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, they were summa- rized using the mean difference (MD) with 95% Results confidence intervals (CI). Where different ques- tionnaires or scales were used, the Standardized PRISMA flow-chart of the study is present- Mean Difference (SMD) was used. We used ed in Figure 1. After full text-review of the se- “change from baseline scores” in the meta-anal- lected studies, two articles were excluded. One ysis of symptom severity. Risk ratios (RR) were study17 did not report relevant outcomes, while calculated for adverse events and treatment with- another study18 compared alginate with domper- drawals. We used a random-effects model to cal- idone. A total of ten RCTs were included10-13,19-24. culate the pooled effect size for all our analyses. Details of these trials are presented in Table I.
Figure 1. Study flow chart.
11847 Table I. Details of included studies.
Study Year Diagnosis of GERD Study Control Sample size Male Gender (%) BMI Treatment drug drug duration Study Control Study Control Study Control
Wilkinson 2019 As per Montreal definition. Frequent troublesome Gaviscon Placebo 212 212 48.1 45.8 28± 5.93 27.7± 5.43 7 days et al12 heartburn and/ or regurgitation (with or without Double dyspepsia symptoms) of at least moderate intensity Action® during the previous 3 months and on at least 5 days during the week before the start of screening. Kim et al10 2019 Episodes of heartburn or regurgitation symptoms A: Lamina G® PPI A: 46 48 A: 17.4 23.4 A: 22.2 22.3± 3.8 4 weeks for at least 3 months without evidence of reflux + PPI B: 24 B: 16.7 ± 2.3 esophagitis in a screening endoscopy; symptoms B: Lamina G® B: 22 of heartburn or regurgitation during the 1-week only ± 3.2 screening period (either ≥4 days of mild symptom or ≥ 2days of moderate to severe symptoms). Coyle et al 2017 Symptomatic GERD as per Montreal definition Gaviscon PPI 26 26 69.2 46.2 30.1± 6.1 30.4± 6.2 7-9 days A*11 despite compliance with once-daily standard Double dose of PPI for at least the previous 4 weeks. Action® + PPI Coyle et al 2017 Symptomatic GERD as per Montreal definition Gaviscon PPI 131 131 37.4 42.7 29.4± 5.3 29.2± 6.2 7-9 days B*11 despite compliance with once-daily standard Double dose of PPI for at least the previous 4 weeks. Action® + PPI Reimer 2016 Symptomatic GERD as per Montreal definition Gaviscon PPI 66 70 34.9 48.6 28.1± 4.9 28± 6.5 7 days et al19 despite compliance with once-daily standard Advance® dose of PPI for at least the previous 4 weeks. + PPI Thomas 2014 GERD symptoms for at least 3 months and on Gaviscon Placebo 56 54 57.1 51.9 29.2± 5.5 30.5± 6.3 7 days et al13 at least 5 of the preceding 7 days. Double Action® Chiu et al20 2013 Heartburn or regurgitation (either one) as main Sodium PPI 92 91 19.6 23.1 23.9± 4 23.5± 2.9 4 weeks symptom at least 2 days a week and had been alginate present for ≥1 month before screening; heartburn or regurgitation (either one) during the 7 days screening period, either with frequency for ≥4 days of mild symptom or ≥2 days of moderate to severe symptom Pouchain 2012 2 to 6 days of GERD episodes per week, with Gaviscon® PPI 120 121 38.2 46.3 26± 5.2 26.2± 4.7 14 days et al21 heartburn, with or without regurgitation Manabe 2012 Moderate or severe heartburn episodes on more Sodium PPI 36 40 50 42.9 NR NR 4 weeks et al22 than 2 days per week for at least 1 month before alginate screening (Alloid G®) + PPI Lai 2006 Classic symptoms including heartburn and/or Alginate Antacid 69 65 36.2 16.9 23.4± 3.8 22.8± 3.8 6 weeks et al23 regurgitation (Topaal®) Giannini 2006 Symptoms heartburn and/or acid regurgitation for Gaviscon Antacid 93 98 NR NR NR NR 2 weeks et al24 at least 3 days in the week prior to study entry Advance®
BMI, Body mass index; GERD, Gastro-esophageal reflux disease; PPI, Proton-pump inhibitors; NR, Not reported *two studies described in the same article
11848 Efficacy and safety of alginate formulations in patients with gastroesophageal reflux disease
In one publication11, two trials were reported. gitation and dyspepsia scores. The exploratory Data from both trials are presented separately. trial of Coyle et al11 reported a significant de- The sample size of the trials varied from 26 to crease in all variables of the HRDQ except for 212 patients per group. Treatment duration also dyspepsia. However, in their confirmatory trial varied from 7 days to up to 6 weeks. in the same publication, the authors reported no We grouped the studies with similar inter- difference between the two treatment groups. vention and control drugs. Four studies com- Similarly, Kim et al10 and Manabe et al22 did not pared treatment with alginate vs placebo/ find any significant differences in the reduc- antacid12,13,23,24. In four publications10,11,19,22, a tion of symptoms with the addition of alginate combination of alginate and PPI was compared to PPI therapy. Manabe et al22, however, found with PPI only, while in three studies10,20,21 sin- a higher number of responders (no symptoms gular alginate therapy was compared with PPI. on day 7) in the alginate + PPI group, with Details of outcomes reported by the included patients reporting a higher number of heart- studies are presented in Table II. burn-free days. Pooled analysis of total RDQ/HRDQ scores Alginate vs. Placebo/Antacid from four trials showed no statistically signifi- Four RCTs12,13,23,24 were included in the Algi- cant difference between the two treatment groups nate vs. Placebo/Antacid sub-group: Gaviscon (SMD: -0.15 95% CI -0.39, 0.08 p=0.20 I2=41%) Double Action (Gaviscon DA®), Gaviscon ad- (Figure 5). There was also no significant differ- vance®, and Topaal® were compared with pla- ences in the incidences of heartburn (SMD: -0.40 cebo/antacid. Descriptive analysis of the results 95% CI -1.08, 0.28 p=0.25 I2=55%), regurgitation from Table II indicates that all four trials report- (SMD: -0.39 95% CI -1.01, 0.22 p=0.20 I2=59%) ed significantly better outcomes with alginates or dyspepsia (SMD: -0.08 95% CI -0.17, 0.01 as compared to the control group. The severity p=0.07 I2=0%) between alginate + PPI and PPI of symptoms was assessed using the RDQ, Visu- groups (Figure 6). Similarly, we found no statis- al analog scale (VAS), or a 4-point Likert scale. tically significant difference in frequency of ad- Symptom-wise data from these questionnaires verse events (RR: 1.01 95% CI 0.74, 1.37 p=0.96 were available for a meta-analysis from three I2=0%) (Figure 7) or treatment withdrawals (RR: trials12,13,23. Our pooled analysis indicated no 1.57 95% CI 0.40, 6.23 p=0.52 I2=0%) between statistically significant difference between algi- two groups (Figure 8). nates and placebo for relief of heartburn (SMD: -1.77 95% CI -3.58, 0.04 p=0.06 I2=99%), regur- Alginate vs. PPI gitation (SMD: -1.83 95% CI -3.74, 0.07 p=0.06 Three studies10,20,21 compared alginates with I2=99%) or dyspepsia (SMD: -1.00 95% CI -2.13, PPI. Data from these trials were not consistent 0.13 p=0.08 I2=97%) (Figure 2). Analysis of the enough for a meta-analysis. Descriptive analysis adverse events indicated no statistically signif- of the results from these studies did not detect icant differences between the two groups (RR: significant differences in treatment outcomes 1.06 95% CI 0.82, 1.37 p=0.66 I2=0%) (Figure 3). between the two groups (Table II). Only one Similarly, there was no difference between the study by Pouchain et al21 reported a significantly two groups for adverse event-related withdraw- greater number of heartburn-free days with algi- als (RR: 1.02 95% CI 0.43, 2.43 p=0.97 I2=0%) nate after day 7. However, all trials reported no (Figure 4). difference in RDQ scores, pain scores, adequate/ complete response, or reduction of nights with Alginate + PPI vs. PPI symptoms. Four publications10,11,19,22 with five trials were available for review in the Alginate + PPI vs. Risk of Bias PPI sub-group. Gaviscon DA®, Gaviscon ad- The authors’ judgment of the risk of bias in vance®, and pure sodium alginate formulations the included studies is presented in Figure 9. The were used in the intervention group. The results overall quality of the trials was high. Methods of from the included studies were not consistent randomization were not clearly described in two (Table II). The trial of Reimer et al19 reported trials10,24. Three trials were open-label22-24. Eight no statistically significant reduction of reflux trials were funded by their respective pharmaceu- and heartburn score, and no difference in regur- tical companies10-13,19-21.
11849 Table II. Outcomes and results in the included studies.
Study Outcomes Results
Alginate vs. Placebo/Antacid Wilkinson 1. ≥ 1.5 points reduction of RDQ score 1. Significantly higher number of patients treated with Gaviscon Double Action responded to treatment et al12 2. Change in RDQ score 2. Significantly greater decrease in RDQ score with Gaviscon Double Action 3. Nights with symptoms 3. No significant difference between the two groups 4. OTE questionnaire 4. Significantly higher change of symptoms reported by patients taking Gavison Double Action Thomas 1. Change in RDQ scores 1. Significantly greater reduction of RDQ scores with Gaviscon Double Action et al13 2. OTE questionnaire 2. Treatment response significantly higher with Gavison Double Action Lai et al23 1. Severity of symptoms on VAS scale 1. Significantly greater reduction of heartburn, regurgitation, vomiting and belching with alginate at 3 weeks but no difference in nausea, epigastric pain, and dysphagia 2. Frequency of heartburn, regurgitation 2. Significantly reduced frequency of heartburn with alginate but no difference in regurgitation and sleep and sleep disturbances disturbances Giannini et al24 1. Severity of symptoms on Likert scale 1. Greater reduction of severity of symptoms in the alginate group 2. Complete resolution of symptoms 2. Higher number of patients reported complete resolution in the alginate group Alginate + PPI vs. PPI Kim et al10 1. Patients with complete resolution of symptoms 1. No significant difference between the two groups 2. Change in RDQ, PAGI-QoL, PAGI-SYM scores 2. No significant difference between the two groups 3. Symptom-free days during treatment period 3. No significant difference between the two groups 4. Nights with symptoms 4. No significant difference between the two groups Coyle et al A*11 1. Change in HRQD scores 1. Significantly greater decrease in HRDQ score with Gaviscon Double Action + PPI for all except dyspepsia 2. Number of responders [Defined as those 2. Significantly greater number of responders with Gaviscon Double Action + PPI patients with a reduction of at least 3 days with HRDQ score (heartburn and regurgitation combined) >0.7] 3. Patient satisfaction scores 3. Significantly improved patient satisfaction with Gaviscon Double Action + PPI 4. Number of symptom free days 4. No significant difference between the two groups 5. Nights with symptoms 5. No significant difference between the two groups Coyle et al B*11 1. Change in HRQD scores 1. No significant difference between the two groups 2. Number of responders [Defined as those 2. No significant difference between the two groups patients with a reduction of at least 3 days with HRDQ score (heartburn and regurgitation combined) >0.7] 3. Patient satisfaction scores 3. No significant difference between the two groups 4. Number of symptom free days 4. No significant difference between the two groups 5. Night time symptoms 5. No significant difference between the two groups
Continued
11850 Table II (continued). Outcomes and results in the included studies.
Study Outcomes Results
Alginate + PPI vs. PPI Reimer et al19 1. Change in HRQD scores 1. Significantly greater reduction of reflux and heartburn score with Gaviscon Advance + PPI but no difference in regurgitation and dyspepsia scores 2. Nights with symptoms 2. Significantly greater reduction of nights with symptoms with Gaviscon Advance + PPI 3. Number of symptom free days 3. No significant difference between the two groups 4. Patient satisfaction scores 4. Significantly higher patient satisfaction with Gaviscon Advance + PPI Manabe et al22 1. Responders (Defined as no symptoms 1. Significantly more responders with Sodium alginate + PPI of heartburn by day 7) 2. Reduction of each symptom 2. No significant difference between the two groups 3. Heartburn-free days 3. Significantly higher with Sodium alginate + PPI Alginate vs. PPI Kim et al10 5. Patients with complete resolution of symptoms 5. No significant difference between the two groups 6. Change in RDQ, PAGI-QoL, PAGI-SYM scores 6. No significant difference between the two groups 7. Symptom-free days during treatment period 7. No significant difference between the two groups 8. Nights with symptoms 8. No significant difference between the two groups Chiu et al20 1. Adequate heartburn or regurgitation relief 1. No significant difference between the two groups (Defined as no more than 1 day of mild heart- burn or regurgitation episodes in the last 7 days before day 28) 2. Change in RDQ scores 2. No significant difference between the two groups 3. Patient satisfaction scores 3. No significant difference between the two groups Pouchain et al21 1. Time to onset of first 24 hour heartburn-free 1. No significant difference between the two groups period 2. Number of heartburn-free days by day 7 2. Significantly greater in PPI group 3. Pain intensity 3. No significant difference between the two groups
HRDQ, Heartburn Reflux Dyspepsia Questionnaire; RDQ, Reflux Disease Questionnaire; OTE, overall treatment evaluation; PAGI, Patient Assessment of Upper Gastrointestinal Disorders; QoL, Quality of life; SYM, Symptom severity index; VAS, visual analog scale. *two studies described in the same article
11851 C.-X. Zhao, J.-W. Wang, M. Gong
Figure 2. Meta-analysis of heartburn, regurgitation and dyspepsia scores for alginate vs. placebo/antacids.
GERD. Current evidence on the efficacy of al- Discussion ginate-based formulations vs. PPI or the role of added alginates with PPI is, however, question- Our systematic review and meta-analysis of able with literature suggestive of no difference current literature encompassing 11 RCTs suggest between the two drugs. The risk of adverse events that alginate may be somewhat more effective with alginates is no greater than that of placebo than placebo/antacids in improving outcomes of or PPIs.
Figure 3. Meta-analysis of adverse events for alginate vs. placebo/antacids.
Figure 4. Meta-analysis of treatment withdrawals for alginate vs placebo/antacids.
11852 Efficacy and safety of alginate formulations in patients with gastroesophageal reflux disease
Figure 5. Meta-analysis of total RDQ/HRDQ scores for alginate + PPI vs. PPI.
Alginate is a naturally occurring polysaccha- last two decades, there has been renewed inter- ride polymer that has been used for the manage- est in the role of alginates for managing GERD ment of GERD symptoms for many decades9. patients, with several studies analyzing its effica- The drug acts by rapidly interacting with gastric cy in a randomized setting. This review analyzes acid forming a raft-like structure over the gastric data from trials published in the last 20 years. contents. During reflux, this gel form preferen- Descriptive analysis of all four trials compar- tially moves into the esophagus thereby reducing ing alginates with placebo/antacids in our review symptoms and also preventing mucosal damage9. have indicated significantly better outcomes with Alginates are capable of eliminating or displac- alginate-based formulations. Due to the hetero- ing the acid pocket away from the esophagogas- geneity of outcomes, a meta-analysis was only tric junction in GERD patients25. Nevertheless, a possible for patient-reported symptom reduction similar effect has also been reported with PPIs26. scores, the results of which did not favor alginates. Therefore,, it is important to know if alginates are Nevertheless, on close examination of the forest superior to placebo or PPIs for managing GERD. plot, it can be seen that the MD of symptom scores First clinical trials of the efficiency of alginates for the three trials was statistically significant for are dating back to 1970s27,28. However, over the all three symptoms, although with the upper end
Figure 6. Meta-analysis of heartburn, regurgitation and dyspepsia scores for alginate + PPI vs. PPI.
11853 C.-X. Zhao, J.-W. Wang, M. Gong
Figure 7. Meta-analysis of adverse events for alginate + PPI vs. PPI. of the 95% CI very close to zero. The upper end of Leiman et al14 that reported significantly high- of 95% CI for the pooled outcomes was also just er treatment response with alginates compared to above zero (heartburn: 0.04; regurgitation: 0.07; placebo/antacids (OR: 4.42; 95% CI 2.45–7.97) but dyspepsia: 0.13) while the lower ends were >2 for demonstrated no statistically significant difference all three symptoms. Thus, despite a non-significant between alginates vs PPIs and Histamine-2 receptor result, there is evidence that alginates may lead to a antagonists (OR:0.58; 95% CI 0.27–1.22). Despite better reduction of GERD symptoms as compared similar results, our review significantly differs from to placebo/antacids. The small effect size may be that of Leiman et al14. The European Medicines attributed to the short duration of two trials includ- Agency guidance29 recommends that the primary ed in our meta-analysis12,13. It has been shown that outcome of trials on GERD patients be a respond- placebo/antacid response in trials shorter than 2 er analysis which should be based on the number of weeks can be as high as 56%14. This can also ex- patients experiencing a clinically relevant reduction plain the larger effect size seen in the trial of Lai et of GERD symptoms. However, in order to pool out- al23 which measured outcomes at three weeks. comes of different studies, the definition of “treat- Our meta-analysis failed to demonstrate any sig- ment response” needs to be similar across trials. nificant benefit of alginate addition to PPI . There Due to significant difference in definitions between was no statistically significant difference in total the included studies, and under-reporting of data by HRDQ/RDQ scores, as well as in the severity of some of the trials, such “response analysis” for pool- heartburn, regurgitation, and dyspepsia scores be- ing ORs was not attempted in our review, and only tween the two groups. Similarly, MD of individual a descriptive analysis was carried out. Our analysis, studies comparing alginate treatment with placebo/ therefore, provides explicit evidence on the efficacy antacids were non-significant, and the lower end of alginates by pooling change of symptoms score of the total effect size was close to -1. Tree trials, measured on a linear scale. A second important dif- directly comparing alginates with PPIs10,20,21 did ference is that our review summarized recent stud- not show any benefit of alginate treatment. Our re- ies with the addition of four new RCTs10-12,19, thus sults are in agreement with previous meta-analysis presenting the latest updated evidence.
Figure 8. Meta-analysis of treatment withdrawal for alginate + PPI vs. PPI.
11854 Efficacy and safety of alginate formulations in patients with gastroesophageal reflux disease
populations (e.g., disease severity) and study duration, as well as variations in the composition of alginate formulations, with some studies using combination of alginates with antacids (Gaviscon DA) and some using pure alginate (Lamina G®). Recent studies do not provide evidence that antacids significantly im- prove GERD symptoms30. Additionally, several tri- als included in our review were sponsored, raising a possibility of conflict of interests. Lastly, inconsistent definitions and reporting in the included studies did not allow a meta-analysis of several outcomes, such as complete response to therapy, symptom-free days, and nights without symptoms. Despite these limitations, our meta-analysis provides a significant update on the efficacy and safety of alginates for GERD. We analysed re- cent studies only (post-2000) to present current evidence on alginates. In contrast to the previous review14, we carried out pooled analysis of RDQ/ HRDQ scores and symptom-wise scores to present comprehensive evidence. A detailed qualitative and quantitative (where possible) analysis was carried out from high-quality studies. Lastly, we grouped studies comparing alginates with antacids/placebo and PPI separately to clearly identify the role of these drugs in the management of GERD.
Conclusions
Our study indicates that alginates may have greater efficacy than placebo/antacids in improv- ing outcomes of GERD. Current evidence on the efficacy of alginate-based formulations vs PPI or the role of added alginates with PPI is, however, questionable and suggests no difference between the two drugs. The risk of adverse events with al- ginates is no greater than that of placebo or PPIs. Figure 9. Risk of bias summary. There is a need for further independent trials com- paring similar alginate formulations with placebo and PPIs, reporting similar outcome measures for In addition to treatment efficacy, our study both long and short term treatment duration. analyzed safety profile of alginates compared to standard/placebo treatment. Data on drug safety was reported by the majority of trials and pooled Acknowledgements analysis indicated no increased risk of adverse Not applicable events with alginate formulations. The number of treatment withdrawals was also not significantly increased with alginates. Funding Our review has a number of limitations. While 11 No funding was received. trials were included in the review, the number of stud- ies in the meta-analysis of treatment outcomes was Availability of data and materials limited There was large heterogeneity in our analysis The datasets used and/or analyzed during the current study are which can be attributed to the differences in the study available from the corresponding author on reasonable request.
11855 C.-X. Zhao, J.-W. Wang, M. Gong
Coyle C, Crawford G, Wilkinson J, Thomas SJ, Authors’ contributions 11) Bytzer P. Randomised clinical trial: addition of CZ conceived and designed the study. JW and MG collect- alginate-antacid (Gaviscon Double Action) to ed the data and performed the literature search. CZ was proton pump inhibitor therapy in patients with involved in the writing of the manuscript. All authors have breakthrough symptoms. Aliment Pharmacol read and approved the final manuscript. Ther 2017; 45: 1524-1533. 12) Wilkinson J, Wade A, Thomas SJ, Jenner B, Hod- gkinson V, Coyle C. Ethical approval Randomized clinical tri- al: a double-blind, placebo-controlled study Not applicable to assess the clinical efficacy and safety of alginate-antacid (Gaviscon Double Action) Conflict of Interests chewable tablets in patients with gastro-oe- sophageal reflux disease. Eur J Gastroenterol The authors declared there is no conflict of interest. Hepatol 2019; 31: 86-93. 13) Thomas E, Wade A, Crawford G, Jenner B, Levinson N, Wilkinson J. Randomised clinical trial: relief of upper gastrointestinal symptoms by an acid References pocket-targeting alginate-antacid (Gaviscon Dou- ble Action) - a double-blind, placebo-controlled, 1) El-Serag HB, Sweet S, Winchester CC, Dent J. Up- pilot study in gastro-oesophageal reflux disease. date on the epidemiology of gastro-oesophageal Aliment Pharmacol Ther 2014; 39: 595-602. reflux disease: a systematic review. Gut 2014; 63: 14) Leiman DA, Riff BP, Morgan S, Metz DC, Falk GW, 871-880. French B, Umscheid CA, Lewis JD. Alginate therapy 2) Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; is effective treatment for GERD symptoms: a Global Consensus Group. The Montreal definition systematic review and meta-analysis. Dis Esoph- and classification of gastroesophageal reflux dis- agus 2017; 30: 1-9. ease: a global evidence-based consensus. 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