Issue III, Summer 2017

In search for a topic to discuss for this Summer edition, I was dealing with recurrence of a problem that has afflicted me for the last six years, namely acid reflux. I am sure many of you share this problem, since it is estimated to affect 18-24% of the US population. In addition to the US, Europeans, South Americans and those living in Middle Eastern countries also have a high incidence of acid reflux (9-26% of the population). In contrast, in East Asia only about 2-8% of adults have acid reflux while in Australia 12% of adults have acid reflux1. By the way Gastroesophageal Reflux Disease (GERD) is similar to acid reflux, but occurs more often and its symptoms are more severe2. The cause of this problem is an abnormal relaxation of the lower esophageal sphincter that allows stomach acid to enter into your esophagus. This can be due age or food/drink such as high fat, peppermint, alcohol and coffee.

It occurred to me that an over-the-counter medication for treatment of acid reflux is Gaviscon, containing alginic acid or sodium alginate! This product is, for some reason, more popular outside of the US. So, I decided to look into how Gaviscon works and whether there were any clinical trials that measured its effectiveness in treating acid reflux. First, Gaviscon in the US and sold by Glaxo Smith Kline has a different formulation than Gaviscon produced by RB/Mead Johnson in the UK. The latter product has sodium alginate as an active ingredient in both the tablets and liquid, while the former product has alginic acid as an inactive ingredient in the tablets and sodium alginate as an inactive ingredient in the liquid. Both these formulations are usually combined with an antacid such as magnesium carbonate. The sodium alginate forms a gel-raft-like structure that acts as a barrier to protect the esophageal tissue from exposure to the gastric acid contents3. The ability of alginic acid (tablets – US formulation) appears to be less effective than the sodium alginate. The alginate containing products not only produce rapid relieve from heart burn but have longer duration and are more effective than simple antacid products4.

Surprisingly, there have been a number of clinical trials comparing products containing alginate for treatment of acid reflux. In a double-blind study5 with 20 reflux patients randomized to Gaviscon Advance (sodium alginate) or antacid (Milk of Magnesia), the number of post-meal reflux (heartburn) was significantly less p<0.03 with Gaviscon Advance vs antacid. An add to this study was visualization, via MRI, of Gaviscon Advance and antacid in the stomach of 12 healthy volunteers 30 min after a meal. With Gaviscon, the MRI showed a “mass” that form at the esophageal gastric junction, while the antacid was in the distal stomach. This “mass” is likely the raft formed by sodium alginate that blocks the entry of stomach acid into the esophagus in patients with acid reflux.

Since in the relatively small study, Gaviscon was significantly better than antacid in decreasing reflux symptoms after a meal, how might it compare with the widely prescribed drug omeprazole, a proton pump inhibitor? This was addressed by Chiu, et al.6 in a randomized clinical trial. This was a four week double blind trial where 195 subjects have non-erosive reflux disease, i.e. no inflammation, erosions or ulcers in the esophagus were treated with a sodium alginate suspension of 20 ml three times/day or with 20 mg of omeprazole once per day. The primary endpoint measured was the percent of patients having adequate relief of their symptoms at day 28. The secondary endpoint was the percent of patient having relief from heartburn or regurgitation as determined from a change of baseline using a Reflux Disease Questionnaire total score at day 14 and 28. The results of this trial showed that sodium alginate (an active ingredient in Gaviscon was as effective as omeprazole in relieving the symptoms of non-erosive acid reflux disease. There was also a low incidence of minor adverse events that was no different between the two groups. Some caveats to this study are that the sodium alginate had to be taken three times per day vs just one 20 mg pill of omeprazole and the study only last 28 days.

There were a number of additional trials comparing Gaviscon Double Action (sodium alginate + antacid) vs a placeob7, Gaviscon Double action vs antacid8 and Gaviscon Advance vs placebo as an add-on therapy in patients having an inadequate response to omeprazole.9 The conclusion for all of these trials was that the Gaviscon product was more effective than placebo, or antacid alone for relief of acid reflux symptoms. Also, Gaviscon Advance as an add-on to an inadequate response to once daily omeprazole led to a significant reduction in symptoms. However, in this study patients were required to take 10 ml of Gaviscon Advance four time per day. This frequency of drug administration would likely lead to patient non-compliance. An interesting survey of the Danish population was conducted using an internet panel thought to be representative of adults in 201210. Participants were asked about their antacid/alginate and proton
pump inhibitor (PPI) use, their reason for using these products and their symptoms that led to use of the medication. There were 52% or 9,390 adults responding to the survey. Antacid/alginate was used by 23%, of which 16% only used antacid/alginate. PPI use was 13.6% with 6.2% being long-term users of this medication. The authors conclude
that there was a worrisome trend in older adult males for long-term use of PPIs, which may be unnecessary. Lastly, a systemic review and meta-analysis of alginate therapy for acid reflux was recent published (May 2017) by Leiman et al11. Their search strategy resulted in 14 clinical studies that met their inclusion criterion, having 2095 subjects. Their statistical analysis showed that alginate-based therapies increased the chances of symptom relief of gastro-esophageal reflux disease (GERD) when compared to placebo
or antacids. When the comparison was made of alginate containing medications vs protein pump inhibitors or histamine type 2 receptor antagonist, alginates appeared less effective, however, the pooled data from the meta-analysis was not statistically significant.

Although acid is the main component of the reflux fluid, it also contains proteases such as pepsin and trypsin. Using an in vitro system, Chater, et al12 found that alginates reduced pepsin activity by up to 54%, but had little effect on trypsin activity. Further, there was a strong positive correlation with amount mannuronate resides and the level of pepsin enzyme activity inhibition. A psper describing the effect of alginate formulations on raft performance was published in August of 201713. Alginate content of Gaviscon Double Action (GDA) performed the best in terms of impeding reflux into the esophagus. It appears that the structure of the alginate raft was the most important element and GDA formed rafts that had the correct level of porosity to allow for longer duration of acid neutralization.

So, what is the take home message from all of these studies? It is clear that the Gaviscon product sold by RB/Mead-Johnson (UK) is superior to antacid in relieving the symptoms of non-erosive acid reflux disease. It may also be competitive to the proton pump inhibitor omeprazole in relieving these symptoms, but additional clinical trials are needed to support this conclusion. This is important since recent studies link prolonged use of PPIs with kidney disease14 and increased risk of heart diesase15. One of the deficits in using Gaviscon is the number of times/day, i.e. 3-4 required to maintain symptom relief. It may be possible to extend the life of the sodium alginate raft by modifying the composition of alginate to slow its bio-degradation and optimize the level of porosity for acid neutralization. This is best accomplished by bio-engineering alginate-producing Pseudomonas bacteria to synthesize a suite of alginates that can be tested for rafts half-life and neutralization of the stomach acid.

References

1. El-Serag HB et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014 Jun;63(6):871-80.
2. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. American Journal of Gastroenterology. 2013 Mar; 108(3):308-28.
3. Kwiatek MA, Roman S, Fareeduddin A, Pandolfino JE, Kahrilas PJ. An alginateantacid formulation (Gaviscon Double Action Liquid) can eliminate or displace the postprandial ’acid pocket’ in symptomatic GERD patients. Alimentary Pharmacology and Therapeutics. 2011;34(1):59–66.
4. Mandel KG, Daggy BP, Brodie DA, Jacoby HI. Review article: alginate-raft formulations in the treatment of heartburn and acid reflux. Alimentary Pharmacology and Therapeutics. 2000;14(6):669–690.
5. Sweis R, Kaufman E, Anggiansah A, Wong T, Dettmar P, Fried M, Schwizer W, Avvari RK, Pal A, Fox M. Post-prandial reflux suppression by a raftforming alginate (Gaviscon Advance) compared to a simple antacid documented by magnetic resonance imaging and pH-impedance monitoring: mechanistic assessment in healthy volunteers and randomized, controlled, double-blind study in reflux patients. Aliment Pharmacol Ther. 2013 Jun;37(11):1093-102. doi: 10.1111/apt.12318. Epub 2013 Apr 18
6. Chiu CT, Hsu CM, Wang CC, Chang JJ, Sung CM, Lin CJ, Chen LW, Su MY, Chen TH. Randomized clinical trial: sodium alginate oral suspension is non-inferior to omeprazole in the treatment of patients with non-erosive gastroesophageal disease. Aliment Pharmacol Ther. 2013 Nov;38(9):1054-64. doi: 10.1111/apt.12482. Epub 2013 Sep 11.
7. Thomas E, Wade A, Crawford G, Jenner B, Levinson N, Wilkinson J. Randomised clinical trial: relief of upper gastrointestinal symptoms by an acid pockettargeting alginate-antacid (Gaviscon Double Action) – a double-blind, placebo-controlled, pilot study in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2014 Mar; 39(6):595-602. doi: 10.1111/apt.12640. Epub 2014 Jan 28.
8. De Ruigh A, Roman S, Chen J, Pandolfino JE, Kahrilas PJ. Gaviscon Double Action Liquid (antacid & alginate) is more effective than antacid in controlling post-prandial oesophageal acid exposure in GERD patients: a double-blind crossover study. Aliment Pharmacol Ther. 2014 Sep;40(5):531-7. doi: 10.1111/apt.12857. Epub 2014 Jul 10.
9. Reimer C, Lødrup AB, Smith G, Wilkinson J, Bytzer P. Randomised clinical trial: alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor. Aliment Pharmacol Ther. 2016 Apr;43(8):899-909. doi: 10.1111/apt.13567. Epub 2016 Feb 22.
10. Lødrup A, Reimer C, Bytzer P. Use of antacids, alginates and proton pump inhibitors: a survey of the general Danish population using an internet panel. Scand J Gastroenterol. 2014 Sep;49(9):1044-50. doi: 10.3109/00365521.2014.923504. Epub 2014 May 30.
11. Leiman DA, Riff BP, Morgan S, Metz DC, Falk GW, French B, Umscheid CA, Lewis JD. Alginate therapy is effective treatment for GERD symptoms: a systematic review and meta-analysis. Dis Esophagus. 2017 May 1;30(5):1-9. doi: 10.1093/dote/dow020.
12. Chater PI, Wilcox MD, Brownlee IA, Pearson JP. Alginate as a protease inhibitor in vitro and in a model gut system; selective inhibition of pepsin but not trypsin. Carbohydr Polym. 2015 Oct 20;131:142-51. doi: 10.1016/j.carbpol.2015.05.062. Epub 2015 Jun 4.
13. Dettmar PW, Gonzalez DG, Fisher J, Flint L, Rainforth D, Herrera AM, Potts M. A comparative study on the raft chemical properties of various alginate antacid raft forming products. Drug Dev Ind Pharm. 2017 Aug 24:1-32. doi: 10.1080/03639045.2017.1371737. [Epub ahead of print]
14. Wijarnpreecha K, Thongprayoon C, Chesdachai S, Panjawatanana P, Ungprasert P, Cheungpasitporn W. Associations of Proton-Pump Inhibitors and H2 Receptor Antagonists with Chronic Kidney Disease: A Meta-Analysis. Dig Dis Sci. 2017 Aug 23. doi: 10.1007/s10620-017-4725-5. [Epub ahead of print]
15. Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, Nead KT, Cooke JP, Leeper NJ. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS One, June 10, 2015 https://doi.org/10.1371/ journal.pone.0124653.

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