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Meta-analysis

Fluvoxamine in Nonhospitalized Patients With Acute COVID-19 Infection and the Lack of Efficacy in Reducing Rates of Hospitalization, Mechanical Ventilation, and Mortality in Placebo-Controlled Trials: A Systematic Review and Meta-Analysis

Bhuta, Sapan MD1; Khokher, Waleed MD1,*; Kesireddy, Nithin MD1; Iftikhar, Saffa MD1; Beran, Azizullah MD1; Mhanna, Mohammed MD1; Patel, Neha J. MD1; Patel, Mitra MD1; Burmeister, Cameron MD, MS1; Assaly, Ragheb MD2

Author Information
American Journal of Therapeutics: May/June 2022 - Volume 29 - Issue 3 - p e298-e304
doi: 10.1097/MJT.0000000000001496

Abstract

INTRODUCTION

Coronavirus disease 2019 (COVID-19) manifests in a broad range of clinical presentations: 33% of patients remain asymptomatic, and of those who are symptomatic, roughly 14% develop severe symptoms and 5% suffer critical symptoms (respiratory failure, shock, or multiorgan dysfunction).1 Mortality is significantly higher among patients requiring hospitalization, particularly those on mechanical ventilation, reported at 24% and 60% respectively.2

Clinical deterioration typically occurs within 9–14 days of initial mild-to-moderate symptoms.3 Available evidence suggests that organ damage in COVID-19 is related to an excessive inflammatory response, leading to numerous investigations into immunomodulatory therapies.4 Recent trials involving glucocorticoids (eg, dexamethasone), interleukin (IL)-6 pathway inhibitors (eg, tocilizumab), and JAK inhibitors (eg, baricitinib) have shown significant benefit in hospitalized patients.5–7 However, options remain limited for outpatients with nonsevere disease, with only monoclonal antibody therapy demonstrating benefit in patients with certain risk factors for severe disease.8

Fluvoxamine, a well-known, widely available, and inexpensive selective serotonin reuptake inhibitor (SSRI) has recently been studied in the setting of acute COVID-19 infection. A few mechanisms suggest why fluvoxamine may be beneficial in acute COVID-19 infection. First, fluvoxamine stimulates the sigma-1 receptor (S1R), which dampens cellular stress by inhibiting inositol-requiring enzyme 1, resulting in downregulation of proinflammatory cytokine production without inhibiting classical inflammatory signaling pathways.9 Second, fluvoxamine is a functional inhibitor of acid sphingomyelinase activity, thus inhibiting the acid sphingomyelinase/ceramide system that SARS-CoV-2 relies on for viral entry.10 In a cell culture model, this mechanism efficiently inhibited the entry and propagation of SARS-CoV-2.11 However, the role of fluvoxamine is currently unclear because of a lack of clinical trials studying its effects and a lack of established historical data for its use as an immunomodulatory or antiviral agent. The aim of our meta-analysis was to investigate the use of fluvoxamine versus placebo in nonhospitalized patients with acute COVID-19 infection in preventing clinical deterioration.

METHODS

Data sources and search strategy

We performed a comprehensive search for published studies indexed in PubMed/MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science from inception to February 10, 2022. We also performed a manual search for additional relevant studies using references of the included articles. From each study, we collected the number of patients who underwent treatment with fluvoxamine or placebo while presenting to an outpatient setting. The following search terms were used: (“fluvoxamine” or “SSRI”), (“coronavirus disease 19” or “COVID-19”), and (“clinical deterioration” or “hospitalization”). The search was not limited by language, study design, or country of origin. Supplemental Digital Content (see Table 1, https://links.lww.com/AJT/A108) shows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist pertain to our manuscript. Supplemental Digital Content (see Table 2, https://links.lww.com/AJT/A108) describes the full search queries used during literature search.

Inclusion and exclusion criteria

We included only full texts of clinical trials including randomized controlled trials (RCTs) and cohort studies. We limited our selection of trials to those that studied nonhospitalized patients only. We excluded animal studies, case reports, case series, reviews, editorials, and letters to editors.

Data extraction

The following data were extracted from the studies: first author name, publication year, country of origin, study design, number of patients, mean age of the patients, gender of the patients, and underlying comorbidities of the patients including asthma and other chronic lung diseases, diabetes, and hypertension. For each arm of the study, the regimen of fluvoxamine or placebo was also extracted. Outcomes of interest were also retrieved including rate of hospitalization, number of patients requiring mechanical ventilation, and mortality. We followed the PRISMA Statement guidelines to select the final studies. Two investigators (S.B. and W.K.) independently performed the search and shortlisted the studies for final review. Discrepancies were resolved by a third reviewer (N.K.).

Outcomes

The primary outcome of interest was the rate of hospitalization. The secondary outcomes were rates of patients requiring mechanical ventilation and mortality.

Statistical analysis

We performed a meta-analysis of the included studies using the Review Manager 5.3 (Cochrane Collaboration, Copenhagen, The Nordic Cochrane Centre). The random-effects model was used to calculate the risk ratios (RR), mean differences, and confidence intervals (CIs). A 95% CI of our desired primary and secondary outcomes was considered, and thus P-value <0.05 was considered statistically significant. Heterogeneity was assessed using Higgins I2 index. An I2 index of 0%–25% implied insignificant heterogeneity, 26%–50% low heterogeneity, 51%–75% moderate heterogeneity, and 76%–100% high heterogeneity.12

Bias assessment

We assessed the quality of the included studies using the Newcastle–Ottawa Scale (NOS) for observational studies and the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) for RCTs.13,14 Two authors (S.B. and W.K.) independently assessed each study for bias. Publication bias assessment was performed qualitatively by visualizing the funnel plot, and quantitatively using Egger regression analysis. A P-value was generated using the Egger analysis and a value of <0.05 was associated with significant publication bias.

RESULTS

Study selection

A total of 180 studies were retrieved by our search strategy. Among these, 29 were eligible for systematic review. Subsequently, we excluded 26 studies because of multiple reasons: 3 studies were performed on nonoutpatient populations, 6 studies included patients who had already been hospitalized for illness related to COVID-19 or something entirely different, 5 studies were excluded because they did not strictly compare fluvoxamine to placebo care, and 12 studies did not report the appropriate outcomes our study was analyzing. Eventually, 3 studies met our inclusion criteria and were included in the meta-analysis.15–17Figure 1 shows the PRISMA flow chart that illustrates how the final studies were selected.

F1
FIGURE 1.:
PRISMA flow diagram for the selection of studies.

Study characteristics

Table 1 shows the baseline characteristics of the studies included in the meta-analysis. All the studies included in the meta-analysis were published between December 2020 and October 2021 and included patients were all recruited from an outpatient setting and had not yet been hospitalized for COVID-19-related illnesses. Based on country of origin, 2 studies originated from USA and 1 from Brazil. Regarding their study design, 2 studies were RCTs and 1 was a nonrandomized prospective cohort study. All the studies were full-text publications; no abstracts were included. A total of 1762 patients were included in these 3 studies; 886 patients received fluvoxamine and 876 patients received placebo treatment. The mean age of the patients in the fluvoxamine group was 49 years, and men represented 45.8% of the total patients in the fluvoxamine group. The mean age of the patients in the placebo group was 49 years, and men represented 40.8% of the total patients in the placebo group.

Table 1. - Study and patient characteristics.
Study, yr Lenze 2020 Reis 2021 Seftel 2021
Study design Randomized clinical trial Randomized clinical trial Nonrandomized prospective cohort
Country United States of America Brazil United States of America
Total patients (fluvoxamine/placebo) 80/72 741/756 65/48
Fluvoxamine group age; mean ± SD 46 ± 17 48 ± 12 44 ± 15
Placebo group age; mean ± SD 45 ± 13 47 ± 13 43 ± 15
Male in fluvoxamine group, n (%) 24 (30) 332 (45) 50 (77)
Male in placebo group, n (%) 19 (26) 303 (40) 35 (73)
Asthma and other chronic lung diseases (fluvoxamine/placebo) 17/9 12/16 2/1
Diabetes type 1 & 2 (fluvoxamine/placebo) 9/8 129/114 11/4
Hypertension (fluvoxamine/placebo) 15/15 106/88 11/17
Fluvoxamine regimen 50 mg on day 1, then 100 mg twice daily for the next 2 d, then 100 mg 3 times daily, for a total of 15 d of treatment 100 mg twice daily for a total of 10 d of treatment 50–100 mg loading dose on day 1, then 50 mg twice daily for the next 13 d, for a total of 14 d of treatment
Placebo regimen Matching placebo pills Matching placebo pills No therapy

Rate of hospitalization

Table 2 provides a summary of the primary and secondary outcomes. After analyzing the data from all 3 studies, 8.5% of the patients that received fluvoxamine after COVID-19 diagnosis required hospitalization within the month compared with 12.2% for those in the placebo group. The difference in rate of hospitalization between the fluvoxamine group and placebo group was found to be nonsignificant (RR 0.26, 95% CI, 0.04–1.73, P = 0.16). The statistical heterogeneity was found to be moderate, with an I2 index of 62% (Pheterogeneity = 0.07). The forest plot representing these findings can be seen in Figure 2.

Table 2. - Study outcomes.
Study, yr Hospitalization Mechanical ventilation Mortality
Fluvoxamine Placebo Fluvoxamine Placebo Fluvoxamine Placebo
Lenze, 2020 0/80 (0.0%) 4/72 (5.6%) 0/80 (0.0%) 1/72 (1.4%) 0/80 (0.0%) 0/72 (0.0%)
Reis, 2021 75/741 (10.1%) 97/756 (12.8%) 26/741 (3.5%) 34/756 (4.5%) 17/741 (2.3%) 25/756 (3.3%)
Seftel, 2021 0/65 (0.0%) 6/48 (12.5%) 0/65 (0.0%) 2/48 (4.2%) 0/65 (0.0%) 1/48 (2.1%)
Total 75/886 (8.5%) 107/876 (12.2%) 26/886 (2.9%) 37/876 (4.2%) 17/886 (1.9%) 26/876 (3.0%)

F2
FIGURE 2.:
Forrest plot comparing fluvoxamine versus placebo for hospitalization rate.

Need for mechanical ventilation

The rate of requiring mechanical ventilation was 2.9% in the fluvoxamine group and 4.2% in the placebo group. The difference in the need for mechanical ventilation was found to be nonsignificant (RR 0.73, 95% CI, 0.45–1.19, P = 0.21). The statistical heterogeneity was also found to be nonsignificant, with an I2 index of 0% (Pheterogeneity = 0.48). The forest plot representing these findings can be seen in Figure 3.

F3
FIGURE 3.:
Forrest plot comparing fluvoxamine versus placebo for rate of requiring mechanical ventilation.

Rate of mortality

The rate of mortality was 1.9% in the fluvoxamine group and 3.0% in the placebo group. The difference in the rate of mortality was found to be nonsignificant (RR 0.67, 95% CI, 0.37–1.22, P = 0.19). The statistical heterogeneity was also found to be nonsignificant, with an I2 index of 0% (Pheterogeneity = 0.53). The forest plot representing these findings can be seen in Figure 4.

F4
FIGURE 4.:
Forrest plot comparing fluvoxamine versus placebo for mortality rate.

Quality and publication bias assessment

The NOS for observational studies determined that the included study was of high quality (see Table 3, Supplemental Digital Content, https://links.lww.com/AJT/A108). The modified Cochrane RoB 2 demonstrated a low risk of bias for the included studies (see Figure 1, Supplemental Digital Content, https://links.lww.com/AJT/A108).

DISCUSSION

Since the onset of the COVID-19 pandemic, numerous repurposed drugs have been explored for treatment of the disease, but the results have been mixed. Available evidence does not support the use of remdesivir, hydroxychloroquine, lopinavir-ritonavir, interferon, azithromycin, favipiravir, ivermectin, or convalescent plasma.18–23 Fortunately, the use of immunomodulatory agents including glucocorticoids (eg, dexamethasone), IL-6 pathway inhibitors (eg, tocilizumab), and JAK inhibitors (eg, baricitinib) has demonstrated meaningful mortality benefit.5–7 However, these therapies are only indicated in hospitalized patients. Thus far, only monoclonal antibody therapy (eg, casirivimab-imdevimab) has shown benefit in early symptomatic outpatients with risk factors for severe illness.8 Hospitalization in the setting of an acute COVID-19 infection is clearly associated with a significantly higher rate of mortality.2 Thus, we conducted a systematic review and meta-analysis to assess the efficacy of fluvoxamine as an agent to prevent hospitalization in patients with acute COVID-19 infection.

At first glance, the use of an SSRI as an antiviral agent may seem inconsequential. However, fluvoxamine has shown a strong affinity for S1R ultimately exerting an immunomodulatory effect via downregulation of pro-inflammatory cytokine production.9 Rosen et al24 demonstrated that in preclinical models of sepsis, S1R is an essential inhibitor of cytokine production, mice lacking S1R quickly succumb to hypercytokinemia leading to multiorgan dysfunction, and the anti-inflammatory action of S1R is conserved across species in human cells, at least ex vivo. Notably, in critically ill patients with severe COVID-19 pneumonia admitted to the intensive care unit (ICU), Calusic et al25 demonstrated a mortality benefit with fluvoxamine.

However, our meta-analysis demonstrates that the use of fluvoxamine was not associated with a statistically significant reduction in the rate of hospitalization, need for mechanical ventilation, or mortality in outpatient adults. Importantly, the 2 RCTs analyzed used the intention-to-treat model, in which patients who were nonadherent to treatment were also included in the final analysis. Using an intention-to-treat model is typically a strength, but can greatly affect the endpoint of smaller underpowered studies, introducing type II errors.26 In the study by Lenze et al,15 19% patients assigned to the fluvoxamine group stopped taking the medication for reasons other than symptom improvement or adverse effect to the medication. In the study by Reis et al17 only 74% of patients reported >80% adherence to the fluvoxamine treatment regimen. Reis et al17 commented on this phenomenon and performed a per-protocol analysis on the 74% of patients that adhered to >80% of the fluvoxamine regimen and found that rates of hospitalization and mortality were significantly reduced in the treatment group compared with the placebo group. However, the overall nonsignificance noted in our meta-analysis, seems to be driven by lack of statistical power and is accentuated by nonadherence to therapy. From a qualitative perspective, the analyzed studies, particularly the RCTs, were well conducted, and showed clinically meaningful results. However, it is important to note that statistical significance is still the preferred metric, and is a vital part of objectively analyzing data collected during clinical trials.

There are several limitations to our meta-analysis. First, the lack of adequately powered trials makes the results extremely fragile to the point where one RCT can have a large impact on the pooled results. Such was the case in our investigation because most of the effect in our analyses was provided by the TOGETHER trial conducted by Reis et al.17 Second, and perhaps even more importantly, the lack of adherence to the fluvoxamine regimen during the trial makes it difficult to definitively support nonsignificant results. Third, there are variations in the dosing of fluvoxamine among the different studies. Finally, the follow-up duration was short: 14 days in the Seftel et al, 15 days in the Lenze et al, and 28 days in the Reis et al studies.15–17 These short follow-up periods limit analysis of the long-term effects of fluvoxamine in the context of COVID-19. Despite the limitations, our study has significant strengths. To our knowledge, this is the first meta-analysis assessing the effect of fluvoxamine in nonhospitalized patients with acute COVID-19 infection. All the studies in our meta-analysis were of high quality based on the RoB2 and NOS quality assessment scales.

Our analysis demonstrated that based on the available evidence, the use of fluvoxamine cannot be justified in the outpatient setting at this time. To confirm or disprove these findings, additional RCTs would be required. However, because of the increasing availability of vaccinations and effective immunomodulatory therapies, it may be difficult to further allocate resources towards studying a repurposed class of therapeutic agents such as SSRIs which has not historically been used for its anti-inflammatory or antiviral properties.

In conclusion, our results demonstrate that there is no significant improvement in the rates of hospitalization, need for mechanical ventilation, and mortality among nonhospitalized adults treated with fluvoxamine when compared with placebo/nontreatment groups.

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Keywords:

Fluvoxamine; Coronavirus disease 2019; hospitalization; nonhospitalized

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