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There is no reasonable evidence to support efficacy of fluvoxamine in prevention of disease deterioration in COVID-19 outpatients: A comment on two recent meta-analyses advocating its use

Published:November 24, 2022DOI:https://doi.org/10.1016/j.jinf.2022.11.016
      To the Editor,
      Two recent Letters to Editor,
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      each including a meta-analysis, argued in favor of efficacy of early commenced fluvoxamine treatment in prevention of disease progression in (mild) COVID-19 (out)patients. There are, however, several points common to both of them that need to be addressed. First, both meta-analyses reported effect estimates pooled across several randomized (placebo) controlled trials (RCTs) but including also two non-randomized, open-label studies in which patients opted to take fluvoxamine or not. These two studies, heavily burdened by sampling/selection bias, contributed a considerable part of the total amount of data.
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      Both meta-analyses
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      used the reported raw (unadjusted) proportions from these studies and combined them with RCT data. Under certain very strict conditions, non-randomized studies might be included in meta-analysis of RCTs,
      • Reeves B.C.
      • Deeks J.J.
      • Jiggins J.P.T.
      • Shea B.
      • Tugwell P.
      • Wells G.A
      • et al.
      Chapter 24: including non-randomized studies on intervention effects.
      but treating non-randomized data as if they were generated in RCTs is bluntly inappropriate.
      • Reeves B.C.
      • Deeks J.J.
      • Jiggins J.P.T.
      • Shea B.
      • Tugwell P.
      • Wells G.A
      • et al.
      Chapter 24: including non-randomized studies on intervention effects.
      Next, both meta-analyses used random-effects pooling combining some very small studies with only a few or no events and some rather large studies (with around 10-fold difference in size between them).
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      While this is not an uncommon practice, it generates a problem in estimation of the across-study variance (τ2)
      • IntHout J.
      • Ioannidis J.P.A.
      • Borm G.F.
      • Goeman J.
      Small studies are more heterogeneous than large ones: a meta-meta-analysis.
      . Namely, and particularly in the case of binary outcomes, small studies (particularly with no or only a few events), are more heterogeneous than the large(r) ones, and variance estimates are much more imprecise.
      • IntHout J.
      • Ioannidis J.P.A.
      • Borm G.F.
      • Goeman J.
      Small studies are more heterogeneous than large ones: a meta-meta-analysis.
      When small and large studies are combined, only one variance estimate is generated which, clearly, does not really fit either of them – it understimates true heterogeneity in small trials, and overestimates it in larger trials – but it is used to assign study weights, and this affects pooled point-estimates and confidence intervals.
      • IntHout J.
      • Ioannidis J.P.A.
      • Borm G.F.
      • Goeman J.
      Small studies are more heterogeneous than large ones: a meta-meta-analysis.
      Finally, both meta-analyses largely focused on hospitalizations as the outcome. Indeed, in this setting, incident hospitalization is a reasonable indicator of disease worsening. However, it is not the only indicator – there are other clinical events that are comparably as informative and are complementary to hospitalizations. For example, any event prompting emergency room visit or other forms of urgent help also illustrates disease progression. If such events are disregarded, one may not only fail to get a full picture of the reality, but this could also bias the estimates related to hospitalization. It is not inconceivable that, for example, a patient requiring urgent help that can be provided during an emergency room visit could benefit from this help in a way that will allow him/her to avoid (imminent) hospitalization. In such a scenario, treatment that results in more such vistis than another one (and is, hence, inferior in terms of preventing disease worsening) might turn out to be comparable or superior regarding hospitalizations (since avoided due to preceding events).
      Table 1 contains all RCTs (cumulatively) included in the two
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      meta-analyses: most of them used composite outcomes to adequately illustrate disease progression. However, Table 1 differs from data used in the published meta-analyses
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      in that: (i) it includes only RCTs (placebo-controlled, double-blind) and no non-randomized studies; (ii) it includes one small RCT conducted in South Korea at the very beginning of the pandemics, althouth only recently published (depicted as “Seo” in Table 1), that was not included – and should have been – in either of the published meta-analyses
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      ; (iii) it indicates that one larger trial (depicted as “Bramante” in Table 1) actually consisted of two fluvoxamine “subtrials” (fluvoxamine+metformin was compared to placebo+metformin, or fluxoxamine+placebo was compared to “double placebo”) that yielded estimates in opposite directions. Finally, Table 1 depicts the outcome more comprehensively illustrative of “disease progression” than just “hospitalization”, used to generate meta-analysis in Fig. 1. Frequentist meta-analysis is based on (random-effects) regression approach to generate estimates of the treatment effect and of heterogeneity at each level of “study size” as a binary moderator (Fig. 1A): (i) two small trials are so different in reported estimates (indicating a “huge” effect or no effect), that a pooled estimate is meaningless. Estimated variance is huge, but meaningless since likely imprecise with no possibility to generate its confidence intervals; (ii) considering large(r) trials, heterogeneity is lower, but still considerable (prediction intervals extend from 56% lower to 72.5% higher relative risk with fluvoxamine), and pooled estimate does not indicate any relevant benefit of fluvoxamine (RR=0.872, 0.647–1.175); (iii) a single estimate across all small and larger trials is also reported (note extremely wide confidence intervals around the estimated τ2) to allow for a comparison of the present and published
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      analyses: it also does not indicate any relevant benefit of fluvoxamine (RR=0.856, 95% CI 0.650–1.127) with prediction intervals extending form 50% lower to 46.6% higher (relatively) risk with fluvoxamine than with placebo. Bayesian random-effects meta-analysis/meta-regression (based on quite different computational background) yields similar results (Fig. 1B): (i) no indication of a benefit based on small RCTs (RR=0.868, 95%HPD CrI 0.463–1.626), with very wide prediction interval (from 2.5 lower to 98% higher relative risk of the outcome with fluvoxamine); (ii) no indication of a benefit based on large RCTs (RR=0.883, 0.679–1.182) with prediction extended from twice lower to 70% higher (relatively) risk with fluvoxamine); (iii) and no indication of a benefit in a random-effect meta-analysis across all trials (RR=0.867, 0.67–1.142), again with wide prediction interval (Fig. 1B).
      Table 1Randomized placebo-controlled trials (all parallel-group, double-blind) of fluvoxamine in COVID-19 outpatients included in the present analysis.
      AuthorPopulationFluvoxamineControlReported outcomeFor the present analysisSource of outcome data
      Lenze 2020
      • Lenze E.J.
      • Mattar C.
      • Zorumski C.F.
      • Stevens A.
      • Schweigher J.
      • Nicol G.E.
      • et al.
      Fluvoxamine vs. placebo and clinical deterioration in outpatients with symptomatic COVID-19.
      USA
      Adult, not vaccinated, PCR-positive, ≤7 days since the symptom onset, ≥92% oxygenation on room air; free of severe comorbidities /immune suppression.Single 50 mg dose; then 2 × 100 mg over 2 days and up-titrated to 3 × 100 mg up to 15 days (if tolerated)Matching placeboNew-onset dyspnea or hospitalization for dyspnea or pneumonia + saturation drop to <92% over 15 daysHospitalization for dyspnea or pneumonia with saturation drop over 15 daysUpdated trial data provided in a review by Lee et al.
      • Lee T.C.
      • Vigod S.
      • Bortolussi-Courval E.
      • Hanula R.
      • Boulware D.R.
      • Lenze E.J.
      • et al.
      Fluvoxamine for outpatient management of COVID-19 to prevent hospitalization. A systematic review and meta-analysis.
      (Figure 2)
      Lenze 2021
      • Lenze E.
      Fluvoxamine for early treatment of covid-19: a fully-remote, randomized placebo controlled trial.
      USA
      Age ≥30 years, confirmed COVID-19, not vaccinated, mild symptoms, ≥92% oxygenation on room air; free of severe comorbidities /immune suppressionUp to 2 × 100 mg, 15 days (as tolerated)Matching placeboNew-onset dyspnea or hospitalization for dyspnea or pneumonia + saturation drop to <92% over 15 daysHospitalization for dyspnea or pneumonia with saturation drop over 15 daysUpdated trial data provided in a review by Lee et al.
      • Lee T.C.
      • Vigod S.
      • Bortolussi-Courval E.
      • Hanula R.
      • Boulware D.R.
      • Lenze E.J.
      • et al.
      Fluvoxamine for outpatient management of COVID-19 to prevent hospitalization. A systematic review and meta-analysis.
      (Figure 2)
      Seo 2022
      • Seo H.
      • Kim H.
      • Bae S.
      • Park S.
      • Chung H.
      • Sung HS
      • et al.
      . Fluvoxamine treatment of patients with symptomatic COVID-19 in a community treatment center: a preliminary result of randomized controlled trial.
      South Korea
      Adult, PCR-positive, ≤7 days since the symptom onset, mild symptoms; free of severe comorbidities /immune suppression.Single 50 mg dose; then 2 × 100 mg, 10 days (as tolerated)Matching placeboSaturation drop to <94% or new onset pneumonia/dyspnea with infiltrate on chest X-ray over 10 daysReported outcomePublished study (text)
      Reis 2022
      • Reis G.
      • dos Santos-Moreira-Silva A.
      • Medeiros Silva D.C.
      • Thabane L.
      • Cruz Milagres A.,.
      • Santiago Ferreira T.
      • et al.
      Effect of early treatment with fluvoxamine on riks of emergeny care and hospitalization among patients with COVID-19: the TOGETHER randomized, platform clinical trial.
      Brazil
      Adult, confirmed COVID-19, ≤7 days since the symptom onset, not vaccinated, mild symptoms + at least one factor suggestive of a high-risk patient2 × 100 mg, 15 daysMatching placeboHospitalization or emergency room visit due to COVID-19 that is >6 h duration over 28 daysReported outcomePublished study (Table 2)
      Bramante 2022
      • Bramante C.T.
      • Huling J.D.
      • Tignanelli C.J.
      • Buse J.B.
      • Liebovitz D.M.
      • Nicklas J.M.
      • et al.
      Randomized trial of metformin, ivermectin and fluvoxamine for COVID-19.
      USA
      Age 30–85 years, overweight-obese, confirmed COVID-19, mild sysmptoms, ≤7 days since the symptom onset + renal or liver or cardiovascular condition associated with a high risk, but not unstable, and not immunocompromised1. Fluvoxamine 2 × 50 mg + placebo, 14 days

      2. Fluvoxamine 2 × 50 mg + metformin, 14 days
      1. “Double” matching placebo

      2. Matching placebo + metformin
      Oxygenation drop to ≤93% or emergency department visit or hospitalization or death over 14 daysOxygenation drop or emergency department visit or hospitalization over 14 days(no patient died)Published study – online supplement, Figure S1C
      McCarthy 2022

      McCarthy M., Naggie S., Boulware D.R., Lindsell C.J., Stweart T.G., Felker M. et al. Fluvoxamine for outpatient treatment of COVID-19: a decentralized, placebo-controlled, randomized, platform clinical trial. meRxiv https://doi.org/10.1101/2022.10.17.22281178

      USA
      Age ≥30 years, confirmed COVID-19, ≤7 days since the symptom onset, mild symptoms2 × 50 mg, 10 daysMatching placeboHospitalization, urgent care, emergency room visit or death over 28 daysHospitalization, urgent care or emergency room visit over 28 days (no patient died)Published study (Table 2)
      Fig. 1
      Fig. 1Meta-analysis of randomized placebo-controlled trials of fluvoxamine outlined in . Please note, “Bramante 2022 1″ refers to a comparison of fluvoxamine + metformin placebo vs. “double” matching placebo, while “Bramante 2022 2″ refers to the comparison of fluvoxamine + metformin vs. fluvoxamine placebo + metformin. Since both comparisons come from the same trial, usually the “overall” estimate of fluvoxamine vs. placebo is referred to. However, as shown here, the two comparisons yielded estimates in opposing directions (albeit, imprecise): by disregarding this discrepancy (as small as it might be) and using the “raw overall estimate”, one artificially reduces heterogeneity across fluvoxamine vs. placebo comparisons. A Frequentist random effects meta-analysis/meta-regression addressed “study size” as a categorical moderator and yielded effect and heterogeneity estimates at each level of the moderator, as well as the overall one (restricted maximum likelihood estimator of τ2, with Hartung-Knapp-Sidik-Jonkman adjustment to t-distribution). B Bayesian random-effects meta-analysis/meta-regression used the same approach, but under the Bayesian framework, with weakly informative prior for τ2 (half Cahuchy, scale=0.5), and moderately informative skeptical prior for the pooled estimate compatible with the a priori hypothesis of no treatment effect [normal (0.0, 0.355) for ln(RR) – assigns 50% probability to RR <1.0, and 50% probability to RR >1.0].
      Overall, the two published meta-analyses
      • Cheema H.A.
      • Jafar U.
      • Elrashedy A.A.
      • Shahid A.
      • Awan R.U.
      • Ehsan M.
      • et al.
      Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.
      ,
      • Marčec R.
      • Dodig V.M.
      • Likić R.
      A meta-analysis regarding fluvoxamine and hospitalization risk of COVID-19 patients. TOGETHER making a difference.
      adopted a choice of the outcome that might not be fully illustrative for the intended purpose, which combined with some methodological drawbacks resulted in estimates that are likely inaccurate, i.e., overtly optimistic. Based on the present analysis, it seems reasonable to conclude that the current best available evidence rather convincingly demonstrates that fluvoxamine – at dosing regimens otherwise viewed as acceptably safe (as one would expect in drug repurposing efforts) - conveys no relevant benefit in this setting.

      Funding

      This work received no funding.

      Data availability

      All data used in this work are presented in the manuscript (Table 1, Fig. 1)

      Declaration of Competing Interest

      I have no financial or non-financial conflict of interest to declare.

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