Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?
D'Arminio Monforte et al.
, Effectiveness of Hydroxychloroquine in COVID-19 disease: A done and dusted situation?
, Int. J. Infectious Diseases, doi:10.1016/j.ijid.2020.07.056
HCQ+AZ adjusted death HR 0.44, p=0.009. Propensity scores include baseline COVID-19 disease severity, age, gender, number of comorbidities, cardio-vascular disease, duration of symptoms, date of admission, baseline plasma CRP. IPW censoring. Retrospective study of 539 COVID-19 hospitalized patients in Milan, with treatment a median of 1 day after admission. HCQ 197 patients, HCQ+AZ 94, control 92. Control group received various other treatments. Authors excluded people receiving other drugs which could have biased the effect of HCQ when used in combination. Residual confounding is possible (e.g., people with CVD were more frequent in control), however people in the control group were more likely to require mechanical ventilation.
risk of death, 34.0% lower, HR 0.66, p = 0.12, treatment 53 of 197 (26.9%), control 47 of 92 (51.1%), NNT 4.1, adjusted per study.
HCQ+AZ, 56.0% lower, HR 0.44, p = 0.009, treatment 22 of 94 (23.4%), control 47 of 92 (51.1%), NNT 3.6, adjusted per study.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
D'Arminio Monforte et al., 29 Jul 2020, retrospective, Italy, peer-reviewed, 5 authors.
Abstract: International Journal of Infectious Diseases 99 (2020) 75–76
Contents lists available at ScienceDirect
International Journal of Infectious Diseases
journal homepage: www.elsevier.com/locate/ijid
Letter to the Editor
Effectiveness of hydroxychloroquine in
COVID-19 disease: A done and dusted deal?
Arshad et al. show evidence for reduced mortality in COVID-19
patients taking hydroxychloroquine alone or with azithromycin in
an observational study in the USA (Arshad et al., 2020). Data on the
effectiveness and toxicity of hydroxychloroquine are controversial
(Liu et al., 2020; Devaux et al., 2020; Gautret et al., 2020; Tang et al.,
2020; Geleris et al., 2020).
A total of 539 COVID-19 hospitalized patients were included in
our cohort in Milan, from February 24 to May 17, 2020, of whom
174 died in hospital (day 14 probability of death: 29.5% – 95%CI:
25.5–34.0). We divided a subset of our cohort into three groups
who started treatment a median of 1 day after admission: those
receiving hydroxychloroquine alone (N = 197), those receiving
hydroxycholoroquine + azithromycin (N = 94), and those receiving
neither (controls) (N = 92). Of the latter group, ten started HIV
antivirals (boosted-lopinavir or –darunavir), one teicoplanin,
twelve immunomodulatory drugs, or corticosteroids, 23 heparin
and 46 remained untreated. The percent of death in the three
groups was 27%, 23%, and 51%. Mechanical ventilation was used in
4.3% of hydroxychloroquine, 14.2% of hydroxychloroquine + azithromycin, and 26.1% of controls. Unweighted and weighted
relative hazards of mortality are shown in Table 1. After adjusting
for several key confounders (see table), the use of hydroxycholoroquine + azithromycin was associated with a 66% reduction in
risk of death as compared to controls; the analysis also suggested
more substantial effectiveness of hydroxychloroquine in patients
with less severe COVID-19 disease (PO2/FiO2 > 300, interaction
p-value <0.0001). Our results are remarkably similar to those
shown by Arshad et al.
Some important weaknesses in Arshad et al.’s analysis have
been pointed out (Lee et al., 2020), but not all of these apply to
our study. Our propensity scores include some of the potential
confounders that were missing in the analysis by Arshad (e.g.,
calendar day of admission, disease severity, cardiovascular
disease (CVD), baseline plasma CRP); second, we have excluded
people receiving other drugs which could have biased the effect
of hydroxychloroquine when used in combination. Third,
although residual confounding is a possibility (e.g., people with
CVD were more frequent in control), people in the control group
were more likely to undergo mechanical ventilation, which is a
conservative bias. These results from two different real-life
settings (Italy and USA), conﬂict with those of two large
randomized trials (Horby et al., 2020; World Health Organization, 2020). Although unmeasured confounding remains
the most likely explanation for the discrepancies, a robust
meta-analysis is still lacking, and we believe that hydroxychloroquine should be further tested in randomised trials. When
best to start treatment is also a question that needs to be
addressed in ad-hoc randomized studies.
Unadjusted and adjusted marginal relative hazards of in-hospital mortality
Unadjusted HR (95% CI)
Control# (n = 92)
Hydroxychloroquine (n = 197)
Hydroxychloroquine + Azithromycin (n = 94)
Control# (n = 41)
Hydroxychloroquine (n = 83)
is less effective
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