European Review for Medical and Pharmacological Sciences 2020; 24: 11845-11857 Efficacy and safety of alginate formulations in patients with gastroesophageal reflux disease: a systematic review and meta-analysis of randomized controlled trials C.-X. ZHAO1, J.-W. WANG2, M. GONG3 1Department of Gastroenterology, Zaozhuang Hospital of Traditional Chinese Medicine, Shandong Province, P.R. China 2Zaozhuang Hospital of Traditional Chinese Medicine, Shandong Province, P.R. China 3Department of Pharmacy, Zaozhuang Municipal Hospital, Shandong Province, P.R. China Abstract. – OBJECTIVE: Alginate formula- Key Words: tions are increasingly being used for treating Alginate, Proton pump inhibitors, Gastroesophage- gastroesophageal reflux disease (GERD). How- al reflux disease, Meta-analysis. ever, the benefits of alginate versus control or proton pump inhibitors (PPIs) are somewhat un- clear. We performed a systematic review and Introduction meta-analysis to summarize data from recent randomized controlled trials (RCTs) comparing Gastroesophageal reflux disease (GERD) is a the efficacy and safety of alginate-based for- common gastrointestinal (GI) ailment that affects mulation with PPIs or control for the treatment of GERD. around 18.1%-27.8% of population in North Amer- 1 MATERIALS AND METHODS: PubMed, Em- ica . Classical symptoms of the disease include dis- base, Scopus, BioMed Central, CENTRAL, and tressing heartburn and acid regurgitations, especial- Google scholar databases were searched from ly after meals. Patients may also experience other st th 1 January 2000 to 15 June 2020. Primary symptoms such as epigastric pain, bloating, dyspha- outcome was a reduction of symptoms while gia, laryngitis, and cough2,3. These symptoms have secondary outcomes were adverse events and treatment withdrawals. Ten articles with 11 RCTs adverse effects on the patients’ quality of life by were included. affecting sleep, routine functioning, social interac- RESULTS: Qualitative analysis of four trials tions as well as mental well-being4,5. Despite being indicated better outcomes with alginates vs. pla- a benign disease, a high prevalence of GERD can cebo/antacids. Our pooled analysis, however, have important socio-economic repercussions6. indicated no statistically significant difference Traditionally, GERD has been classified into between alginates and placebo/antacids for re- two major groups, based on diagnostic endosco- lief of heartburn, regurgitation, or dyspepsia. Similarly, no difference was seen between a py: erosive GERD and non-erosive reflux disease 2 combination of alginate and PPI vs. PPI alone for (NERD) . Proton pump inhibitors (PPIs) are usu- reduction of heartburn, regurgitation, or dyspep- ally the first-line of therapy for erosive GERD. sia symptoms. The risk of adverse events and However, there have been concerns over the re- treatment withdrawal did not differ between the sponse to PPIs in NERD patients7. Acid pocket, a two groups in either comparison. Descriptive reservoir of unbuffered highly acidic gastric se- analysis of studies comparing alginate vs. PPI indicated no difference between the two drugs. cretions located in the proximal stomach, can en- CONCLUSIONS: Our study indicates that algi- ter the esophagus after the opening of the esoph- nates may have greater efficacy than placebo/ agogastric junction8 . Targeting this acid pocket antacids in improving outcomes of GERD. How- therefore can lead to the effective management of ever, current evidence on the efficacy of algi- the condition. Alginate-based formulations react nate-based formulations vs. PPI or the role of with the gastric acid and form a gel “raft” that added alginates with PPI is questionable, and floats over the gastric contents. The formation of suggests no difference between the two drugs. The risk of adverse events with alginates is no this raft over the acid pocket acts as a physical 9 greater than that of placebo or PPIs. barrier for the reflux of gastric contents . Corresponding Author: Miao Gong, MD; e-mail: [email protected] 11845 C.-X. Zhao, J.-W. Wang, M. Gong To date, several trials have investigated the effi- discussion. After screening, the bibliography of cacy of alginate-based formulations and compared included studies and review articles on the subject them with PPIs with mixed results10-13. In 2017, Lei- were hand searched for any missed references. man et al14 assessed the efficacy of alginate-based formulations in a systematic review and meta-anal- Inclusion Criteria ysis, and reported that alginate may be effective for Only randomized controlled trials (RCTs) were the treatment of GERD. However, in that review, eligible to be included in the review. We further de- only odds ratios (OR) of treatment effectiveness fined the inclusion criteria based on the PICO (Popu- were pooled from the included studies, with var- lation, Intervention, Comparison, Outcome) frame- ied definitions of treatment response. There was work as follows: Population: studies conducted on no analysis of patient-reported tools such as Heart- adult patients (>18 years) with GERD; Intervention: burn Reflux Dyspepsia Questionnaire (HRDQ) any kind of alginate formulations with or without and Reflux Disease Questionnaire (RDQ), as well other drugs like PPI; Comparison: placebo, antac- as no analysis of adverse events. Furthermore, the ids, or PPI; Outcomes: reduction of symptoms and majority of the studies in their review were pub- adverse events. Only English language studies were lished before 2000. In light of these limitations and included. Studies on erosive esophagitis, non-RCTs, recent publications of additional RCTs10,12 , there retrospective studies, single-arm studies, and stud- is a need for an updated review of current data to ies not reporting relevant data were also excluded. generate high-quality evidence. The main goal of his systematic review and meta-analysis is to sum- Data Extraction marise data from recent studies comparing the effi- After mutual agreement on the inclusion of cacy and safety of alginate-based formulation with studies, data were extracted by two reviewers in- PPIs or control for the treatment of GERD. dependently. Data regarding authors, publication year, study type, diagnosis, sample size, demo- graphic details, intervention and control drugs, Materials and Methods study outcomes, and treatment period were ex- tracted. The primary outcome of the interest of Search Strategy our analysis was the reduction in GERD symp- The review was designed and implemented toms. The secondary outcome was the risk of ad- based on the guidelines of the PRISMA statement verse events and adverse event-related treatment (Preferred Reporting Items for Systematic Reviews withdrawal. Any other outcomes reported by the and Meta-analyses)15 and the Cochrane Handbook included studies were reported descriptively. for Systematic Reviews of Intervention16, except for protocol registration. The electronic databases of Risk of Bias Assessment PubMed, Embase, Scopus, BioMed Central, CEN- The Cochrane Collaboration risk assessment TRAL, and Google scholar were searched by two tool was used for assessing the quality of includ- reviewers independently. Search limits were from ed RCTs16. Two reviewers independently assessed 1st January 2000 to 15th June 2020. For the search, each study. The following seven domains were we used a combination of MeSH terms and free-text used for quality assessment: random sequence keywords. Two sets of key-words (one for the drug generation, allocation concealment, blinding of and other for the disease) were searched in different participants and personnel, blinding of outcome combinations. The first set of key-words were: “al- assessment, incomplete outcome data, and se- ginate”, “sodium alginate”, “alginic acid”, “alginic lective reporting. The study was judged to have acid-polyethyl methacrylate”, “Gaviscon”, and “al- “high”, “unclear”, or “low” risk of bias for each gicon”. For the disease, the following terms were domain. Any disagreements were resolved by dis- used: “gastro-oesophageal reflux”, “gastroesopha- cussion. geal reflux”, “non-erosive reflux disease”, “GERD”, “NERD” AND “endoscopy negative reflux dis- Statistical Analysis ease”. After removing the duplicates, screening Studies were grouped studies based on the of titles and abstracts was performed as a first similarity of intervention and controls into algi- step, followed by the review of the full text of the nate vs. placebo/antacids; alginate + PPI vs. PPI, potential studies. Both reviewers assessed indi- and alginate vs. PPI groups. Meta-analysis was vidual articles based on the inclusion and exclu- conducted if at least three trials reported similar sion criteria. Any disagreements were resolved by outcomes, otherwise, a descriptive analysis was 11846 Efficacy and safety of alginate formulations in patients with gastroesophageal reflux disease conducted. “Review Manager” (RevMan, version Heterogeneity was assessed using the I2 statistic. 5.3; Nordic Cochrane Centre [Cochrane Collab- I2 values of 25-50% represented low, values of oration], Copenhagen, Denmark; 2014) was used 50-75% medium, and more than 75% represented for the meta-analysis. Outcome data was en- substantial heterogeneity. Due to the inclusion of tered into the meta-analysis software and cross- fewer than 10 studies per meta-analysis, funnel checked for correctness. Since GERD symptoms plots were not used to assess publication bias. were recorded by patient-reported questionnaires and as continuous outcomes,