoms at baseline to 22% after 4 weeks of treatment. The majority of patients documented relief within 10 minutes of taking the medication (67%) and most within 20 minutes (91%). Very few adverse events or serious adverse events were reported, and these were consistent with the normal population incidences. Serum sodium levels remained unchanged. Daytime Nocturnal This prospective open-label study shows that LG is both safe and highly efficacious in the treatment of heartburn and GER symptoms in pregnancy. Strugala V, et al. ISRN Obstet Gynecol. 2012;2012:481870.

35. Alginate-based reflux suppressant vs. magnesium-aluminum antacid gel for treatment of heartburn in pregnancy A randomized double-blind controlled trial 100 pregnant women at less than 36 weeks gestation with heartburn at least twice per week were randomized to alginate-based reflux suppressant (n=50) Magnesium- aluminum antacid gel (n=50) There was no difference between treatment and control groups in (Table) improvement of heartburn frequency and intensity 50% reduction of frequency and intensity of heartburn quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. The efficacy of the alginate-based reflux suppressant was comparable with the magnesium- aluminium antacid gel in the treatment of heartburn in pregnancy. Meteerattanapipat P, et al. Sci Rep. 2017 Mar 20;7:44830.

36. First-line recommendations regarding treatment in GERD Guidelines for GERD diagnosis and management Recommendations for treatment NICE 2014 Guidelines PPIs + alginate/ antacid as self-treatment WGO 2015 Guidelines Alginate and antacid therapy after dietary changes in patients with less than 2 episodes of reflux/ weekShort -term treatment with a oncedaily PPIs in patients with more frequent and severe episodes of heartburn Japanese Gastroenterological Society 2016 Guidelines PPIs for 8 weeks ± alginate and antacid therapy for symptoms relief American College of Gastroenterology 2013 Guidelines Dietary regime and life style changes 8-week course of PPIs Consensus of Gastroesophageal Reflux Disease in Taiwan 2015 Double dosage of PPIs Prokinetics and alginate therapy as additional drugs for patients with nonerosive esophagitis ACG 2022 guidelines When lifestyle modifications fail, antacids (aluminum-, calcium-, or magnesium-containing), alginates, and sucralfate are the first-line therapeutic agents for management of GERD during pregnancy Singeap AM et al. Romanian Journal of Medical Practice 2020;15(3-72). Katz PO et al. The American Journal of Gastroenterology 2022; 117(1):27-56. .

37. Summary: GERD Hyperacidity disorders are very common in the Indian population GERD prevalence in India ranges between 8 - 20% Treatment goals of Hyperacidity disorders include: ( i ) eliminating symptoms; (ii) healing GI mucosa; (iii) preventing relapse; (iv) managing or preventing complications Treatment options include - antacids, prokinetics & anti-secretory drugs Antacids – first-line drugs for symptomatic treatment of heartburn; however, does not prevent any reflux episodes

38. Summary: Alginate-antacid combination Unique, non-systemic, physical, rather than pharmacological, mode of action Prevention of gastric/postprandial reflux Topical protection of esophageal mucosa Faster onset of action & sustained duration of action up to 4 hours Improves reflux symptom index & Reflux finding score Proven efficacy & safety for Relief of post-prandial acid reflux & acid pocket Regurgitation-dominant GERD Combination with PPIs in patients with severe or PPI-unresponsive GERD Heartburn of pregnancy