Published with written permission of Dr. Neil Schluger
Th e new england journal o f medicine
n engl j med nejm.org 1
From the Divisions of General Medicine,
Infectious Diseases, and Pulmonary, Allergy,
and Critical Care Medicine, Department
of Medicine (J.G., J.Z., M.B., A.L.,
D.M., C.K., R.G.B., M.E.S., N.W.S.), the
Departments of Biostatistics (Y.S.) and
Epidemiology ( J.P., R.G.B., N.W.S.), Mailman
School of Public Health, and the Department
of Biomedical Informatics (G.H.),
Vagelos College of Physicians and Surgeons,
Columbia University, and New
York–Presbyterian Hospital–Columbia University
Irving Medical Center (J.G., J.Z.,
M.B., A.L., D.M., C.K.,R.G.B., M.E.S.,
N.W.S.) — all in New York. Address reprint
requests to Dr. Schluger at the Division
of Pulmonary, Allergy, and Critical
Care Medicine, Columbia University Irving
Medical Center, PH-8 E., Rm. 101,
622 W. 168th St., New York, NY 10032, or
at ns311@
cumc
.columbia
.edu.
This article was published on May 7, 2020,
at NEJM.org.
DOI: 10.1056/NEJMoa2012410
Copyright © 2020 Massachusetts Medical Society.
BACKGROUND
Hydroxychloroquine has been widely administered to patients with Covid-19 without
robust evidence supporting its use.
METHODS
We examined the association between hydroxychloroquine use and intubation or
death at a large medical center in New York City. Data were obtained regarding
consecutive patients hospitalized with Covid-19, excluding those who were intubated,
died, or discharged within 24 hours after presentation to the emergency
department (study baseline). The primary end point was a composite of intubation
or death in a time-to-event analysis. We compared outcomes in patients who received
hydroxychloroquine with those in patients who did not, using a multivariable
Cox model with inverse probability weighting according to the propensity score.
RESULTS
Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within
24 hours after presentation and were excluded from the analysis. Of the remaining
1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine
(600 mg twice on day 1, then 400 mg daily for a median of 5 days);
45.8% of the patients were treated within 24 hours after presentation to the emergency
department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients
were more severely ill at baseline than those who did not receive hydroxychloroquine
(median ratio of partial pressure of arterial oxygen to the fraction of inspired
oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event
(180 patients were intubated, of whom 66 subsequently died, and 166 died without
intubation). In the main analysis, there was no significant association between
hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence
interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses.
CONCLUSIONS
In this observational study involving patients with Covid-19 who had been admitted
to the hospital, hydroxychloroquine administration was not associated with either a
greatly lowered or an increased risk of the composite end point of intubation or
death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19
are needed. (Funded by the National Institutes of Health.)
ABSTRACT
Observational Study of Hydroxychloroquine
in Hospitalized Patients with Covid-19
Joshua Geleris, M.D., Yifei Sun, Ph.D., Jonathan Platt, Ph.D., Jason Zucker, M.D.,
Matthew Baldwin, M.D., George Hripcsak, M.D., Angelena Labella, M.D.,
Daniel Manson, M.D., Christine Kubin, Pharm.D., R. Graham Barr, M.D., Dr.P.H.,
Magdalena E. Sobieszczyk, M.D., M.P.H., and Neil W. Schluger, M.D.
Original Article
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The aminoquinolines chloroquine
and hydroxychloroquine are widely used
in the treatment of malaria and rheumatic
diseases, and they have been suggested as
effective treatments for coronavirus disease 2019
(Covid-19) on the grounds of both antiinflammatory
and antiviral effects.1-4 In the United States,
the Food and Drug Administration issued an
Emergency Use Authorization on March 30, 2020,
that allowed the use of these drugs in patients
with Covid-19 who were not enrolled in clinical
trials. Guidelines suggested that these drugs be
administered to hospitalized patients who had
evidence of pneumonia,5 and to date, they have
been used in many thousands of patients with
acute Covid-19 around the world. However, to date,
there have been no robust clinical trials that have
shown efficacy of these agents for this illness,
and the data that are available come from small
studies that have either been uncontrolled or underpowered
to detect meaningful clinical effects.
The original report of hydroxychloroquine as
a treatment for Covid-19 described 26 patients
who had been treated in an open-label, singlegroup
study that involved contemporaneous, but
nonrandomized controls in hospitals in France.6
Patients were treated with hydroxychloroquine at
a dose of 200 mg three times daily for 10 days.
Data from this study were reported as showing
the effectiveness of hydroxychloroquine in reducing
the viral burden in treated patients (65.0%
clearance by day 5, vs. 18.8% clearance by day 5 in
untreated patients). However, data from 6 patients
who received hydroxychloroquine were excluded
from the analysis because of clinical worsening or
loss to follow-up, which makes it difficult to interpret
the findings.
Recent work suggests that hydroxychloroquine
has more potent antiviral properties than chloroquine,
as well as a better safety profile.7 In accordance
with clinical guidelines developed at our
medical center, hydroxychloroquine was suggested
as treatment for hospitalized patients with
Covid-19 and respiratory difficulty, as indicated by
a low resting oxygen saturation, during the period
in which patients in this report were admitted.
We examined the association between hydroxychloroquine
use and respiratory failure at a large
medical center providing care to a substantial
number of patients with Covid-19 in New York City.
We hypothesized that hydroxychloroquine use
would be associated with a lower risk of a composite
end point of intubation or death in analyses
that were adjusted for major predictors of respiratory
failure and weighted according to propensity
scores assessing the probability of hydroxychloroquine
use.
Methods
Setting
We conducted this study at New York–Presbyterian
Hospital (NYP)–Columbia University Irving Medical
Center (CUIMC), a quaternary, acute care hospital
in northern Manhattan. We obtained samples
from all admitted adults who had a positive
test result for the virus SARS-CoV-2 from analysis of
nasopharyngeal or oropharyngeal swab specimens
obtained at any point during their hospitalization
from March 7 to April 8, 2020. Follow-up
continued through April 25, 2020. These tests were
conducted by the New York State Department of
Health until the NYP–CUIMC laboratory developed
internal testing capability with a reversetranscriptase–
polymerase-chain-reaction assay on
March 11, 2020. Patients who were intubated, who
died, or who were transferred to another facility
within 24 hours after presentation to the emergency
department were excluded from the analysis.
The institutional review board at CUIMC approved
this analysis under an expedited review.
A guidance developed by the Department of
Medicine and distributed to all the house staff
and attending staff at our medical center suggested
hydroxychloroquine as a therapeutic option for
Figure 1. Study Cohort.
Study baseline was defined as 24 hours after arrival at the emergency department.
Covid-19 denotes coronavirus disease 2019.
1376 Were included in the propensityscore–
matched and regression analyses
1446 Adult patients were admitted with
Covid-19 during the study period
70 Were excluded
26 Were intubated before study
baseline
28 Were intubated and died
before study baseline
3 Died before study baseline
13 Were transferred to other
facility before study baseline
n engl j med nejm.org 3
Hydroxychloroquine in Patients with Covid-19
patients with Covid-19 who presented with moderate-
to-severe respiratory illness, which was defined
as a resting oxygen saturation of less than
94% while they were breathing ambient air. The
suggested hydroxychloroquine regimen was a
loading dose of 600 mg twice on day 1, followed
by 400 mg daily for 4 additional days. Azithromycin
at a dose of 500 mg on day 1 and then 250
mg daily for 4 more days in combination with
hydroxychloroquine was an additional suggested
therapeutic option. The azithromycin suggestion
was removed on April 12, 2020, and the hydroxychloroquine
suggestion was removed on April 29,
2020. The decision to prescribe either or both
medications was left to the discretion of the treating
team for each individual patient.
Patients receiving sarilumab were allowed to
continue hydroxychloroquine. Patients receiving
remdesivir as part of a randomized trial either did
not receive or had completed a course of treatment
with hydroxychloroquine.
Data Sources
We obtained data from the NYP–CUIMC clinical
data warehouse. This warehouse contains all the
clinical data available on all inpatient and outpatient
visits to one of the CUIMC facilities (see the
Data Extraction section in the Supplementary Appendix,
available with the full text of this article
at NEJM.org). No data were manually abstracted
from the electronic medical record or charts. The
data obtained included patients’ demographic details,
insurance status, vital signs, laboratory test
results, medication administration data, historical
and current medication lists, historical and current
diagnoses, clinical notes, historical discharge disposition
for previous inpatient hospitalizations,
and ventilator use data.
Variables Assessed
From the clinical data warehouse, we obtained the
following data elements for each patient: age; sex;
patient-reported race and ethnic group; current
insurance carrier; the first recorded vital signs
on presentation; the ratio of the partial pressure
of arterial oxygen to the fraction of inspired oxygen
(Pao2:Fio2) at admission, estimated with the
use of methods developed by Brown and colleagues8,9
(see the Data Extraction section in the
Supplementary Appendix); the first recorded bodymass
index as calculated for measured height and
weight (the body-mass index is the weight in
kilograms divided by the square of the height in
meters), grouped on the basis of the Centers for
Disease Control and Prevention guidelines for
adults; the first recorded inpatient laboratory
tests; past and current diagnoses; patient-reported
smoking status; and medication administration
at baseline. Details of the variables assessed
are provided in the Supplementary Appendix.
Hydroxychloroquine Exposure
Patients were defined as receiving hydroxychloroquine
if they were receiving it at study baseline
or received it during the follow-up period before
intubation or death. Study baseline was defined
as 24 hours after arrival at the emergency department.
End Point
The primary end point was the time from study
baseline to intubation or death. For patients who
died after intubation, the timing of the primary
end point was defined as the time of intubation.
Statistical Analysis
We calculated bivariate frequencies to examine
the associations among the preadmission variables
described above. Patients without a primary
end-point event had their data censored on April
25, 2020.
Cox proportional-hazards regression models
were used to estimate the association between
hydroxychloroquine use and the composite end
point of intubation or death. An initial multivariable
Cox regression model included demographic
factors, clinical factors, laboratory tests,
and medications. In addition, to help account for
the nonrandomized treatment administration of
hydroxychloroquine, we used propensity-score
methods to reduce the effects of confounding. The
individual propensities for receipt of hydroxychloroquine
treatment were estimated with the use
of a multivariable logistic-regression model that
included the same covariates as the Cox regression
model. Associations between hydroxychloroquine
use and respiratory failure were then estimated
by multivariable Cox regression models
with the use of three propensity-score methods.
The primary analysis used inverse probability
weighting. In the inverse-probability-weighted
analysis, the predicted probabilities from the
propensity-score model were used to calculate the
stabilized inverse-probability-weighting weight.10
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Table 1. Characteristics of Patients Receiving or Not Receiving Hydroxychloroquine, before and after Propensity-Score Matching.*
Characteristic Unmatched Patients Propensity-Score–Matched Patients†
Hydroxychloroquine
(N = 811)
No
Hydroxychloroquine
(N = 565)
Hydroxychloroquine
(N = 811)
No
Hydroxychloroquine
(N = 274)
Age — no. (%)
<40 yr 80 (9.9) 105 (18.6) 80 (9.9) 28 (10.2)
40–59 yr 217 (26.8) 142 (25.1) 217 (26.8) 69 (25.2)
60–79 yr 367 (45.3) 220 (38.9) 367 (45.3) 118 (43.1)
≥80 yr 147 (18.1) 98 (17.3) 147 (18.1) 59 (21.5)
Female sex — no. (%) 337 (41.6) 258 (45.7) 337 (41.6) 113 (41.2)
Race and ethnic group — no. (%)‡
Non-Hispanic white 74 (9.1) 57 (10.1) 97 (12.0) 36 (13.1)
Non-Hispanic black 89 (11.0) 92 (16.3) 120 (14.8) 40 (14.6)
Hispanic 412 (50.8) 286 (50.6) 530 (65.4) 172 (62.8)
Other 48 (5.9) 36 (6.4) 64 (7.9) 26 (9.5)
Missing data 188 (23.2) 94 (16.6) 0 0
Body-mass index — no. (%)§
<18.5 13 (1.6) 13 (2.3) 18 (2.2) 7 (2.6)
18.5–24.9 147 (18.1) 98 (17.3) 184 (22.7) 53 (19.3)
25.0–29.9 224 (27.6) 157 (27.8) 279 (34.4) 96 (35.0)
30.0–39.9 218 (26.9) 133 (23.5) 268 (33.0) 99 (36.1)
≥40.0 52 (6.4) 20 (3.5) 62 (7.6) 19 (6.9)
Missing data 157 (19.4) 144 (25.5) 0 0
Insurance — no. (%)
Medicaid 165 (20.3) 146 (25.8) 166 (20.5) 54 (19.7)
Medicare 396 (48.8) 261 (46.2) 399 (49.2) 141 (51.5)
No insurance 79 (9.7) 49 (8.7) 79 (9.7) 29 (10.6)
Commercial insurance 166 (20.5) 106 (18.8) 167 (20.6) 50 (18.2)
Missing data 5 (0.6) 3 (0.5) 0 0
Current smoking — no. (%) 89 (11.0) 68 (12.0) 89 (11.0) 32 (11.7)
Past diagnoses — no. (%)
Chronic lung disease¶ 146 (18.0) 105 (18.6) 146 (18.0) 49 (17.9)
Diabetes 301 (37.1) 190 (33.6) 301 (37.1) 94 (34.3)
Hypertension 398 (49.1) 38 (6.7) 398 (49.1) 146 (53.3)
Cancer 109 (13.4) 67 (11.9) 109 (13.4) 35 (12.8)
Chronic kidney disease 133 (16.4) 105 (18.6) 133 (16.4) 61 (22.3)
Transplantation, HIV infection, or
immune-suppressive medications
40 (4.9) 18 (3.2) 40 (4.9) 11 (4.0)
Medications at baseline — no. (%)
Statin 308 (38) 197 (34.9) 308 (38) 107 (39.1)
ACE inhibitor or ARB 236 (29.1) 142 (25.1) 236 (29.1) 85 (31.0)
Systemic glucocorticoid 216 (26.6) 57 (10.1) 216 (26.6) 42 (15.3)
Direct oral anticoagulant or warfarin 76 (9.4) 47 (8.3) 76 (9.4) 24 (8.8)
n engl j med nejm.org 5
Hydroxychloroquine in Patients with Covid-19
Kaplan–Meier curves and Cox models that used
the inverse-probability-weighting weights were
reported.
We conducted a secondary analysis that used
propensity-score matching and another that included
the propensity score as an additional covariate.
In the propensity-score matching analysis,
the nearest-neighbor method was applied to
create a matched control sample. Additional sensitivity
analyses included the same set of analyses
with the use of a different study baseline of 48
hours after arrival to the emergency department
as well as analyses that defined the exposure as
receipt of the first dose of hydroxychloroquine
before study baseline only. Multiple imputation
was used to handle missing data, and model estimates
and standard errors were calculated with
Rubin’s rules.11 The nonparametric bootstrap
method was used to obtain 95% pointwise confidence
intervals for the inverse-probability-weighted
Kaplan–Meier curves. The statistical analyses
were performed with the use of R software, version
3.6.1 (R Project for Statistical Computing).
Results
Characteristics of the Cohort
Of 1446 consecutive patients with Covid-19 who
were admitted to the hospital between March 7
and April 8, 2020, a total of 70 patients were ex-
Characteristic Unmatched Patients Propensity-Score–Matched Patients†
Hydroxychloroquine
(N = 811)
No
Hydroxychloroquine
(N = 565)
Hydroxychloroquine
(N = 811)
No
Hydroxychloroquine
(N = 274)
Azithromycin 486 (59.9) 127 (22.5) 486 (59.9) 102 (37.2)
Other antibiotic agent 604 (74.5) 305 (54.0) 604 (74.5) 183 (66.8)
Tocilizumab 58 (7.2) 12 (2.1) 58 (7.2) 9 (3.3)
Remdesivir 22 (2.7) 5 (0.9) 22 (2.7) 5 (1.8)
Initial vital signs — median (IQR)
Systolic blood pressure — mm Hg 125 (111–139) 127 (111–144) 125 (111–139) 126 (110–138)
Diastolic blood pressure — mm Hg 75 (67–82) 76 (68–84) 75 (67–82) 74 (65–83)
Heart rate — beats/min 98 (86–111) 97 (83–109) 98 (86–111) 97 (84–108)
Oxygen saturation — % 94 (90–96) 96 (94–98) 94 (90–96) 94.5 (92–96)
Respiratory rate — breaths/min 20 (18–22) 18 (18–20) 20 (18–22) 19.5 (18–22)
Calculated Pao2:Fio2 223 (160–303) 360 (248–431) 223 (160–303) 273 (185–360)
Initial laboratory tests — median (IQR)‖
d-Dimer — μg/ml 1.25 (0.76–2.28) 1.1 (0.59–2.35) 1.26 (0.76–2.29) 1.33 (0.66–2.45)
Ferritin — ng/ml 785 (420–1377) 481 (213–989) 777 (417–1370) 552 (283–1095)
Lactate dehydrogenase — U/liter 414 (322–546) 333 (246–448) 412 (321–544) 370 (273–515)
C-reactive protein — mg/liter 125 (75–199) 76 (20–150) 125 (74–199) 106 (48–183)
Procalcitonin — ng/ml 0.21 (0.11–0.53) 0.14 (0.09–0.39) 0.21 (0.11–0.53) 0.18 (0.10–0.45)
Neutrophil count per mm3 5.06 (3.64–7.26) 4.53 (2.72–6.81) 5.05 (3.63–7.26) 4.95 (3.20–7.30)
Lymphocyte count per mm3 0.94 (0.65–1.28) 1.02 (0.64–1.47) 0.95 (0.66–1.30) 0.98 (0.68–1.37)
* ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, Fio2 fraction of inspired oxygen, HIV human immunodeficiency
virus, IQR interquartile range, and Pao2 partial pressure of arterial oxygen.
† Data for patients included in the propensity-score–matched analysis were multiply imputed.
‡ Data on race and ethnic group, as reported by the patient, were obtained from the clinical data warehouse.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ Chronic lung disease was defined as chronic obstructive pulmonary disease, asthma, or chronic bronchitis.
‖ In the unmatched analysis, data on the d-dimer level were missing for 291 patients, on the ferritin level for 168, on the lactate dehydrogenase
level for 153, on the C-reactive protein level for 150, on the procalcitonin level for 121, on the neutrophil count for 33, and on the lymphocyte
count for 33. Multiple imputation was used to account for missing data in the propensity-score–matched analysis.
Table 1. (Continued.)
6 n engl j med nejm.org
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cluded from this study because they had already
had intubation or death, were discharged after
inpatient admission, or were directly admitted to
alternative facilities within 24 hours after presentation
to the emergency department. Thus, 1376
patients were included in the analysis (Fig. 1).
Over a median follow-up of 22.5 days, 346
patients (25.1%) had a primary end-point event
(166 patients died without being intubated, and
180 were intubated). At the time of data cutoff
on April 25, a total of 232 patients had died (66
after intubation), 1025 had survived to hospital
discharge, and 119 were still hospitalized (only
24 of whom were not intubated) (Table S1 in the
Supplementary Appendix).
Of the 1376 patients, 811 (58.9%) received
hydroxychloroquine (median duration of treatment,
5 days) and 565 (41.1%) did not. Among
the patients who received hydroxychloroquine,
45.8% received it in the 24 hours between their
presentation to the emergency department and the
start of study follow-up, and 85.9% received it
within 48 hours after presentation to the emergency
department. The timing of the first dose
of hydroxychloroquine after presentation to the
medical center is shown in Figure S3. The distribution
of the patients’ baseline characteristics
according to hydroxychloroquine exposure is
shown in Table 1, both in the unmatched and
propensity-score–matched analytic samples. In the
unmatched sample, hydroxychloroquine exposure
differed according to age group, sex, race and
ethnic group, body-mass index, insurance, smoking
status, and current use of other medications.
Hydroxychloroquine-treated patients had a lower
Pao2:Fio2 at baseline than did patients who did
not receive hydroxychloroquine (median, 233 vs.
360 mm Hg). In addition to the 27 patients listed
in Table 1 who received remdesivir according to
compassionate use, 30 patients in the study cohort
were enrolled in randomized, blinded, placebocontrolled
trials of that investigational agent or of
sarilumab.
The distribution of the estimated propensity
scores for receipt of hydroxychloroquine among
patients who did and did not receive hydroxychloroquine
is shown in Figure S1. The odds ratios
(with 95% confidence intervals) for receipt of hydroxychloroquine
according to all the variables
included in the propensity-score model are shown
in Table S2. The C-statistic of the propensity-score
model was 0.81. In the matched analytic sample,
811 patients were exposed to hydroxychloroquine
and 274 were not exposed. The differences between
hydroxychloroquine and pretreatment
variables were attenuated in the propensity-score–
matched samples as compared with the unmatched
samples (Table 2 and Fig. S2).
Study End Points
Among the 1376 patients included in the analysis,
the primary end point of respiratory failure developed
in 346 patients (25.1%); a total of 180 patients
were intubated, and 166 died without intubation.
In the crude, unadjusted analysis, patients who
had received hydroxychloroquine were more likely
to have had a primary end-point event than were
patients who did not (hazard ratio, 2.37; 95% CI,
1.84 to 3.02) (Table 2). In the primary multivariable
analysis with inverse probability weighting
according to the propensity score, there was no
significant association between hydroxychloroquine
use and the composite primary end point
(hazard ratio, 1.04; 95% CI, 0.82 to 1.32) (Fig. 2).
Table 2. Associations between Hydroxychloroquine Use and the Composite
End Point of Intubation or Death in the Crude Analysis, Multivariable
Analysis, and Propensity-Score Analyses.
Analysis Intubation or Death
No. of events/no. of patients at risk (%)
Hydroxychloroquine 262/811 (32.3)
No hydroxychloroquine 84/565 (14.9)
Crude analysis — hazard ratio (95% CI) 2.37 (1.84–3.02)
Multivariable analysis — hazard ratio (95% CI)* 1.00 (0.76–1.32)
Propensity-score analyses — hazard ratio (95% CI)
With inverse probability weighting† 1.04 (0.82–1.32)
With matching‡ 0.98 (0.73–1.31)
Adjusted for propensity score§ 0.97 (0.74–1.28)
* Shown is the hazard ratio from the multivariable Cox proportional-hazards
model, with stratification according to sex, chronic lung disease, and bodymass
index, and with additional adjustment for age, race and ethnic group,
insurance, current smoking, past diagnoses, current medications, vital statistics,
and laboratory tests on presentation. The analysis included all 1376
patients.
† Shown is the primary analysis with a hazard ratio from the multivariable Cox
proportional-hazards model with the same strata and covariates with inverse
probability weighting according to the propensity score. The analysis included
all the patients.
‡ Shown is the hazard ratio from a multivariable Cox proportional-hazards
model with the same strata and covariates with matching according to the
propensity score. The analysis included 1085 patients (811 who received hydroxychloroquine
and 274 who did not).
§ Shown is the hazard ratio from a multivariable Cox proportional-hazards
model with the same strata and covariates, with additional adjustment for the
propensity score. The analysis included all the patients.
n engl j med nejm.org 7
Hydroxychloroquine in Patients with Covid-19
There was also no significant association between
treatment with azithromycin and the composite
end point (hazard ratio, 1.03; 95% CI, 0.81 to 1.31).
Additional multivariable propensity-score analyses
yielded similar results (Table 2). Multiple additional
sensitivity analyses, including analyses
that used a different baseline at 48 hours after
presentation and analyses with treatment defined
as receipt of the first dose of hydroxychloroquine
before study baseline, showed similar results
(Table S3).
Discussion
In this analysis involving a large sample of consecutive
patients who had been hospitalized with
Covid-19, the risk of intubation or death was not
significantly higher or lower among patients who
received hydroxychloroquine than among those
who did not (hazard ratio, 1.04; 95% CI, 0.82 to
1.32). Given the observational design and the
relatively wide confidence interval, the study
should not be taken to rule out either benefit or
harm of hydroxychloroquine treatment. However,
our findings do not support the use of hydroxychloroquine
at present, outside randomized clinical
trials testing its efficacy.
As we noted in the introduction, the findings
from an early study showing a benefit of hydroxychloroquine
in 26 patients who had been treated
in French hospitals are difficult to interpret, given
the small size of that study, the lack of a randomized
control group, and the omission of 6 patients
from the analysis.6 A clinical trial testing two
doses of chloroquine in patients with Covid-19
planned to include 440 patients but was halted
after 81 patients had been enrolled because of
excessive QTc prolongation and an indication of
higher mortality in the high-dose group (in
which patients received 600 mg twice daily for
10 days) than in the low-dose group (in which
patients received 450 mg daily for 4 days after an
initial dose of 450 mg administered twice on the
first day).12
Two small, randomized trials from China have
been reported. Physicians in Wuhan randomly
assigned 62 patients with mild illness to either
the control group (in which patients could receive
supplemental oxygen, unspecified antiviral agents,
antibiotic agents, and immune globulin, with or
without glucocorticoids) or the experimental group
(in which patients also received 400 mg of hydroxychloroquine
daily). This report has not yet
been fully peer-reviewed, but results were posted
to the MedRxiv website for public comment.13 Investigators
reported a faster mean time to clinical
recovery (resolution of fever and cough and improvement
on chest radiography) in the experimental
group than in the control group. Four patients
(all in the control group) had progression to severe
infection. A small, randomized trial involving
30 patients in Shanghai reported on outcomes in
patients treated with 400 mg of hydroxychloroquine
daily for 5 days, as compared with a control
group in which patients received “conventional
treatment only.”14 This trial showed that by day
7, a total of 86% of the patients in the hydroxychloroquine-
treated group and 93% of those in
the control group had negative results on viral
throat swabs. All the patients in this trial also
received aerosolized interferon alfa by nebulizer.
A randomized clinical trial is the best approach
to determine whether benefit can be ascribed
to any given therapeutic intervention because
this trial design minimizes the two major
problems inherent in observational studies: unmeasured
confounding and bias. With the analytic
approaches we used in this examination of
Figure 2. Freedom from Composite End Point of Intubation or Death.
The shaded areas represent pointwise 95% confidence intervals.
ProbabilityofBeingEvent-free
1.00
0.75
0.50
0.25
0.00
0 5 10 15 20 25 30
Days
Hydroxychloroquine
No hydroxychloroquine
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Th e new england journal o f medicine
our observational cohort, we have tried to minimize
possible confounding in a variety of ways.
In the main analysis, a multivariable regression
model with inverse probability weighting
according to the propensity score, there was no
significant association between hydroxychloroquine
use and the risk of intubation or death. We
also performed a series of analyses using several
propensity-score approaches. Findings were similar
in multiple sensitivity analyses. The consistency
of the results across these analyses is reassuring.
In our analysis, we adjusted for likely
confounders, including age, race and ethnic group,
body-mass index, diabetes, underlying kidney disease,
chronic lung disease, hypertension, baseline
vital signs, Pao2:Fio2, and inflammatory markers
of the severity of illness. Despite this extensive
adjustment, it is still possible that some amount
of unmeasured confounding remains. Additional
limitations of our study include missing data
for some variables and potential for inaccuracies
in the electronic health records, such as lack of
documentation of smoking and coexisting illness
for some patients. Nonetheless, we used contemporary
methods to deal with missing data to
minimize bias. Finally, the single-center design
may limit the generalizability of these results.
Clinical guidance at our medical center has
been updated to remove the suggestion that patients
with Covid-19 be treated with hydroxychloroquine.
In our analysis involving a large
sample of consecutive patients who had been
hospitalized with Covid-19, hydroxychloroquine
use was not associated with a significantly higher
or lower risk of intubation or death (hazard ratio,
1.04; 95% CI, 0.82 to 1.32). The study results
should not be taken to rule out either benefit or
harm of hydroxychloroquine treatment, given the
observational design and the 95% confidence interval,
but the results do not support the use of
hydroxychloroquine at present, outside randomized
clinical trials testing its efficacy.
Supported in part by grants (RO1-LM006910, RO1-HL077612,
RO1-HL093081, and RO1-HL121270) from the National Institutes
of Health.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We acknowledge the dedication, commitment, and sacrifice
of the staff, providers, and personnel in our institution through
the Covid-19 crisis and the suffering and loss of our patients as
well as in their families and our community.
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