Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Axfors et al.
, Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative..
, Nature, doi:10.1038/s41467-021-22446-z (meta analysis)
Meta analysis assigning 89% weight to the RECOVERY and SOLIDARITY trials, producing the same result. These trials used excessively high non-patient-customized dosage in very sick late stage patients, results are not generalizable to typical dosage or earlier treatment. For CQ, 97% weight is assigned to Borba et al., a study that does not have a control group (the study compares two different dosages of CQ). Of the 29 early treatment trials (including 6 RCTs), authors included the results of only one where they include a non-hospitalized death.
Currently there are 36 HCQ early treatment studies
and meta analysis shows:
Axfors et al., 18 Sep 2020, peer-reviewed, 97 authors.
Mortality outcomes with hydroxychloroquine and
chloroquine in COVID-19 from an international
collaborative meta-analysis of randomized trials
Substantial COVID-19 research investment has been allocated to randomized clinical trials
(RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or
early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine
on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on
hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://
osf.io/QESV4/). We systematically identiﬁed unpublished RCTs (ClinicalTrials.gov, WHO
International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020),
and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause
mortality has been extracted (publications/preprints) or requested from investigators and
combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% conﬁdence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespeciﬁed
subgroup analyses include patient setting, diagnostic conﬁrmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials
(1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine
are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which
employed relatively high doses and included 4716 and 1853 patients, respectively (67% of
the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11
(95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15,
21.13, I² = 0%; 4 trials; 307 patients). We identiﬁed no subgroup effects. We found that
treatment with hydroxychloroquine is associated with increased mortality in COVID-19
patients, and there is no beneﬁt of chloroquine. Findings have unclear generalizability to
outpatients, children, pregnant women, and people with comorbidities.
A full list of authors and their afﬁliations appears at the end of the paper.
NATURE COMMUNICATIONS | (2021)12:2349 | https://doi.org/10.1038/s41467-021-22446-z | www.nature.com/naturecommunications
NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-22446-z
oronavirus disease 2019 (COVID-19) caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
has the potential of progression into respiratory failure
and death1. More than 1,500,000 persons with COVID-19 globally have died by December 20202, and treatment options are
limited3. The COVID-19 pandemic has caused a hitherto
unprecedented search for possible therapies, with almost 700
clinical trials initiated in the ﬁrst quarter of 2020—and one in ﬁve
of these trials target hydroxychloroquine (HCQ) or chloroquine
(CQ)4. This remarkable attention was primarily due to in vitro
data5, immunomodulatory capacities6, and the oral formulation
and well-documented safety proﬁles.
In March 2020, the US Food and Drug Administration (FDA)
issued an Emergency Use Authorization of HCQ7 and the
number of prescriptions and usage outside clinical studies
skyrocketed8. In many countries, HCQ or CQ were listed in
treatment guidelines for COVID-19 (including,..
is less effective
Please send us corrections, updates, or comments. Vaccines and
treatments are complementary. All practical, effective, and safe means should
be used based on risk/benefit analysis. No treatment, vaccine, or intervention
is 100% available and effective for all current and future variants. We do not
provide medical advice. Before taking any medication, consult a qualified
physician who can provide personalized advice and details of risks and
benefits based on your medical history and situation. FLCCC
provide treatment protocols.