Figure 1 . Data sources and curation (see text for details).A. Raw data was prepared by the Croatian Institute for Public
Health from several databases that it maintains. COVID-19 patients were
identified based on positive polymerase chain reaction (PCR) or rapid
antigen testing (RAT) performed at dedicated public testing points or
hospitals (ICD-10 code U07.1), or based on epidemiological/clinical
criteria (ICD-10 code U07.2) and individual data were linked to
databases on vaccination, deceased persons, hospitalizations and Central
Heath Information System. B . Anonymized data were “tidied-up”
by exclusion of patients first diagnosed by PCR testing when seeking
hospital assistance regardless of the reason, so as to retain only
outpatients; subjects younger than 16 years and those with
missing/erroneous entries on key variables. Also, repeated COVID-19
episodes were excluded and cut-off date for index COVID-19 diagnosis was
set at August 15, 2021. Based on International Classification of Disease
version 10 (ICD-10) code entries and Anatomical Therapeutic Chemical
(ATC) code entries patients were classified into subsets (Group A, Group
B, Group C) in respect to issuance of prescriptions for fluvoxamine and
underlying morbidity. Definitions of Group A (patients burdened with
conditions requiring antidepressant/anxyolytic treatment and prescribed
fluvoxamine around the time of COVID-19 diagnosis), Group B (patients
patients burdened with conditions requiring antidepressant/anxyolytic
treatment not prescribed with fluvoxamine) and Group C patients
(patients free of psychiatric difficulties and of respective treatments)
are detailed in Table 1.
Figure 2 . Raw incidence (percentage) of COVID-related
hospitalization, all-cause 30-day hospitalization and of COVID-related
mortality (composite) (see Patients and Methods for definitions) across
the patient subsets: Group A (patients burdened with conditions
requiring antidepressant/anxyolytic treatment and prescribed fluvoxamine
around the time of COVID-19 diagnosis), Group B (patients burdened with
similar psychiatric difficulties, but not prescribed with fluvoxamine)
and Group C (patients free of psychiatric difficulties and of respective
treatments).
Figure 3. Analysis of outcomes (see Patients and Methods for
definitions) in matched sets of patients burdened with conditions
requiring antidepressant/anxyolytic treatment and prescribed (Group A)
or not prescribed (Group B) fluvoxamine, and those free of such
difficulties and related treatments (Group C) around the time of
COVID-19 diganosis. Depicted are proportions (percentages) of patients
with outcomes in each matched set and respective relative risks (RR).
Priors for Bayes estimates: skeptical is moderately informative
normal prior centered at 0.0 for Ln(RR) with standard deviation 0.355 –
gives equal (50%) probability to an RR above and an RR below unity with
95% probability for an RR between 0.5 and 2.0; optimistic is a
moderately informative normal prior centered at -0.199 for Ln(RR) (i.e.,
18% relative risk reduction) with standard deviation 0.40 – suggests a
benefit but leaves 30% probability of an RR >1.0;pesimistic is a weakly informative normal prior centered at 0.199
for Ln(RR) (i.e., 22% relative risk increase) with standard deviation
0.77 – suggests harm (of the same extent as benefit suggested by the
optimistic prior), but leaves 40% probability of an RR <1.0.
Figure 4 . Differences between Group A patients (burdened with
conditions requiring antidepressant/anxyolytic treatment and prescribed
fluvoxamine around the time of COVID-19 diagnosis) and Group B patients
(suffer similar psychiatric difficulties, but are not prescribed with
fluvoxamine), i.e., control patients, regarding the outcomes of interest
(see Patients and Methods for definitions) generated in network
meta-analysis (frequentist and Bayes) that included Group A vs. Group B,
Group A vs. Group C and Group B vs. Group C comparisons in matched sets.A . Meta-analysis based on weighted proportions. Direct,
indirect and total (combined, network) differences. B.Meta-analysis based on Ln (RR) generated in primary Bayesian analysis
with moderately informative skeptical prior (shown in Figure 3). Only
total (combined) effects are shown (as in A, direct and indirect effects
were consistent).