VIRUS C20 THE LANCET NAO PARA A CLOROQUINA 22 MAY 2020
Published Online
May 22, 2020
https://doi.org/10.1016/
S0140-6736(20)31180-6
See Online/Comment
https://doi.org/10.1016/
S0140-6736(20)31174-0
Brigham and Women’s Hospital
Heart and Vascular Center and
Harvard Medical School,
Boston, MA, USA
(Prof M R Mehra MD);
Surgisphere Corporation,
Chicago, IL, USA (S S Desai MD);
University Heart Center,
University Hospital Zurich,
Zurich, Switzerland
(Prof F Ruschitzka MD);
Department of Biomedical
Engineering, University
of Utah, Salt Lake City, UT, USA
(A N Patel MD); and
HCA
Research Institute, Nashville,
TN, USA (A N Patel)
Correspondence to:
Prof Mandeep R Mehra, Brigham
and Women’s Hospital Heart and
Vascular Center and Harvard
Medical School, Boston,
MA 02115, USA
mmehra@bwh.harvard.edu
Hydroxychloroquine or chloroquine with or without a
macrolide for treatment of COVID-19: a multinational
registry analysis
https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31180-6.pdf
Hydroxychloroquine or chloroquine with or without a
macrolide for treatment of COVID-19: a multinational
registry analysis
Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel
*******************************************************************
Summary
Background Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being
widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when
used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment
regimens are poorly evaluated in COVID-19.
Methods We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a
macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included
patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2.
Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment
groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a
macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of
the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation,
as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality
and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or
ventricular fibrillation).
Findings 96032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study
period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received
chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received
hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10698 (11·1%) patients died in
hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying
cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition,
and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine
(18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531),
chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each
independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%),
hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983),
chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were
independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.
Interpretation We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with
a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased
in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.
Funding William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Introduction
The absence of an effective treatment against severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection has led clinicians to redirect drugs that are
known to be effective for other medical conditions to the
treatment of COVID-19. Key among these repurposed
therapeutic agents are the antimalarial drug chloroquine
and its analogue hydroxychloroquine, which is used for
the treatment of autoimmune diseases, such as systemic
lupus erythematosus and rheumatoid arthritis.1,2 These
drugs have been shown in laboratory conditions to have
antiviral properties as well as immunomodulatory
effects.3,4 However, the use of this class of drugs for
COVID-19 is based on a small number of anecdotal
experiences that have shown variable responses in
uncontrolled observational analyses, and small, openlabel, randomised trials that have largely been
inconclusive.5,6 The combination of hydroxychloroquine
with a second-generation macrolide, such as azithromycin (or clarithromycin), has also been advocated,
Published Online
May 22, 2020
https://doi.org/10.1016/
S0140-6736(20)31180-6
See Online/Comment
https://doi.org/10.1016/
S0140-6736(20)31174-0
Brigham and Women’s Hospital
Heart and Vascular Center and
Harvard Medical School,
Boston, MA, USA
(Prof M R Mehra MD);
Surgisphere Corporation,
Chicago, IL, USA (S S Desai MD);
University Heart Center,
University Hospital Zurich,
Zurich, Switzerland
(Prof F Ruschitzka MD);
Department of Biomedical
Engineering, University
of Utah, Salt Lake City, UT, USA
(A N Patel MD); and HCA
Research Institute, Nashville,
TN, USA (A N Patel)
Correspondence to:
Prof Mandeep R Mehra, Brigham
and Women’s Hospital Heart and
Vascular Center and Harvard
Medical School, Boston,
MA 02115, USA
mmehra@bwh.harvard.edu
Articles
2 www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6
despite limited evidence for its effectiveness.7
Previous
studies have shown that treatment with chloroquine,
hydroxychloroquine, or either drug combined with a
macrolide can have the cardiovascular adverse effect of
prolongation of the QT interval, which could be a
mechanism that predisposes to ventricular arrhythmias.8,9
Although several multicentre randomised controlled
trials are underway, there is a pressing need to provide
accurate clinical guidance because the use of chloroquine
or hydroxychloroquine along with macrolides is
widespread, often with little regard for potential risk.
Some countries have stockpiled these drugs, resulting in
a shortage of these medications for those that need
them for approved clinical indications.10 The purpose of
this study was to evaluate the use of chloroquine or
hydroxychloroquine alone or in combination with a
macrolide for treatment of COVID-19 using a large
multinational registry to assess their real-world application. Principally, we sought to analyse the association
between these treatment regimens and in-hospital death.
Secondarily, we aimed to evaluate the occurrence of
de-novo clinically significant ventricular arrhythmias.
Methods
Registry features and data acquisition
We did a multinational registry analysis of the use of
hydroxychloroquine or chloroquine with or without a
macrolide for treatment of COVID-19. The registry
comprised 671 hospitals located in six continents
(appendix p 3). The Surgical Outcomes Collaborative
(Surgisphere Corporation, Chicago, IL, USA) consists of
de-identified data obtained by automated data extraction
from inpatient and outpatient electronic health records,
supply chain databases, and financial records. The
registry uses a cloud-based health-care data analytics
platform that includes specific modules for data
acquisition, data warehousing, data analytics, and data
reporting. A manual data entry process is used for quality
assurance and validation to ensure that key missing
values are kept to a minimum. The Surgical Outcomes
Collaborative (hereafter referred to as the Collaborative)
ensures compliance with the US Food and Drug
Administration (FDA) guidance on real-world evidence.
Real-world data are collected through automated data
transfers that capture 100% of the data from each healthcare entity at regular, predetermined intervals, thus
reducing the impact of selection bias and missing values,
and ensuring that the data are current, reliable, and
relevant. Verifiable source documentation for the
elements include electronic inpatient and outpatient
medical records and, in accordance with the FDA
guidance on relevance of real-world data, data acquisition
is performed through use of a standardised Health Level
Seven-compliant data dictionary, with data collected on a
Research in context
Evidence before this study
We searched MEDLINE (via PubMed) for articles published up
to April 21, 2020, using the key words “novel coronavirus”,
“2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “therapy”,
“hydroxychloroquine”, “chloroquine”, and “macrolide”. Moreover,
we screened preprint servers, such as Medrxiv, for relevant articles
and consulted the web pages of organisations such as the
US National Institutes of Health and WHO. Hydroxychloroquine
and chloroquine (used with or without a macrolide) are widely
advocated for treatment of COVID-19 based on in-vitro evidence
of an antiviral effect against severe acute respiratory syndrome
coronavirus 2. Their use is based on small uncontrolled studies
and in the absence of evidence from randomised controlled trials.
Concerns have been raised that these drugs or their combination
with macrolides could result in electrical instability and
predispose patients to ventricular arrhythmias. Whether these
drugs improve outcomes or are associated with harm in
COVID-19 remains unknown.
Added value of this study
In the absence of reported randomised trials, there is an urgent
need to evaluate real-world evidence related to outcomes with
the use of hydroxychloroquine or chloroquine (used with or
without macrolides) in COVID-19. Using an international,
observational registry across six continents, we assessed
96032 patients with COVID-19, of whom 14888 were treated
with hydroxychloroquine, chloroquine, or their combination
with a macrolide. After controlling for age, sex, race or
ethnicity, underlying comorbidities, and disease severity at
baseline, the use of all four regimens was associated with an
increased hazard for de-novo ventricular arrythmia and death
in hospital. This study provides real-world evidence on the use
of these therapeutic regimens by including a large number of
patients from across the world. Thus, to our knowledge, these
findings provide the most comprehensive evidence of the use
of hydroxychloroquine and chloroquine (with or without a
macrolide) for treatment of COVID-19.
Implications of all the available evidence
We found no evidence of benefit of hydroxychloroquine or
chloroquine when used either alone or with a macrolide.
Previous evidence was derived from either small anecdotal
studies or inconclusive small randomised trials. Our study
included a large number of patients across multiple
geographic regions and provides the most robust real-world
evidence to date on the usefulness of these treatment
regimens. Although observational studies cannot fully
account for unmeasured confounding factors, our findings
suggest not only an absence of therapeutic benefit but also
potential harm with the use of hydroxychloroquine or
chloroquine drug regimens (with or without a macrolide)
in hospitalised patients with COVID-19.
See Online for appendix
Articles
www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6 3
prospective ongoing basis. The validation procedure for
the registry refers to the standard operating procedures
in place for each of the four ISO 9001:2015 and
ISO 27001:2013 certified features of the registry: data
acquisition, data warehousing, data analytics, and data
reporting.
The standardised Health Level Seven-compliant data
dictionary used by the Collaborative serves as the focal
point for all data acquisition and warehousing. Once this
data dictionary is harmonised with electronic health
record data, data acquisition is completed using automated
interfaces to expedite data transfer and improve data
integrity. Collection of a 100% sample from each healthcare entity is validated against financial records and
external databases to minimise selection bias. To reduce
the risk of inadvertent protected health information
disclosures, all such information is stripped before storage
in the cloud-based data warehouse. The Collaborative is
intended to minimise the effects of information bias and
selection bias by capturing all-comer data and consecutive
patient enrolment by capturing 100% of the data within
electronic systems, ensuring that the results remain
generalisable to the larger population. The Collaborative is
compliant with the US Agency for Healthcare Research
and Quality guidelines for registries. With the onset of the
COVID-19 crisis, this registry was used to collect data
from hospitals in the USA (that are selected to match
the epidemiological characteristics of the US population)
and internationally, to achieve representation from diverse populations across six continents. Data have been
collected from a variety of urban and rural hospitals,
academic or community hospitals, and for-profit and nonprofit hospitals. The data collection and analyses are
deemed exempt from ethics review.
Study design
We included all patients hospitalised between
Dec 20, 2019, and April 14, 2020, at hospitals participating
in the registry and with PCR-confirmed COVID-19
infection, for whom a clinical outcome of either hospital
discharge or death during hospitalisation was recorded.
A positive laboratory finding for SARS-CoV-2 was defined
as a positive result on high-throughput sequencing or
reverse transcription-quantitative PCR assay of nasal or
pharyngeal swab specimens, and this finding was used
for classifying a patient as positive for COVID-19.
COVID-19 was diagnosed, at each site, on the basis of
WHO guidance.11 Patients who did not have a record of
testing in the database, or who had a negative test, were
not included in the study. Only one positive test was
necessary for the patient to be included in the analysis.
Patients who received either hydroxychloroquine or
a chloroquine analogue-based treatment (with or without a second-generation macrolide) were included in
the treatment group. Patients who received treatment
with these regimens starting more than 48 h after
COVID-19 diagnosis were excluded. We also excluded
data from patients for whom treatment was initiated
while they were on mechanical ventilation or if they were
receiving therapy with the antiviral remdesivir. These
specific exclusion criteria were established to avoid
enrolment of patients in whom the treatment might have
started at non-uniform times during the course of their
COVID-19 illness and to exclude individuals for whom
the drug regimen might have been used during a critical
phase of illness, which could skew the interpretation of
the results. Thus, we defined four distinct treatment
groups, in which all patients started therapy within 48 h
of an established COVID-19 diagnosis: chloroquine
alone, chloroquine with a macrolide, hydroxychloroquine
alone, or hydroxychloroquine with a macrolide. All other
included patients served as the control population.
Data collection
Patient demographics, including age, body-mass index
(BMI), sex, race or ethnicity, and continent of origin
were obtained. Underlying comorbidities (based on
International Classification of Diseases, tenth revision,
clinical modification codes) present in either the inpatient
or outpatient electronic health record were collected, which
included cardiovascular disease (including coronary artery
disease, congestive heart failure, and history of a cardiac
arrhythmia), current or previous history of smoking,
history of hypertension, diabetes, hyperlipidaemia, or
chronic obstructive pulmonary disease (COPD), and
presence of an immunosuppressed condition (steroid
use, pre-existing immunological condition, or current
chemotherapy in individuals with cancer). We collected
data on use of medications at baseline, including cardiac
Figure 1: Study profile
81144 in control group
98262 hospitalised patients
with COVID-19
96032 patients included
2230 excluded
276 taking remdesivir
1102 started a chloroquine
analogue while on
mechanical ventilation
852 received chloroquine
analogue more than
48 h after COVID-19
diagnosis
14888 in treatment groups
1868 received chloroquine
3783 received chloroquine
with macrolide
3016 received
hydroxychloroquine
6221 received
hydroxychloroquine
with macrolide
Articles
4 www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6
medications (angiotensin converting enzyme [ACE]
inhibitors, angiotensin receptor blockers, and statins) or
use of antiviral therapy other than the drug regimens
being evaluated. The initiation of hydroxychloroquine or
chloroquine during hospital admission was recorded,
including the time of initiation. The use of secondgeneration macrolides, specifically azithromycin and
clarithromycin, was similarly recorded. A quick sepsisrelated organ failure assessment (qSOFA) was calculated
for the start of therapy (including a scored calculation of
the mental status, respiratory rate, and systolic blood
pressure) and oxygen saturation (SPO2) on room air was
recorded, as measures of disease severity.
Outcomes
The primary outcome of interest was the association
between use of a treatment regimen containing chloroquine or hydroxychloroquine (with or without a secondgeneration macrolide) when initiated early after COVID-19
diagnosis with the endpoint of in-hospital mortality.
The secondary outcome of interest was the association
between these treatment regimens and the occurrence of
clinically significant ventricular arrhythmias (defined as
the first occurrence of a non-sustained [at least 6 sec] or
sustained ventricular tachycardia or ventricular fibrillation)
during hospitalisation. We also analysed the rates of
progression to mechanical ventilation use and the total
and intensive care unit lengths of stay (in days) for patients
in each group.
Statistical analysis
For the primary analysis of in-hospital mortality,
we controlled for confounding factors, including
demographic variables, comorbidities, disease severity
at presentation, and other medication use (cardiac
medications and other antiviral therapies). Categorical
variables are shown as frequencies and percentages, and
continuous variables as means with SDs. Comparison of
continuous data between groups was done using the
unpaired t-test and categorical data were compared using
Fisher’s exact test. A p value of less than 0·05 was
considered significant. Multiple imputation for missing
values was not possible because for disease and drug
variables, there were no codes to indicate that data were
missing; if the patient’s electronic health record did not
include information on a clinical characteristic, it was
assumed that the characteristic was not present.
Cox proportional hazards regression analysis was
done to evaluate the effect of age, sex, race or ethnicity
(using white race as a reference group), comorbidities
(BMI, presence of coronary artery disease, presence of
congestive heart failure, history of cardiac arrhythmia,
diabetes, or COPD, current smoker, history of hypertension, immunocompromised state, and history of
hyperlipidaemia), medications (cardiac medications,
antivirals, and the treatment regimens of interest), and
severity of illness scores (qSOFA <1 and SPO2 <94%) on
the risk of clinically significant ventricular arrhythmia
(using the time from admission to first occurrence, or if
the event did not occur, to the time of discharge) and
mortality (using the time from admission to inpatient
mortality or discharge). Age and BMI were treated as
Survivors (n=85334) Non-survivors (n=10698) p value
Age, years 53·1 (17·5) 60·0 (17·6) <0·0001
BMI, kg/m² 27·0 (5·1) 31·8 (6·4) <0·0001
Obese, BMI >30 kg/m² 22992 (26·9%) 6518 (60·9%) <0·0001
Sex
Female 40169 (47·1%) 4257 (39·8%) <0·0001
Male 45 165 (52·9%) 6441 (60·2%) <0·0001
Race or ethnicity
White 57 503 (67·4%) 6717 (62·8%) <0·0001
Black 7219 (8·5%) 1835 (17·2%) <0·0001
Hispanic 4948 (5·8%) 1030 (9·6%) <0·0001
Asian 12657 (14·8%) 862 (8·1%) <0·0001
Native American 1023 (1·2%) 56 (0·5%) <0·0001
Other 1984 (2·3%) 198 (1·9%) 0·0019
Comorbidities at baseline
Coronary artery disease 9777 (11·5%) 2360 (22·1%) <0·0001
Congestive heart failure 1828 (2·1%) 540 (5·0%) <0·0001
Arrhythmia 2700 (3·2%) 681 (6·4%) <0·0001
Diabetes 10963 (12·8%) 2297 (21·5%) <0·0001
Hypertension 21948 (25·7%) 3862 (36·1%) <0·0001
Hyperlipidaemia 26480 (31·0%) 3718 (34·8%) <0·0001
COPD 2603 (3·1%) 574 (5·4%) <0·0001
Current smoker 7972 (9·3%) 1516 (14·2%) <0·0001
Former smoker 14681 (17·2%) 1872 (17·5%) 0·45
Immunocompromised 2406 (2·8%) 462 (4·3%) <0·0001
Medications
ACE inhibitor 7521 (8·8%) 428 (4·0%) <0·0001
Statin 8506 (10·0%) 739 (6·9%) <0·0001
Angiotensin receptor blocker 5190 (6·1%) 659 (6·2%) 0·75
Antiviral 35 189 (41·2%) 3738 (34·9%) <0·0001
Disease severity
qSOFA <1 71457 (83·7%) 7911 (73·9%) <0·0001
SPO2 <94% 7188 (8·4%) 2129 (19·9%) <0·0001
Treatment group
Chloroquine alone 1561 (1·8%) 307 (2·9%) <0·0001
Chloroquine with macrolide* 2944 (3·4%) 839 (7·8%) <0·0001
Hydroxychloroquine alone 2473 (2·9%) 543 (5·1%) <0·0001
Hydroxychloroquine with
macrolide*
4742 (5·6%) 1479 (13·8%) <0·0001
Outcomes
De-novo ventricular arrhythmia 839 (1·0%) 400 (3·7%) <0·0001
Non-ICU length of stay, days 9·0 (6·2) 9·8 (7·4) <0·0001
ICU length of stay, days 2·1 (3·7) 9·4 (10·6) <0·0001
Total length of stay, days 11·1 (7·3) 19·2 (14·4) <0·0001
Mechanical ventilation 4821 (5·6%) 4533 (42·4%) <0·0001
Data are mean (SD) or n (%). BMI=body-mass index. COPD=chronic obstructive pulmonary disease. ACE=angiotensinconverting enzyme. qSOFA=quick sepsis-related organ failure assessment. SPO2=oxygen saturation. ICU=intensive care
unit. *Macrolides include only azithromycin or clarithromycin.
Table 1: Demographics and comorbidities of patients by survival or non-survival during hospitalisation
Articles
www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6 5
continuous variables and all other data were treated as
categorical variables in the model. From the model, hazard
ratios (HRs) with 95% CIs were estimated for included
variables to determine their effect on the risk of in-hospital
mortality (primary endpoint) or subsequent mechanical
ventilation or death (composite endpoint). Independence
of survival times (or time to first arrhythmia for the
ventricular arrhythmia analysis) was confirmed. Proportionality between the predictors and the hazard was
validated through an evaluation of Schoenfeld residuals,
which found p>0·05 and thus confirmed proportionality.
To minimise the effect of confounding factors, a
propensity score matching analysis was done individually
for each of the four treatment groups compared with a
control group that received no form of that therapy.
For each treatment group, a separate matched control
was identified using exact and propensity-score matched
criteria with a calliper of 0·001. This method was used
to provide a close approximation of demographics,
comorbidities, disease severity, and baseline medications
between patients. The propensity score was based on the
following variables: age, BMI, gender, race or ethnicity,
comorbidities, use of ACE inhibitors, use of statins, use
of angiotensin receptor blockers, treatment with other
antivirals, qSOFA score of less than 1, and SPO2 of less
than 94% on room air. The patients were well matched,
with standardised mean difference estimates of less than
10% for all matched parameters.
Additional analyses were done to examine the
robustness of the estimates initially obtained. Individual
Control group
(n=81 144)
Chloroquine
(n=1868)
Chloroquine with
macrolide* (n=3783)
Hydroxychloroquine
(n=3016)
Hydroxychloroquine with
macrolide* (n=6221)
Age, years 53·6 (17·6) 55·1 (18·0) 54·9 (17·7) 55·1 (17·9) 55·2 (17·7)
BMI, kg/m² 27·4 (5·4) 27·8 (6·1) 28·2 (5·8) 28·4 (5.9) 28·5 (5·9)
Sex
Female 37 716 (46·5%) 845 (45·2%) 1718 (45·4%) 1388 (46·0%) 2759 (44·3%)
Male 43428 (53·5%) 1023 (54·8%) 2065 (54·6%) 1628 (54·0%) 3462 (55·7%)
Race or ethnicity
White 54403 (67·1%) 1201 (64·3%) 2418 (63·9%) 2074 (68·8%) 4124 (66·3%)
Black 7519 (9·3%) 203 (10·9%) 369 (9·8%) 287 (9·5%) 676 (10·9%)
Hispanic 4943 (6·1%) 108 (5·8%) 273 (7·2%) 194 (6·4%) 460 (7·4%)
Asian 11 504 (14·2%) 301 (16·1%) 603 (15·9%) 366 (12·1%) 745 (12·0%)
Native American 922 (1·1%) 19 (1·0%) 37 (1·0%) 33 (1·1%) 68 (1·1%)
Other 1853 (2·3%) 36 (1·9%) 83 (2·2%) 62 (2·1%) 148 (2·4%)
Comorbidities
Coronary artery disease 10076 (12·4%) 284 (15·2%) 515 (13·6%) 421 (14·0%) 841 (13·5%)
Congestive heart failure 1949 (2·4%) 50 (2·7%) 103 (2·7%) 78 (2·6%) 188 (3·0%)
Arrhythmia 2861 (3·5%) 63 (3·4%) 126 (3·3%) 108 (3·6%) 223 (3·6%)
Diabetes 11058 (13·6%) 258 (13·8%) 584 (15·4%) 447 (14·8%) 913 (14·7%)
Hypertension 21437 (26·4%) 560 (30·0%) 1095 (28·9%) 891 (29·5%) 1827 (29·4%)
Hyperlipidaemia 25 538 (31·5%) 607 (32·5%) 1164 (30·8%) 941 (31·2%) 1948 (31·3%)
COPD 2647 (3·3%) 55 (2·9%) 144 (3·8%) 111 (3·7%) 220 (3·5%)
Current smoker 7884 (9·7%) 190 (10·2%) 428 (11·3%) 342 (11·3%) 644 (10·4%)
Former smoker 14049 (17·3%) 321 (17·2%) 648 (17·1%) 509 (16·9%) 1026 (16·5%)
Immunocompromised 2416 (3·0%) 53 (2·8%) 122 (3·2%) 90 (3·0%) 187 (3·0%)
Baseline disease severity
qSOFA <1 67 316 (83·0%) 1530 (81·9%) 3051 (80·7%) 2477 (82·1%) 4994 (80·3%)
SPO2 <94% 7721 (9·5%) 209 (11·2%) 413 (10·9%) 323 (10·7%) 651 (10·5%)
Outcomes
De-novo ventricular arrhythmia 226 (0·3%) 81 (4·3%) 246 (6·5%) 184 (6·1%) 502 (8·1%)
Non-ICU length of stay, days 9·1 (6·4) 8·8 (6·2) 9·0 (6·6) 8·9 (6·2) 9·1 (6·7)
ICU length of stay, days 2·6 (5·0) 4·3 (6·8) 4·9 (8·1) 4·3 (6·8) 4·7 (7·8)
Total length of stay, days 11·7 (8·4) 13·2 (9·1) 13·8 (11·0) 13·2 (9·3) 13·8 (10·7)
Mechanical ventilation 6278 (7·7%) 403 (21·6%) 814 (21·5%) 616 (20·4%) 1243 (20·0%)
Mortality 7530 (9·3%) 307 (16·4%) 839 (22·2%) 543 (18·0%) 1479 (23·8%)
Ventilator or mortality 10703 (13·2%) 531 (28·4%) 1288 (34·0%) 877 (29·1%) 2120 (34·1%)
Data are mean (SD) or n (%). BMI=body-mass index. COPD=chronic obstructive pulmonary disease. qSOFA=quick sepsis-related organ failure assessment. SPO2=oxygen
saturation. ICU=intensive care unit. *Macrolides include only clarithromycin and azithromycin.
Table 2: Patient demographics and characteristics by treatment group
Articles
6 www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6
analyses by continent of origin and sex-adjusted analyses
using Cox proportional hazards models were performed.
A tipping-point analysis (an analysis that shows the effect
size and prevalence of an unmeasured confounder that
could shift the upper boundary of the CI towards null)
was also done. All statistical analyses were done with
R version 3.6.3 and SPSS version 26.
Role of the funding source
The funder of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report. The corresponding author and coauthor ANP had full access to all the data in the study
and had final responsibility for the decision to submit
for publication.
Results
96032 hospitalised patients from 671 hospitals were
diagnosed with COVID-19 between Dec 20, 2019, and
April 14, 2020 and met the inclusion criteria for this study
(figure 1). All included patients completed their hospital
course (discharged or died) by April 21, 2020. Patients
who were hospitalised during the study period without a
completed course were unable to be analysed. The study
cohort included 63 315 (65·9%) patients from North
America, 16 574 (17·3%) from Europe, 7555 (7·9%) from
Asia, 4402 (4·6%) from Africa, 3577 (3·7%) from South
America, and 609 (0·6%) from Australia (details of the
number of hospitals per continent are presented in the
appendix, p 3). The mean age was 53·8 years (SD 17·6),
44 426 (46·3%) were women, mean BMI was 27·6 kg/m²
(SD 5·5; 29 510 [30·7%] were obese with BMI ≥30 kg/m²),
64220 (66·9%) were white, 9054 (9·4%) were black,
5978 (6·2%) were Hispanic, and 13 519 (14·1%) were of
Asian origin (appendix p 4). In terms of comorbidities,
30 198 (31·4%) had hyperlipidaemia, 25 810 (26·9%) had
hypertension, 13 260 (13·8%) had diabetes, 3177 (3·3%)
had COPD, 2868 (3·0%) had an underlying immunosuppressed condition, 16 553 (17·2%) were former smokers,
and 9488 (9·9%) were current smokers. In terms of preexisting cardiovascular disease, 12 137 (12·6%) had
coronary artery disease, 2368 (2·5%) had a history of
congestive heart failure, and 3381 (3·5%) had a history of
arrhythmia. The mean length of stay in hospital was
9·1 days (SD 6·4), with an overall in-hospital mortality of
10 698 (11·1%) of 96 032. The use of other antivirals was
recorded in 38 927 (40·5%) patients as treatment for
COVID-19. The most common antivirals were lopinavir
with ritonavir (12 304 [31·6%]), ribavirin (7904 [20·3%]),
and oseltamivir (5101 [13·1%]). Combination therapy
with more than one of these antiviral regimens was used
for 6782 (17·4%) patients.
The treatment groups included 1868 patients who
were given chloroquine alone, 3016 given hydroxychloroquine alone, 3783 given chloroquine with a macrolide
and 6221 given hydroxychloroquine and a macrolide.
The median time from hospitalisation to diagnosis of
COVID-19 was 2 days (IQR 1–4). The mean daily dose
and duration of the various drug regimens were as
follows: chloroquine alone, 765 mg (SD 308) and
6·6 days (2·4); hydroxychloroquine alone, 596 mg (126)
and 4·2 days (1·9); chloroquine with a macrolide,
790 mg (320) and 6·8 days (2·5); and hydroxychloroquine
with a macrolide, 597 mg (128) and 4·3 days (2·0).
Additional details of the study cohort are provided in the
appendix (pp 4–5).
Demographic variables and comorbidities were compared among survivors and non-survivors (table 1). Nonsurvivors were older, more likely to be obese, more likely
to be men, more likely to be black or Hispanic, and to
have diabetes, hyperlipidaemia, coronary artery disease,
congestive heart failure, and a history of arrhythmias.
Non-survivors were also more likely to have COPD and
to have reported current smoking.
The distribution of demographics, comorbidities, and
outcomes between the four treatment groups are shown
in table 2. No significant between-group differences were
found among baseline characteristics or comorbidities.
Ventricular arrhythmias were more common in the
Figure 2: Independent predictors of in-hospital mortality
Age and BMI are continuous variables. The 95% CIs have not been adjusted for multiple testing and should not be
used to infer definitive effects. ACE=angiotensin-converting enzyme. BMI=body mass index. COPD=chronic
obstructive pulmonary disease. HR=hazard ratio. qSOFA=quick sepsis-related organ failure assessment.
SPO2=oxygen saturation.
Age (per year)
BMI (per kg/m2
)
Female
White
Black
Hispanic
Asian
Coronary artery disease
Congestive heart failure
Arrhythmia
Diabetes
Hypertension
Hyperlipidaemia
COPD
Current smoker
Immunosuppressed condition
ACE inhibitor
Statin
Angiotensin receptor blocker
qSOFA <1
SPO2 <94%
Chloroquine alone
Hydroxychloroquine alone
Chloroquine and macrolide
Hydroxychloroquine and macrolide
HR (95% CI)
1·010 (1·009–1·011)
1·063 (1·060–1·067)
0·825 (0·793–0·858)
Reference
1·344 (1·276–1·415)
1·495 (1·400–1·597)
0·717 (0·668–0·769)
1·134 (1·082–1·188)
1·756 (1·609–1·915)
1·626 (1·504–1·758)
1·206 (1·151–1·264)
1·302 (1·252–1·355)
1·125 (1·081–1·171)
1·190 (1·093–1·294)
1·268 (1·201–1·340)
1·081 (0·985–1·187)
0·566 (0·514–0·624)
0·793 (0·736–0·855)
0·989 (0·914–1·071)
0·758 (0·726–0·792)
1·664 (1·587–1·746)
1·365 (1·218–1·531)
1·335 (1·223–1·457)
1·368 (1·273–1·469)
1·447 (1·368–1·531)
0·1 1·0 10·0
Decreased risk of death Increased risk of death
Articles
www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6 7
treatment groups compared with the control population.
Mortality was higher in the treatment groups compared
with the control population (p<0·0001; appendix pp 15–18).
Independent predictors of in-hospital mortality are
shown in figure 2. Age, BMI, black race or Hispanic
ethnicity (versus white race), coronary artery disease,
congestive heart failure, history of arrhythmia, diabetes,
hypertension, hyperlipidaemia, COPD, being a current
smoker, and immunosuppressed condition were associated with a higher risk of in-hospital death. Female sex,
ethnicity of Asian origin, use of ACE inhibitors (but not
angiotensin receptor blockers), and use of statins
was associated with reduced in-hospital mortality risk.
Compared with the control group (9·3%), hydroxychloroquine alone (18·0%; HR 1·335, 95% CI 1·223–1·457),
hydroxychloroquine with a macrolide (23·8%; 1·447,
1·368–1·531), chloroquine alone (16·4%; 1·365, 1·218–1·531),
and chloroquine with a macrolide (22·2%; 1·368,
1·273–1·469) were independently associated with an
increased risk of in-hospital mortality. The multivariable
Cox regression analyses by continent are shown in the
appendix (pp 6–11), as well as data from the sex-adjusted
multivariable logistic regression analyses (pp 12–13) and
a separate Cox regression analysis for the combined
endpoint of mechanical ventilation or mortality (p 14).
Independent predictors of ventricular arrythmia are
shown in figure 3. Coronary artery disease, congestive
heart failure, history of cardiac arrhythmia, and COPD
were independently associated with an increased risk
of de-novo ventricular arrhythmias during hospitalisation. Compared with the control group (0·3%),
hydroxychloroquine alone (6·1%; HR 2·369, 95% CI
1·935–2·900), hydroxychloroquine with a macrolide
(8·1%; 5·106, 4·106–5·983), chloroquine alone (4·3%;
3·561, 2·760–4·596), and chloroquine with a macrolide
(6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular
arrhythmia during hospitalisation.
Analyses using propensity score matching by treatment
group are shown in the appendix (pp 15–18). The results
indicated that the associations between the drug
regimens and mortality, need for mechanical ventilation,
length of stay, and the occurrence of de-novo ventricular
arrhythmias were consistent with the primary analysis.
A tipping point analysis was done to assess the
effects of an unmeasured confounder on the findings of
significance with hydroxychloroquine or chloroquine
(appendix pp 19–20). For chloroquine, hydroxychloroquine, and chloroquine with a macrolide, a hypothetical
unobserved binary confounder with a prevalence of
50% in the exposed population would need to have an
HR of 1·5 to tip this analysis to non-significance at
the 5% level. For a comparison with the observed
confounders in this study, if congestive heart failure
(which has an HR of 1·756) were left out of the model, it
would need to have a prevalence of approximately 30%
in the population to lead to confounding in the analysis.
Similarly, for hydroxychloroquine with a macrolide,
a hypothetical unobserved binary confounder with a
prevalence of 37% in the exposed population would need
to have an HR of 2·0 to tip this analysis to nonsignificance at the 5% level. Again, congestive heart
failure (which has an HR of 1·756) would need to have a
prevalence of approximately 50% in the population to
lead to confounding in the analysis, had it not been
adjusted for in the Cox proportional hazards model.
Discussion
In this large multinational real-world analysis, we did
not observe any benefit of hydroxychloroquine or
chloroquine (when used alone or in combination with a
macrolide) on in-hospital outcomes, when initiated early
after diagnosis of COVID-19. Each of the drug regimens
of chloroquine or hydroxychloroquine alone or in
combination with a macrolide was associated with an
increased hazard for clinically significant occurrence of
ventricular arrhythmias and increased risk of in-hospital
death with COVID-19.
The use of hydroxychloroquine or chloroquine in
COVID-19 is based on widespread publicity of small,
Figure 3: Independent predictors of ventricular arrhythmias during hospitalisation
Age and BMI are continuous variables. The 95% CIs have not been adjusted for multiple testing and should not be
used to infer definitive effects. ACE=angiotensin-converting enzyme. BMI=body mass index. COPD=chronic
obstructive pulmonary disease. HR=hazard ratio. qSOFA=quick sepsis-related organ failure assessment.
SPO2=oxygen saturation.
HR (95% CI)
Age (per year)
BMI (per kg/m2
)
Female
White
Black
Hispanic
Asian
Coronary artery disease
Congestive heart failure
Arrhythmia
Diabetes
Hypertension
Hyperlipidaemia
COPD
Current smoker
Immunosuppressed state
ACE inhibitor
Statin
Angiotensin receptor blocker
Antiviral
qSOFA <1
SPO2 <94%
Chloroquine alone
Hydroxychloroquine alone
Chloroquine and macrolide
Hydroxychloroquine and macrolide
0·994 (0·991–0·997)
0·985 (0·976–0·994)
0·966 (0·861–1·082)
Reference
0·980 (0·822–1·168)
1·130 (0·910–1·402)
0·943 (0·792–1·123)
1·830 (1·613–2·076)
3·914 (3·283–4·665)
4·119 (3·525–4·812)
0·848 (0·724–0·993)
0·941 (0·831–1·065)
1·059 (0·938–1·195)
1·585 (1·256–2·001)
0·950 (0·796–1·133)
0·815 (0·604–1·101)
1·044 (0·852–1·279)
0·973 (0·797–1·187)
1·043 (0·831–1·307)
1·008 (0·898–1·130)
1·134 (0·984–1·308)
0·849 (0·710–1·016)
3·561 (2·760–4·596)
2·369 (1·935–2·90)
4·011 (3·344–4·812)
5·106 (4·357–5·983)
0·1 1·0 10·0
Decreased risk of ventricular arrhythmia Increased risk of ventricular arrhythmia
Articles
8 www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6
uncontrolled studies, which suggested that the combination of hydroxychloroquine with the macrolide
azithromycin was successful in clearing viral replication.7
On March 28, 2020, the FDA issued an emergency use
authorisation for these drugs in patients if clinical trial
access was unavailable.12 Other countries, such as China,
have issued guidelines allowing for the use of chloroquine
in COVID-19.13 Several countries have been stockpiling the drugs, and shortages of them for approved
indications, such as for autoimmune disease and rheumatoid arthritis, have been encountered.10 A retrospective
observational review of 368 men with COVID-19 treated
at the US Veterans Affairs hospitals raised concerns
that the use of hydroxychloroquine was associated with
a greater hazard of death; however, the baseline characteristics among the groups analysed were dissimilar and
the possibility of bias cannot be ruled out.14 Another
observational study in 181 patients from France reported
that the use of hydroxychloroquine at a dose of 600 mg
per day was not associated with a measurable clinical
benefit in patients with COVID-19 pneumonia.15 Our
large-scale, international, real-world analysis supports
the absence of a clinical benefit of chloroquine and
hydroxychloroquine and points to potential harm in
hospitalised patients with COVID-19.
Chloroquine and hydroxychloroquine are associated
with concerns of cardiovascular toxicity, particularly
because of their known relationship with electrical
instability, characterised by QT interval prolongation
(the time taken for ventricular depolarisation and
repolarisation). This mechanism relates to blockade
of the hERG potassium channel,16 which lengthens
ventricular repolarisation and the duration of ventricular
action potentials. Under specific conditions, early afterdepolarisations can trigger ventricular arrhythmias.9
Such propensity for arrhythmia provocation is more
often seen in individuals with structural cardiovascular
disease, and cardiac injury has been reported to occur
with high frequency during COVID-19 illness.17,18
Furthermore, individuals with cardiovascular disease
represent a vulnerable population that experience worse
outcomes with COVID-19.19,20 Pathological studies have
pointed to derangements in the vascular endothelium
and a diffuse endotheliitis noted across multiple organs
in COVID-19.21 Whether patients with underlying
cardiovascular disease and those that experience de-novo
cardiovascular injury have a greater predilection to
ventricular arrhythmias with chloroquine or its analogues remains uncertain but plausible. COVID-19
is exemplified by initial viral replication followed
by enhanced systemic inflammation.22 The use of
chloroquine or hydroxychloroquine in combination with
a macrolide is designed to use their antimicrobial
properties in a synergistic manner.23 Macrolides, such as
azithromycin and clarithromycin, are antibiotics with
immunomodulatory and anti-inflammatory effects.24
However, these drugs prolong the QT interval and
increase the risk of sudden cardiac death.8,9 In a preliminary analysis, Borba and colleagues25 reported a doubleblind, randomised trial with 81 adult patients who were
hospitalised with severe COVID-19 at a tertiary care
facility in Brazil. This study suggested that a higher
dose of chloroquine represented a safety hazard,
especially when taken concurrently with azithromycin
and oseltamivir. In another cohort study of 90 patients
with COVID-19 pneumonia, Mercuro and colleagues26
found that the concomitant use of a macrolide was
associated with a greater change in the corrected QT
interval. Our study did not examine the QT interval but
instead directly analysed the risk of clinically significant
ventricular arrythmias. We showed an independent
association of the use of either hydroxychloroquine or
chloroquine with the occurrence of de-novo ventricular
arrhythmias. We also note that the hazard of de-novo
ventricular arrhythmias increased when the drugs were
used in combination with a macrolide.
In our analysis, which was dominated by patients
from North America, we noted that higher BMI emerged
as a risk marker for worse in-hospital survival. Obesity
is a known risk factor for cardiac arrhythmias and sud -
den cardiac death.27,28 The most commonly reported
arrhythmias are atrial fibrillation and ventricular tachycardia. Although age, race, and BMI were predictive
of an increased risk for death with COVID-19 in our
analysis, they were not found to be associated with
an increased risk of ventricular arrhythmias on our
multivariable regression analysis. The only variables
found to be independently predictive of ventricular
arrhythmias were the four treatment regimens, along
with underlying cardiovascular disease and COPD.
Thus, the presence of cardiovascular comorbidity in the
study population could partially explain the observed
risk of increased cardiovascular toxicity with the use of
chloroquine or hydroxychloroquine, especially when
used in combination with macrolides. In this investigation, consistent with our previous findings in a
smaller cohort of 8910 patients,20 we found that women
and patients being treated with ACE inhibitors (but not
angiotensin receptor blockers) or statins had lower
mortality with COVID-19. These findings imply that
drugs that stabilise cardiovascular function and
improve endothelial cell dysfunction might improve
prognosis, independent of the use of cardiotoxic drug
combinations.21
Our study has several limitations. The association of
decreased survival with hydroxychloroquine or chloroquine treatment regimens should be interpreted
cautiously. Due to the observational study design, we
cannot exclude the possibility of unmeasured confounding factors, although we have reassuringly noted
consistency between the primary analysis and the
propensity score matched analyses. Nevertheless, a
cause-and-effect relationship between drug therapy and
survival should not be inferred. These data do not apply
Articles
www.thelancet.com Published online May 22, 2020 https://doi.org/10.1016/S0140-6736(20)31180-6 9
to the use of any treatment regimen used in the
ambulatory, out-of-hospital setting. Randomised clinical
trials will be required before any conclusion can be
reached regarding benefit or harm of these agents in
COVID-19 patients. We also note that although we
evaluated the relationship of the drug treatment
regimens with the occurrence of ventricular arrhythmias, we did not measure QT intervals, nor did we
stratify the arrhythmia pattern (such as torsade de
pointes). We also did not establish if the association of
increased risk of in-hospital death with use of the drug
regimens is linked directly to their cardiovascular risk,
nor did we conduct a drug dose-response analysis of the
observed risks. Even if these limitations suggest a
conservative interpretation of the findings, we believe
that the absence of any observed benefit could still
represent a reasonable explanation.
In summary, this multinational, observational, realworld study of patients with COVID-19 requiring
hospitalisation found that the use of a regimen containing hydroxychloroquine or chloroquine (with or
without a macrolide) was associated with no evidence of
benefit, but instead was associated with an increase in
the risk of ventricular arrhythmias and a greater hazard
for in-hospital death with COVID-19. These findings
suggest that these drug regimens should not be used
outside of clinical trials and urgent confirmation from
randomised clinical trials is needed.
Contributors
The study was conceived and designed by MRM and ANP. Acquisition of
data and statistical analysis of the data were supervised and performed by
SSD. MRM drafted the manuscript and all authors participated in critical
revision of the manuscript for important intellectual content. MRM and
ANP supervised the study. All authors approved the final manuscript and
were responsible for the decision to submit for publication.
Declaration of interests
MRM reports personal fees from Abbott, Medtronic, Janssen, Mesoblast,
Portola, Bayer, Baim Institute for Clinical Research, NupulseCV,
FineHeart, Leviticus, Roivant, and Triple Gene. SSD is the founder of
Surgisphere Corporation. FR has been paid for time spent as a
committee member for clinical trials, advisory boards, other forms of
consulting, and lectures or presentations; these payments were made
directly to the University of Zurich and no personal payments were
received in relation to these trials or other activities. ANP declares no
competing interests.
Acknowledgments
The development and maintenance of the Surgical Outcomes
Collaborative database was funded by Surgisphere Corporation
(Chicago, IL, USA). This study was supported by the William Harvey
Distinguished Chair in Advanced Cardiovascular Medicine at Brigham
and Women’s Hospital (Boston, MA, USA). We acknowledge Jide
Olayinka (Surgisphere) for their helpful statistical review of the
manuscript.
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