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Use of Famotidine and Risk of Severe Course of Illness in Patients With COVID-19

A Meta-analysis
      To The Editor:
      The article by Ghosh et al,
      • Ghosh R.
      • Chatterjee S.
      • Dubey S.
      • Lavie C.J.
      Famotidine against SARS-CoV2: a hope or hype?.
      in which they discuss the potential of famotidine to regulate innate and adaptive immune responses, provides a rationale to repurpose famotidine for the treatment of coronavirus disease 2019 (COVID-19). There have been few studies evaluating the use of famotidine in patients with COVID-19, and thus we performed a meta-analysis to summarize the overall effect of famotidine on the clinical outcomes in this patient population.
      We searched PubMed, Google Scholar, and medRxiv (preprint repository) databases, up to March 31, 2021, for studies evaluating the risk of a severe course of illness among famotidine users with COVID-19 compared with nonusers, with the following keywords and their MeSH terms: COVID-19, famotidine, and histamine-2 recepto antagonist, without language restrictions. Studies were included if they were original, observational (prospective or retrospective) studies, included patients with COVID-19 with documented use of famotidine, and reported adjusted estimates for mortality and other severe clinical outcomes with the use of famotidine relative to nonuse of famotidine. Each included article was independently evaluated by 2 authors (C.S.K. and S.S.H.), who extracted the study characteristics and measures of effect. The quality of observational studies was evaluated using the Newcastle-Ottawa Scale.
      • Wells G.
      • Shea B.
      • O’Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • Tugwell P.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013.
      The outcome of interest was the development of a severe course of illness, characterized by death or other severe clinical outcomes. Adjusted measures of association and the corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model. Cochran's Q heterogeneity test (Q test) and its related metric, the I2 statistics, were used to evaluate heterogeneity across studies. The meta-analysis was performed with Meta XL, version 5.3 (EpiGear International, Queensland, Australia).
      Our literature search yielded 46 unique abstracts. After deduplication and application of the eligibility criteria, 6 relevant articles were shortlisted for inclusion through full-text examination. Of these, 2 studies were excluded, as they reported no mortality or other severe clinical outcomes in COVID-19. Study characteristics are depicted in the Table.
      • Yeramaneni S.
      • Doshi P.
      • Sands K.
      • Cooper M.
      • Kurbegov D.
      • Fromell G.
      Famotidine use is not associated with 30-day mortality: a coarsened exact match study in 7158 hospitalized COVID-19 patients from a large healthcare system.
      • Shoaibi A.
      • Fortin S.
      • Weinstein R.
      • Berlin J.
      • Ryan P.
      Comparative effectiveness of famotidine in hospitalized COVID-19 patients.
      • Mather J.F.
      • Seip R.L.
      • McKay R.G.
      Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19.
      • Freedberg D.E.
      • Conigliaro J.
      • Wang T.C.
      • et al.
      Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study.
      • Zhou J.
      • Wang X.
      • Lee S.
      • et al.
      Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study [published online ahead of print December 4, 2020].
      All studies were retrospective and are deemed good quality with a Newcastle-Ottawa Scale ranging from 7 to 8 (Table). The meta-analysis of 3 studies
      • Shoaibi A.
      • Fortin S.
      • Weinstein R.
      • Berlin J.
      • Ryan P.
      Comparative effectiveness of famotidine in hospitalized COVID-19 patients.
      ,
      • Mather J.F.
      • Seip R.L.
      • McKay R.G.
      Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19.
      ,
      • Zhou J.
      • Wang X.
      • Lee S.
      • et al.
      Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study [published online ahead of print December 4, 2020].
      (n=31,563), which provided adjusted hazard ratio (aHR), revealed a nonsignificant association between the use of famotidine and the hazard for a severe course of illness in patients with COVID-19, relative to nonuse of famotidine (Figure; pooled HR=0.83; 95% CI, 0.49 to 1.41). Similarly, a separate meta-analysis of 2 studies
      • Yeramaneni S.
      • Doshi P.
      • Sands K.
      • Cooper M.
      • Kurbegov D.
      • Fromell G.
      Famotidine use is not associated with 30-day mortality: a coarsened exact match study in 7158 hospitalized COVID-19 patients from a large healthcare system.
      ,
      • Mather J.F.
      • Seip R.L.
      • McKay R.G.
      Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19.
      (n=1928), which provided adjusted odds ratio (aOR), revealed a nonsignificant association between the use of famotidine and the odds for a severe course of illness in patients with COVID-19, relative to nonuse of famotidine (Supplemental Figure, available online at http://www.mayoclinicproceedings.org); pooled OR=0.85; 95% CI, 0.27 to 2.63).
      TableCharacteristics of Included Studies
      StudyCountryDesignTotal number of patientsAge (median/mean unless otherwise specified)Severe course of illness
      In the study by Cheung et al,7 the severe course of illness was defined as requirement for intensive care unit admission, intubation, or death. In the study by Yeramaneni et al,3 the severe course of illness was defined as death within 30 days of hospitalization. In the study by Shoaibi et al,4 the severe course of illness was defined as combined death and/or the requirement for mechanical ventilation, tracheostomy, or extracorporeal membrane oxygenation. In the study by Mather et al,5 the severe course of illness was defined as a composite of death or requirement for ventilation. In the study by Freedberg et al,6 the severe course of illness was defined as a composite of death or endotracheal intubation from day 2 to day 30 of hospitalization.
      Covariates adjustmentNOS
      Famoti-dine users (n/N; %)Nonusers of famoti-dine (n/N; %)Adjusted estimate
      Zhou et al
      • Zhou J.
      • Wang X.
      • Lee S.
      • et al.
      Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study [published online ahead of print December 4, 2020].
      Hong KongRetrospective database review3144All patients=44.8Not reportedNot reportedOR=1.34 (0.24-6.06)Age, comorbidities, use of co-medications, neutrophil count, lymphocyte count, serum platelet level, serum urea level, serum creatinine level, serum albumin level, serum glucose level7
      Yeramaneni et al
      • Yeramaneni S.
      • Doshi P.
      • Sands K.
      • Cooper M.
      • Kurbegov D.
      • Fromell G.
      Famotidine use is not associated with 30-day mortality: a coarsened exact match study in 7158 hospitalized COVID-19 patients from a large healthcare system.
      United StatesRetrospective,multienter1156Famotidine users=62.2

      Nonusers of famotidine =62.1
      62/410 (15.1)73/746 (9.8)OR=1.49 (0.80-2.79)Age, sex, race, ethnicity, BMI, comorbidities8
      Shoaibi et al
      • Shoaibi A.
      • Fortin S.
      • Weinstein R.
      • Berlin J.
      • Ryan P.
      Comparative effectiveness of famotidine in hospitalized COVID-19 patients.
      United StatesRetrospective database review26,027Famotidine users with ≥60 years: 55.2%326/1623 (20.0)5534/24404 (22.7)HR=1.00 (0.86-1.16)Age, sex, index month, comorbidities8
      Mather et al
      • Mather J.F.
      • Seip R.L.
      • McKay R.G.
      Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19.
      United StatesRetrospective, single center772Famotidine users=63.3

      Nonusers of famotidine =66.4
      36/83 (43.3)495/689 (71.8)OR=0.47 (0.23-0.97)

      HR=0.50 (0.31-0.79)
      Age, sex, race, smoking status, BMI, comorbidities, National Early Warning Score7
      Freedberg et al
      • Freedberg D.E.
      • Conigliaro J.
      • Wang T.C.
      • et al.
      Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study.
      United StatesRetrospective, single center1620Famotidine users with >65 years: 47.6%

      Famotidine users with >65 years: 42.6%
      8/84 (9.5)332/1536 (21.6)HR=0.42 (0.21-0.85)Age, sex, race, BMI, comorbidities, initial oxygen requirements8
      BMI, body mass index; HR, hazard ratio; NOS, Newcastle-Ottawa Scale; OR, odds ratio.
      a In the study by Cheung et al,
      • Zhou J.
      • Wang X.
      • Lee S.
      • et al.
      Proton pump inhibitor or famotidine use and severe COVID-19 disease: a propensity score-matched territory-wide study [published online ahead of print December 4, 2020].
      the severe course of illness was defined as requirement for intensive care unit admission, intubation, or death. In the study by Yeramaneni et al,
      • Yeramaneni S.
      • Doshi P.
      • Sands K.
      • Cooper M.
      • Kurbegov D.
      • Fromell G.
      Famotidine use is not associated with 30-day mortality: a coarsened exact match study in 7158 hospitalized COVID-19 patients from a large healthcare system.
      the severe course of illness was defined as death within 30 days of hospitalization. In the study by Shoaibi et al,
      • Shoaibi A.
      • Fortin S.
      • Weinstein R.
      • Berlin J.
      • Ryan P.
      Comparative effectiveness of famotidine in hospitalized COVID-19 patients.
      the severe course of illness was defined as combined death and/or the requirement for mechanical ventilation, tracheostomy, or extracorporeal membrane oxygenation. In the study by Mather et al,
      • Mather J.F.
      • Seip R.L.
      • McKay R.G.
      Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19.
      the severe course of illness was defined as a composite of death or requirement for ventilation. In the study by Freedberg et al,
      • Freedberg D.E.
      • Conigliaro J.
      • Wang T.C.
      • et al.
      Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study.
      the severe course of illness was defined as a composite of death or endotracheal intubation from day 2 to day 30 of hospitalization.
      Figure thumbnail gr1
      FigurePooled hazard ratio of severe course of illness in patients with COVID-19 with the use of famotidine relative to nonuse of famotidine.
      The finding of our meta-analysis suggests no significant benefits with the use of famotidine in terms of reducing the risk of a severe course of illness in patients with COVID-19. Since the suppression of gastric acid by famotidine may lead to impaired clearance of the novel coronavirus, the possibility that impaired viral clearance negates the potential benefits conferred by the use of famotidine in COVID-19 requires further evaluation. However, the studies included in our meta-analysis are of retrospective design, and thus generalizability of the findings may be limited. Prospective studies are required to substantiate our findings.

      Supplemental Online Material

      References

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        • Chatterjee S.
        • Dubey S.
        • Lavie C.J.
        Famotidine against SARS-CoV2: a hope or hype?.
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        • Shea B.
        • O’Connell D.
        • Peterson J.
        • Welch V.
        • Losos M.
        • Tugwell P.
        The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013.
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        • Doshi P.
        • Sands K.
        • Cooper M.
        • Kurbegov D.
        • Fromell G.
        Famotidine use is not associated with 30-day mortality: a coarsened exact match study in 7158 hospitalized COVID-19 patients from a large healthcare system.
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        • Shoaibi A.
        • Fortin S.
        • Weinstein R.
        • Berlin J.
        • Ryan P.
        Comparative effectiveness of famotidine in hospitalized COVID-19 patients.
        Preprint. medRxiv. 2020;
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        • Seip R.L.
        • McKay R.G.
        Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19.
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        Gastroenterology. 2020; 159: 1129-1131.e3
        • Zhou J.
        • Wang X.
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        (Gut)

      Linked Article

      • Famotidine Against SARS-CoV2: A Hope or Hype?
        Mayo Clinic ProceedingsVol. 95Issue 8
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          Coronavirus disease 2019 (COVID-19) is globe-trotting, and thousands of researchers and stakeholders are spending repose-less days and sleepless nights in search of effective therapies. Currently, the entire research sphere is dealing with a pandemic triad: hypes, hypotheses, and hopes. In the absence of a specific antiviral agent or vaccine against novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), “repurposing” of old time-tested medications is being tried. Famotidine is the most recent addition to this trend, creating a lot of hustle among the public and stirring criticism in the scientific arena.
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      • In Reply–Use of Famotidine and Risk of Severe Course of Illness in Patients With COVID-19: A Meta-analysis
        Mayo Clinic ProceedingsVol. 96Issue 5
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          Kow and colleagues' interest in our recent letter to the editor1 regarding the potential for famotidine in COVID-19 infection was much appreciated. Obviously, their meta-analysis is small and probably not adequately powered but still suggested 37% and 7% reductions in severe disease in the general and adjusted analyses, respectively: obviously, with wide confidence intervals that were not close to statistical significance. A large-scale randomized study that was adequately powered, preferably with famotidine, started early in COVID-19, would be required to fully determine the full potential of the benefits of famotidine in COVID-19; this type of study is likely not coming in this pandemic.
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