key: cord-0685149-kpnotaao authors: Sethia, R.; Prasad, M.; Jagannath, S.; Nischal, N.; Soneja, M.; Garg, P.; Shalimar, title: Efficacy of Famotidine for COVID-19: A Systematic Review and Meta-analysis date: 2020-09-30 journal: nan DOI: 10.1101/2020.09.28.20203463 sha: aa9c0017188d8c2ad77fb28510c33f3d33c317aa doc_id: 685149 cord_uid: kpnotaao Background: Coronavirus Disease 2019 (COVID-19) pandemic continues unabated in many parts of the world. In the absence of any definite antiviral therapy except some benefit of remdesivir, there is an ongoing search for effective therapy. Famotidine has been shown to reduce mortality in hospitalized patients in a few studies. We conducted a systematic review on the use of famotidine in COVID-19. Methods: We searched the databases Medline, Embase, Cochrane CENTRAL and Medrxiv. Title/abstract screening, full text screening and data abstraction were carried out in by two reviewers. Case series, cohort studies and randomized trials were included. Results: Five studies were eligible for inclusion: all were retrospective cohort or case series. Low quality evidence suggests a likely clinical benefit for the use of famotidine in decreasing mortality in hospitalized patients with moderate to severe COVID-19. A meta-analysis of two cohort studies showed a statistically significant decrease in the composite outcome for death and intubation with famotidine (HR 0.44, 95% CI 0.27 to 0.73). Conclusion: Further evidence from RCTs is required for famotidine to treat COVID 19. S A R S - C o V - 2 , Coronavirus Disease 2019 (COVID-19), the illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to pose enormous burden on healthcare system with significant morbidity and mortality. As of 19th September 2020, COVID-19 has resulted in close to one million deaths worldwide. (1) There is no proven effective therapy for COVID-19. Remdesivir is the only antiviral that has shown some clinical benefit but without any reduction in mortality. A globally implemented, safe vaccination program seems to be the only hopeful long term solution, but is at least 6 months away. Moreover, the safety and efficacy of any vaccine candidate is yet to be proven. Therefore, there is a need for effective therapy to reduce mortality. Famotidine, a H2 receptor antagonist, has been in clinical use for many decades for reducing gastric acid production in the treatment of peptic ulcer and gastroesophageal reflux disease. It has an excellent safety profile and being off patent, is cheap. Famotidine has been shown to bind papain-like protease (PLpro) and 3 chymotrypsin-like protease (Mpro) of SARSCoV-2 in in silico molecular docking studies.(2) However, the inhibition has not been confirmed. Famotidine has been shown to reduce mortality in hospitalized patients with COVID-19 in a few studies. (3) (4) (5) We conducted a systematic review to assess the effect of famotidine on the clinical outcomes in patients with COVID-19. To assess the effectiveness and safety of famotidine in patients with COVID-19. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was adhered to in the present report.(6) The following inclusion criteria were used for eligibility: Type of participants: We included studies on patients with all grades of severity of COVID-19. Type of interventions: We included studies assessing famotidine in humans with COVID-19. Type of outcomes: We included studies reporting the following outcomes: Medrxiv and SSRN for pre-print articles. Editorials, letters, news, reviews, expert opinions, case reports, and studies without original data were excluded. Reference lists of retrieved articles and pertinent reviews were also searched for relevant articles. No language restriction was imposed. Titles and abstracts were screened by two reviewers (RS, PG) independently. Full texts of articles considered potentially eligible were obtained. The data were abstracted by two reviewers independently and risk of bias was assessed. Disagreement was resolved by discussion. The following data were extracted: study design, inclusion criteria, number of patients, patient characteristics, dose, duration and timing of famotidine, co-medications, outcomes and method of adjustment (for cohort studies and case series). Risk of bias was assessed using the revised version of Newcastle Ottawa Scale for Cohort studies and the JBL checklist for case series. (7,8) We calculated pooled risk ratio and 95% CI using the Generic Inverse Variance approach. Random effects model was used to conduct the meta-analysis. We carried out the statistical . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.28.20203463 doi: medRxiv preprint analysis using Review Manager 5.3. Heterogeneity was assessed using visual inspection of forest plot and the I 2 statistic. We used GRADE methodology to rate certainty of evidence for outcomes as high, moderate, low or very low (9). Our search yielded 13 titles and abstracts -all were identified from the electronic database search. We excluded 8 articles based on a review of the title and abstract, leaving 5 articles for full review. These five studies were found eligible on full text screening; one of these was a preprint articles that has not been peer reviewed. These 5 studies were included in the systematic review. (4,5,3,10,11). (Fig 1) The studies included were 3 cohort studies and 2 case series. All studies included patients hospitalized with COVID-19. Three cohort studies (3, 4, 11) and one case series (10) included mostly patients with severe COVID-19, and one case series included patients with mild to moderate COVID-19.(5) (Table 1) The five selected studies included a total of 2643 patients with COVID-19 of whom 312 patients received famotidine. All except 10 patients were hospitalized with moderate-severe illness. The dose of famotidine varied from 40-233 mg/day given for 5-21 days. Two cohort studies including . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In all three cohort studies, risk of bias was low for selection of exposed and non-exposed population and assessment of exposure (3, 4, 11) . All three cohort studies were assessed to have low risk of bias from outcome being present at the start of the study. However, adequate adjustment and assessment of prognostic factors were not carried out by one study (11) . Follow up was adequate for all outcomes in the cohort studies; however, all cohort studies were assessed as being high risk of bias for co-interventions being dissimilar in the two groups. Both case series reported consecutive and complete inclusion of participants and the condition being measured in a standard, reliable way (5, 10) . Both also clearly reported the demographics of participants and clinical information. However, one case series did not report the criteria for inclusion. A meta-analysis of two cohort studies showed a statistically significant decrease in the composite outcome for death and intubation with the use of Famotidine (HR 0.44, 95% CI 0.27 to 0.73). There was no heterogeneity in this meta-analysis (I 2 =0%) (Fig 2) . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.28.20203463 doi: medRxiv preprint The certainty in evidence was assessed as very low using the GRADE approach. The certainty was rated down for risk of bias, as the included studies were observational studies with possible residual confounding. (Table 2) 4. Discussion: The present systematic review found that the use of famotidine was associated with a reduction The present systematic review and meta-analysis is the first, to the best of our knowledge, to address the role of famotidine in COVID-19. It incorporates a comprehensive search of three major databases, as well as pre-print articles. In addition, we used to GRADE approach to rate the certainty in evidence, thus paying due attention to methodological issues like risk of bias, imprecision, indirectness and inconsistency. There are many limitations of the present study which are inherent to the included studies. First, the studies included in the analysis had a small number of patients treated with famotidine. Studies were single-center and retrospective observational studies with their associated bias. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.28.20203463 doi: medRxiv preprint Multiple other drugs were used for the management of patients, which could have influenced the clinical outcomes In conclusion, the available evidence suggests a potential role of famotidine in the management of COVID-19, which needs to be explored in randomized controlled trials. Conflicts of interest: None declared . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.28.20203463 doi: medRxiv preprint Yes . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . ( 1 0 ) r a d i o l o g i c a l o u t c o m e a s w e l l a s s t a t i s t i c a l l y s i g n i f i c a n t i m p r o v e m e n t i n c l i n i c a l a n d b i o c h e m i c a l p a r a m e t e r . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.28.20203463 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 30, 2020. . https://doi.org/10.1101/2020.09.28.20203463 doi: medRxiv preprint Johns Hopkins Coronavirus Resource Center Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19 Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Department of Veterans Affairs (US) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations Hospitalized COVID-19 Patients Treated With Celecoxib and High Dose Famotidine Adjuvant Therapy Show Significant Clinical Responses Social Science Research Network Dual-histamine receptor blockade with cetirizine -famotidine reduces pulmonary symptoms in COVID-19 patients Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases Histamine receptor 2 modifies dendritic cell responses to microbial ligands Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: a nationwide cohort study with propensity score matching Comparative Trial of the Safety and Efficacy of Standard of Care (SOC) Plus Famotidine vs SOC Plus Placebo for the Treatment of COVID-19 in Hospitalized Adults