Background
Ivermectin
was shown to inhibit severe acute respiratory syndrome coronavirus 2
replication in vitro, which has led to off-label use, but clinical
efficacy has not been described previously.
Research Question
Does ivermectin benefit hospitalized coronavirus disease 2019 (COVID-19) patients?
Study Design and Methods
Charts
of consecutive patients hospitalized at four Broward Health hospitals
in Florida with confirmed COVID-19 between March 15 and May 11, 2020,
treated with or without ivermectin were reviewed. Hospital ivermectin
dosing guidelines were provided, but treatment decisions were at the
treating physician’s discretion. The primary outcome was all-cause
in-hospital mortality. Secondary outcomes included mortality in patients
with severe pulmonary involvement, extubation rates for mechanically
ventilated patients, and length of stay. Severe pulmonary involvement
was defined as need for Fio2 ≥
50%, noninvasive ventilation, or invasive ventilation at study entry.
Logistic regression and propensity score matching were used to adjust
for confounders.
Results
Two
hundred eighty patients, 173 treated with ivermectin and 107 without
ivermectin, were reviewed. Most patients in both groups also received
hydroxychloroquine, azithromycin, or both. Univariate analysis showed
lower mortality in the ivermectin group (15.0% vs 25.2%; OR,
0.52; 95% CI, 0.29-0.96; P = .03). Mortality also was
lower among ivermectin-treated patients with severe pulmonary
involvement (38.8% vs 80.7%; OR, 0.15; 95% CI, 0.05-0.47;
P = .001). No significant differences were found in
extubation rates (36.1% vs 15.4%; OR, 3.11; 95% CI,
0.88-11.00; P = .07) or length of stay. After multivariate
adjustment for confounders and mortality risks, the mortality
difference remained significant (OR, 0.27; 95% CI, 0.09-0.80; P =
.03). One hundred ninety-six patients were included in the
propensity-matched cohort. Mortality was significantly lower in the
ivermectin group (13.3% vs 24.5%; OR, 0.47; 95% CI,
0.22-0.99; P < .05), an 11.2% (95% CI,
0.38%-22.1%) absolute risk reduction, with a number needed to treat of
8.9 (95% CI, 4.5-263).
Interpretation
Ivermectin
treatment was associated with lower mortality during treatment of
COVID-19, especially in patients with severe pulmonary involvement.
Randomized controlled trials are needed to confirm these findings.
Key Words
Abbreviations:
COVID-19 (coronavirus disease 2019), IQR (interquartile range), MAP (mean arteria pressure), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)Ivermectin
previously was studied as a therapeutic option for viral infections,
with data showing some in vitro activity against a broad range of
viruses, including HIV, dengue, influenza, and Zika virus, likely
through inhibition of IMP α/β1-mediated nuclear import of viral
proteins.
1
,2
Wagstaff et al3
demonstrated that ivermectin was a potent in vitro inhibitor of
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), showing a
99.8% reduction in viral RNA after 48 h. Reports can be found on
the Internet of physicians worldwide treating Coronavirus disease 2019
(COVID-19) empirically with ivermectin since late April 2020. According
to ClinicalTrials.gov,
currently 37 studies are investigating the usefulness of ivermectin in
COVID-19. However, in vivo efficacy of ivermectin in SARS-CoV-2
infection in humans has not been reported previously.In
the late 1970s, ivermectin was developed as a new class of drug to
treat parasitic infections. Initially used in veterinary medicine, it
soon was found to be safe and effective in humans. It has been used
successfully to treat onchocerciasis and lymphatic filariasis in
millions of people worldwide as part of a global drug donation program.
About 3.7 billion doses of ivermectin have been distributed in
mass drug administration campaigns globally over the past 30 years.
Presently, ivermectin is approved for use in humans in several
countries to treat onchocerciasis, lymphatic filariasis,
strongyloidiasis, and scabies.
1
Based
on the data drug safety sheet for ivermectin (New Drug Application
Identifier: 50-742/S-022), side effects were uncommon and limited.
Reported side effects with more than 1% occurrence included
elevation in alanine aminotransferase and aspartate aminotransferase
(2%), nausea (2%), diarrhea (2%), decreased leukocyte count (3%),
peripheral edema (3%), tachycardia (3%), dizziness (3%), and pruritus
(3%). A pharmacokinetic study of 166 patients reported side effects of
headache (6%), dysmenorrhea (5.5%), upper respiratory infection symptoms
(1.8%), and diarrhea (1.8%).
5
Methods
Patients
Sequentially
consecutive hospitalized patients at four Broward Health-associated
hospitals in South Florida with laboratory-confirmed infection with
SARS-CoV-2 during their admission were reviewed in this study. The list
of confirmed cases was provided by the hospitals’ epidemiology
departments. Enrollment dates ranged from March 15, 2020, through May
11, 2020. Confirmatory testing was performed by nasopharyngeal swab
using a Food and Drug Administration Emergency Use Authorized COVID-19
molecular assay for the detection of SARS-CoV-2 RNA. Patients younger
than 18 years and those who were pregnant or incarcerated were excluded
from data collection based on institutional review board requirements.
Patients who had at least two separate admissions placing them in both
groups also were excluded.
Study Procedures
Records
were abstracted by four of the authors, and all data were reviewed
subsequently and confirmed by the lead author. Baseline data were
collected at the time of ivermectin administration for the ivermectin
group; for the usual care group, baseline was either the time of
administration of hydroxychloroquine or, if not used, at the time of
admission. Information collected included COVID-19 testing results,
patient demographics, pre-existing comorbid conditions, initial vital
signs, laboratory results, and the use of corticosteroids,
hydroxychloroquine, and azithromycin to describe the cohort and to
identify potential confounders between groups. Severity of pulmonary
involvement was assessed at the time of baseline data collection and was
categorized as severe or nonsevere. Patients were considered to have
severe pulmonary involvement if they required an Fio2
of 50% or more, high-flow nasal oxygen, noninvasive ventilation,
or intubation and mechanical ventilation. The nonsevere pulmonary
criteria encompassed patients who required no supplemental oxygen or low
Fio2 (ie, venturi mask 40% or less or up to 6 L/min of low-flow nasal cannula), independent of laboratory findings.
Patients
were categorized into two treatment groups based on whether they
received ivermectin at any time during the hospitalization. Patients in
the ivermectin group received at least one oral dose of ivermectin at
200 μg/kg in addition to usual clinical care. A second dose could be
given at the discretion of the treating physician at day 7 of treatment.
Ivermectin is not currently approved by the Food and Drug
Administration for COVID-19 treatment. The decision to prescribe
ivermectin, hydroxychloroquine, azithromycin, or other medications was
at the discretion of the treating physicians; however, hospital
guidelines were established for the safe use and dosing of these agents.
These guidelines included a baseline ECG and mandatory cardiac and QTc
monitoring for patients receiving hydroxychloroquine (alone or in
combination with azithromycin), avoidance of azithromycin if patient’s
baseline QTc was more than 460 msec, and discontinuation of
hydroxychloroquine if a concerning elevation in QTc occurred or if the
patient’s cardiologist recommended discontinuation. Oxygen and
ventilatory support were applied per the customary care. Empiric use of
ivermectin was given explicitly for COVID-19.
Outcomes
The
primary outcome was all-cause in-hospital mortality. A patient was
considered a survivor if he or she left the hospital alive or if his or
her status in the hospital changed from active care to awaiting transfer
to a skilled facility. Two consecutive nasopharyngeal swab specimens
showing negative results for SARS-CoV-2, collected ≥ 24 h
apart, were necessary for a patient to be accepted to the local skilled
nursing facilities.
Secondary
outcomes included subgroup mortality of patients with severe pulmonary
involvement, extubation rates for patients requiring mechanical
ventilation, and length of hospital stay. Length of stay was calculated
from day of admission to either the day of discharge or to patient
death.
Statistical Analysis
Univariate analysis of the primary mortality outcome and comparisons between treatment groups were determined by the Student t test for parametric continuous variables or the Mann-Whitney U test for nonparametric continuous variables as appropriate, and by the Pearson χ 2 test for categorical variables. The method of Hodges-Lehman was used to estimate median differences with 95% CIs.
To
adjust for confounders and between-group differences, a multivariate
analysis was performed using stepwise binary logistic regression.
Patient variables included in the analysis were age, sex, comorbidities
of diabetes, chronic lung disease, cardiovascular disease, and
hypertension, smoking status, severity of pulmonary involvement, need
for mechanical ventilation at study entry, BMI, peripheral white blood
count, absolute lymphocyte count, and use of corticosteroids based on
bivariate associations within our data, a priori plausibility, and
documented associations with mortality from previous studies. Adjusted
ORs with 95% CIs were computed to show level of certainty. Analyses
were based on nonmissing data, and missing data were not imputed.
Missingness of 1% was found for peripheral WBC count, 5% for
smoking status, and 7% for absolute lymphocyte count.
We
performed a secondary analysis using propensity score matching to
reduce the effects of confounding and the likelihood of selection bias.
Propensity matching was performed using a nearest-neighbor algorithm
with 1:1 matching without replacement and a caliper distance of less
than 0.2. Variables for propensity scoring included those variables from
the univariate between-groups analysis of the unmatched cohort that had
a P value of less than .2 (age, sex, pulmonary condition,
hypertension , HIV status, severe pulmonary presentation, and exposure
to corticosteroids, hydroxychloroquine, or azithromycin). Race, WBC
count, absolute lymphocyte count, and need for mechanical ventilation
before or on the day of study entry also were added as potential
clinical confounders.
All tests were two-sided and a P
value < .05 was considered statistically significant.
Statistical analyses were conducted using IBM SPSS version 26.0
software, R version 3.5.3 software (R Foundation for Statistical
Computing), and SPSS PS-matching software (sourceforge.net).
This
study was conducted in accordance with tenets of the amended
Declaration of Helsinki. The protocol was approved by the institutional
review board for the Broward Health Hospital System (Identifier:
2020-034-BHMC). The authors assume responsibility for the accuracy and
completeness of the data and analyses, as well as for the fidelity of
the study.
Results
Characteristics of the Patients
Three
hundred seven patients were admitted for COVID-19 during the period
studied. Four patients were not reviewed because of multiple admissions,
11 did not have COVID-19 confirmed at the time of the study, and 12
were excluded because their age was younger than 18 years, they were
pregnant, or they were incarcerated. The remaining cohort of 280
patients comprised 173 treated with ivermectin and 107 in the usual care
group. Most patients received a single dose of ivermectin; however, 13
patients received a second dose of ivermectin for ongoing signs or
symptoms on day 7 of treatment. Follow-up data for all outcomes were
available through May 19, 2020. No patients were lost to follow-up for
the primary outcome. At the time of analysis, all patients in both
groups had met the end point of death, discharge alive, or awaiting
transfer to a skilled facility. Of those awaiting transfer, in the
control group, one patient was awaiting transfer to hospice because of
an unrelated terminal illness and one patient was awaiting negative
COVID-19 test results to proceed with unrelated surgery. In the
ivermectin group, five patients were in stable condition, awaiting
transfer to skilled facility or rehabilitation, and one patient was
improving clinically.
Baseline characteristics and between-group comparisons for unmatched and propensity-matched cohorts are shown in Table 1.
Before matching, hypertension and corticosteroid use were more
prevalent in the ivermectin group, whereas the use of hydroxychloroquine
and hydroxychloroquine plus azithromycin were higher in the usual care
group.
Table 1Patient Characteristics by Treatment Group
| Demographic Characteristic | Unmatched Cohort | Matched Cohort | ||||||
|---|---|---|---|---|---|---|---|---|
| Total (N = 280) | Usual Care (n = 107) | Ivermectin (n = 173) | P Value | Total (N = 196) | Usual Care (n = 98) | Ivermectin (n = 98) | P Value | |
| Age, y | 59.6 ± 17.9 | 58.6 ± 18.5 | 60.2 ± 17.6 | .45 | 59.6 ± 17.5 | 59.04 ± 17.7 | 60.07 ± 17.4 | .68 |
| Female sex | 127 (45.4) | 43 (41.2) | 84 (48.6) | .17 | 78 (39.8) | 39 (39.8) | 39 (39.8) | 1.0 |
| Race or ethnicity | .36 | 1.0 | ||||||
| Black | 153 (54.6) | 55 (51.4) | 98 (56.6) | 108 (55.1) | 54 (55.1) | 54 (55.1) | ||
| White | 76 (27.1) | 35 (32.7) | 41 (23.7) | 55 (28.1) | 27 (27.6) | 28 (28.6) | ||
| Hispanic | 33 (11.7) | 12 (11.2) | 21 (12.1) | 23 (11.7) | 12 (12.5) | 111 (11.2) | ||
| Other or not identified | 13 (4.6) | 5 (4.7) | 13 (7.5) | 10 (5.1) | 5 (5.1) | 5 (5.1) | ||
| Current or former smoker | 46/255 (18.0) | 22/99 (22.3) | 24/156 (15.6) | .40 | 31/180 (22.2) | 20/90 (22.2) | 11/90 (12.2) | .11 |
| No. of comorbidities | 1.66 ± 1.34 | 1.60 ± 1.46 | 1.70 ± 1.27 | .57 | 1.56 ± 1.33 | 1.58 ± 1.43 | 1.53 ± 1.22 | .79 |
| Diabetes | 90 ± 32.1 | 31 ± 29.0 | 59 ± 34.1 | .37 | 59 ± 30.1 | 30 ± 30.6 | 29 ± 29.6 | .88 |
| Cardiac | 43 ± 15.4 | 18 ± 16.8 | 25 ± 14.5 | .59 | 27 ± 13.8 | 16 ± 16.3 | 11 ± 11.2 | .30 |
| Pulmonary | 28 ± 10.0 | 14 ± 13.1 | 14 ± 8.9 | .18 | 18 ± 10.1 | 10 ± 10.2 | 8 ± 8.2 | .62 |
| Obesity | 114 ± 40.7 | 42 ± 39.3 | 72 ± 41.6 | .70 | 79 ± 40.3 | 39 ± 39.8 | 40 ± 40.1 | .88 |
| Renal | 24 ± 8.6 | 10 ± 9.4 | 14 ± 8.1 | .72 | 16 ± 8.2 | 9 ± 9.2 | 7 ± 7.1 | .60 |
| Cancer | 17 ± 6.1 | 8 ± 7.5 | 9 ± 5.2 | .44 | 14 ± 7.1 | 7 ± 7.1 | 7 ± 7.1 | 1.00 |
| Hypertension | 50 ± 17.9 | 13 ± 12.2 | 37 ± 21.4 | .05 | 26 ± 13.2 | 12 ± 12.2 | 14 ± 14.3 | .67 |
| Neurologic | 28 ± 10.0 | 8 ± 7.5 | 20 ± 11.6 | .27 | 17 ± 8.7 | 8 ± 8.2 | 9 ± 9.2 | .80 |
| HIV infection | 9 ± 3.2 | 1 ± 1 | 8 ± 4.6 | .09 | 3 ± 1.5 | 1 ± 1.0 | 2 ± 2.0 | .56 |
| Thyroid | 23 ± 8.2 | 7 ± 6.6 | 16 ± 9.3 | .42 | 15 ± 7.7 | 7 ± 7.1 | 8 ± 8.2 | .79 |
| BMI | 30.0 ± 7.8 | 29.8 ± 7.2 | 30.1 ± 8.2 | .81 | 29.4 ± 6.6 | 29.4 ± 6.3 | 29.4 ± 6.9 | .95 |
| Pulmonary severity | .46 | |||||||
| Severe | 75 (26.8) | 26 (24.3) | 49 (28.3) | .12 | 47 (24.0) | 22 (22.4) | 25 (25.5) | .62 |
| Intubated at study entry | 38 (13.6) | 15 (14.0) | 23 (13.3) | .86 | 25 (12.8) | 11 (11.2) | 14 (14.3) | .52 |
| Heart rate | 86.0 (75.0-98.0) | 86.0 (74.0-97.0) | 86.0 (75.5-98.0) | .65 | 85.5 (74.0-98.0) | 86.0 (73.0-97.5) | 85.0 (74-98.0) | .88 |
| MAP (mm Hg) | 93 (82.3-103.0) | 90 (81.0-103.0) | 94 (83-103) | .24 | 92.5 (82.0-103.0) | 91.0 (81.0-103.2) | 93.0 (82.0-103.0) | .74 |
| MAP ≤ 70 mm Hg | 13/260 (5.0) | 6/89 (6.7) | 7/171 (4.1) | .35 | 7 (3.6) | 4 (4.1) | 3 (3.1) | .70 |
| Corticosteroid | 90 (32.1) | 21 (19.6) | 69 (39.8) | .001 | 46 (23.2) | 21 (21.4) | 25 (25.5) | .5 |
| Hydroxychloroquine | 260 (92.9) | 104 (97.2) | 156 (90.2) | .03 | 190 (96.9) | 95 (96.9) | 95 (96.9) | 1.00 |
| Azithromycin | 243 (86.7) | 99 (92.5) | 144 (83.2) | .03 | 177 (90.3) | 90 (91.8) | 87 (88.7) | .47 |
| Peripheral WBC count (× 109/L) | 7.3 (5.6-10.2; n = 277) | 7.0 (5.7-8.9; n = 106) | 7.6 (5.5-11.1; n = 171) | .41 | 6.9 (5.3-9.3) | 7.0 (5.8-9.0) | 6.9 (5.2-9.8) | .69 |
| Lymphocyte count (× 109/L) | 1.15 (0.78-1.56; n = 260) | 1.14 (0.84-1.49; n = 102) | 1.20 (0.77-1.67; n = 158) | .62 | 1.13 (0.77-1.52) | 1.15 (0.87-1.45) | 1.19 (0.75-1.57) | .88 |
Data
are presented as No. (%), mean ± SD, or median (interquartile range),
unless otherwise indicated. MAP = mean arterial pressure.
a Asian, Native American, Pacific Islander, or not identified.
Propensity
score matching created a total of 98 matched pairs. After matching, no
statistically significant differences were found between the two groups.
Eight patients in the propensity-matched group received a second dose
of ivermectin on day 7.
Outcomes
Unadjusted outcomes for the unmatched cohort and outcomes in the propensity-matched cohort are shown in Table 2.
For the unmatched cohort, overall mortality was significantly lower in
the ivermectin group than in the usual care group
(15.0% vs 25.2% for ivermectin and usual care,
respectively; P = .03). Mortality also was lower for
ivermectin-treated patients in the subgroup of patients with severe
pulmonary involvement (38.8% vs. 80.7% for ivermectin and
usual care, respectively; P = .001). On univariate
analysis, patients receiving corticosteroids showed a higher mortality
than those who did not receive corticosteroids
(30.0% vs 13.7%; OR, 2.7; 95% CI, 1.47-4.99; P =
.001); however, corticosteroids were more likely to have been
prescribed for severe patients (58.6% vs 22.4% for severe
and nonsevere, respectively; OR, 4.91; 95% CI, 2.78-8.63; P < .001).
Table 2Univariate Clinical Outcomes by Treatment Group
| Outcome | Unmatched Cohort | Matched Cohort | ||||||
|---|---|---|---|---|---|---|---|---|
| Control Subjects (n = 107) | Ivermectin (n = 173) | OR or Difference (95% CI) | P Value | Control Subjects (n = 98) | Ivermectin (n = 98) | OR or Difference (95% CI) | P Value | |
| Mortality | . . . | . . . | . . . | . . . | . . . | . . . | . . . | . . . |
| Total | 27 (25.2) | 26 (15.0) | 0.52 (0.29-0.96) | 0.03 | 24 (24.5) | 13 (13.3) | 0.47 (0.22-0.99) | 0.045 |
| Severe | 21/26 (80.7) | 19/49 (38.8) | 0.15 (0.05-0.47) | 0.001 | 18/22 (81.8) | 8/25 (32.0) | 0.27 (0.08-0.92) | 0.002 |
| Nonsevere | 6/81 (7.4) | 7/124 (5.6) | 0.75 (0.24-2.3) | 0.61 | 6/76(7.9) | 4/74 (5.4) | 0.97 (0.61-1.54) | 0.78 |
| Successful extubation | 4/26 (15.4) | 13/36 (36.1) | 3.11 (0.88-11.00) | 0.07 | 3/22 (15.4) | 7/18 (38.9) | 1.91 (0.43-8.46) | 0.14 |
| Length of stay | 7.0 (4.0-10.0) | 7.0 (4.0-13.3) | 0 (-1 to 2) | 0.34 | 7.0 (4.0-10.0) | 7.0 (3.0-13.0) | 0 (-2 to 1) | 0.88 |
Data are presented as No./Total No. (%) or median (interquartile range) unless otherwise indicated.
Results
were similar, with lower mortality in the ivermectin-treated patients
for the matched cohort for the group as a whole and for the subgroup
with severe pulmonary involvement (Table 2).
In the matched cohort, ivermectin was associated with an absolute risk
reduction of 11.2% (95% CI, 0.38%-22.1%) and a corresponding
number needed to treat of 8.9 (95% CI, 4.5-263) to prevent one
death. We found no difference in median hospital length of stay or in
extubation rates in either the unmatched or matched cohorts. Of note, 1
of the 13 patients who received a second dose of ivermectin died; this
patient was not in the propensity-matched cohort.
Multivariate
analysis was performed on the unmatched cohort, adjusting for
demographic factors and between-group differences in mortality risks.
Independent predictors of in-hospital mortality included treatment
group, age, severe pulmonary disease category, and reduced lymphocyte
count (Table 3).
Because race was not a significant predictor after adjustment, a
further analysis was performed that showed that White patients were
significantly older than Black patients (mean age, 66.8 vs 59.1 y;
mean difference, 7.7 y; 95% CI, 3.0-12.4 y; P = .001) and that Hispanic patients (mean age, 49.8 y; mean difference, 17.0 y; 95% CI, 9.6-24.4 y; P < .001).
Table 3Multivariate Analysis of Factors Associated With Mortality
| Variable | OR (95% CI) | P Value |
|---|---|---|
| Treatment group | . . . | . . . |
| Ivermectin | 0.27 (0.09-0.80) | .03 |
| Control subject | Reference | . . . |
| Age | 1.05 (1.02-1.09) | .003 |
| Sex | . . . | . . . |
| Female | 0.42 (0.24-1.82) | .42 |
| Male | Reference | . . . |
| Smoking status | . . . | . . . |
| Current or former smoker | 3.49 (0.71-17.32) | .13 |
| Nonsmoker | Reference | . . . |
| Race | . . . | .18 |
| Black | 0.64 (0.21-1.94) | .43 |
| Hispanic | 0.14 (0.02-1.22) | .08 |
| Other | 0.62 (0.05-7.92) | .71 |
| White | Reference | . . . |
| Comorbidities | . . . | . . . |
| Diabetes | 1.17 (0.39-3.55) | .78 |
| Cardiac | 1.51 (0.43-5.22) | .52 |
| Pulmonary | 0.15 (0.20-1.84) | .15 |
| Hypertension | 0.72 (0.17-3.08) | .66 |
| No comorbidities | Reference | . . . |
| BMI | 0.97 (0.89-1.07) | .58 |
| Severe presentation | 11.41 (3.42-38.09) | < .001 |
| Intubated at study entry | 2.96 (0.73-12.06) | .13 |
| MAP ≤ 70 mm Hg | 1.82 (0.17-19.1) | .62 |
| Corticosteroid treatment | 1.71 (0.57-5.16) | .34 |
| Peripheral WBC count | 1.08 (0.96-1.23) | .22 |
| Lymphocyte count | 3.65 (1.25-10.60) | .02 |
MAP = mean arterial pressure.
Discussion
In
this multihospital retrospective cohort study, we observed a
significant association of ivermectin with improved survival for
patients admitted with COVID-19. This association also was seen in the
subset of patients with severe pulmonary disease. These findings were
confirmed after multivariate adjustment for comorbidities and
differences between groups, and also in a propensity score-matched
cohort. Similar to other studies, we noted that older age, cardiac
disease, current or former smoking, more severe pulmonary involvement at
presentation, higher WBC counts, and lower lymphocyte counts emerged as
risk markers for in-hospital mortality.
The
overall mortality, and mortality in intubated patients, in our usual
care group was similar to what was reported in previous studies.
Richardson et al
6
reported an overall mortality of 21% in a New York City cohort,
with a mortality of 88% in intubated patients. Zhou et alRichardson S, Hirsch JS, Narasimha M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area [published online ahead of print April 22, 2020]. JAMA. https://doi.org/10.1001/jama.2020.6775.5.
7
reported 28.2% mortality in a cohort of hospitalized patients in
Wuhan, China; the intubated patients showed a mortality of 96.9%. In
contrast to Magagnoli et al,8
we did not see a higher mortality effect for hydroxychloroquine. This
may have been because of the small number of patients who were not
treated with this agent; thus, our study was underpowered to detect a
difference in mortality from hydroxychloroquine treatment. We also
hypothesize that precautionary measures in the hospitals’ protocol for
hydroxychloroquine use could have prevented fatal arrhythmias from
developing. These included baseline electrocardiography and daily QTc
monitoring by telemetry for any patient receiving hydroxychloroquine or
combination therapy, avoidance of azithromycin if patient’s baseline QTc
was more than 460 msec, and discontinuation of hydroxychloroquine
if a concerning elevation in QTc occurred or if the patient’s
cardiologist recommended discontinuation. In contrast to Horby
et al,9
we did not find a mortality benefit for patients who were prescribed
corticosteroids in our multivariate analysis, which included several
severity covariates. These findings are likely explainable by
physicians’ choice to reserve use of corticosteroids for the most
seriously ill patients, because the study was performed before the
results of the RECOVERY trial were published.Horby P, Lim WS, Emberson JR, et al. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19-preliminary report [published online ahead of print July 7, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021426.
9
Horby P, Lim WS, Emberson JR, et al. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19-preliminary report [published online ahead of print July 7, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021426.
We
also did not confirm a higher risk of mortality in Black patients in
comparison with White patients after controlling for age. Prior reports
showed lower survival rates among Black and Hispanic patients
10
; however, Price et al11
also found no racial differences in mortality. In our hospital
population, White patients were significantly older, which is reflective
of our catchment area and may be responsible for the discrepancy.Price CC, Altice FL, Shyr Y, et al. Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes [published online ahead of print 2020]. Chest. doi:https://doi.org/10.1016/j.chest.2020.06.006.
We
did not observe a significant difference in hospital length of stay
between the groups (median, 7 days for both groups) despite the
lower mortality. Possible explanation could include delay in discharging
patients to other facilities (skilled nursing facilities, inpatient
rehabs, and so forth) because of a delay in obtaining required repeat
COVID-19 testing results. Patients who died were included in
length-of-stay measurements.
Use of
mechanical ventilation was not adopted as an outcome of interest,
because guidelines and practice patterns for intubation criteria changed
throughout the length of the study. We were unable to determine ICU
length of stay and ventilatory-free days in the ICU because overflow
conditions during the pandemic placed critically ill patients in the
emergency room and other non-ICU environments, and therefore, we could
not determine ICU stay accurately. We did not find a lower mortality in
the subgroup of nonsevere patients treated with ivermectin; however, our
study was not powered to assess these differences because the overall
mortality in nonsevere patients was low. Similarly, the study was not
powered to determine whether extubation rates were higher in the
ivermectin group. These should be investigated further with a larger
randomized controlled trial.
Interpretation
Our
study has several limitations. Because of the retrospective
observational nature of the study, despite adjustment for known
confounders and propensity score matching, we cannot exclude the
possibility of unmeasured confounding factors. Although more of the
control group was enrolled in the first weeks of the study, suggesting
the possibility of timing bias, this may be offset by preferential
treatment of more severe patients with ivermectin early in the study
because of low initial availability. We also did not find consistently
different mortality outcomes with time over the short duration of this
study. We also did not find evidence of immortal time bias, because only
one of the control patients died fewer than 5 days from admission,
the average time from admission to death was 11 days, and the vast
majority of patients received ivermectin in 2 days or fewer. If we
omit the patient with potential immortal time from the analysis, the
mortality difference remains significant in both unmatched
(15.0% vs 24.5% for ivermectin and usual care,
respectively; P < .05) and matched (12.4% vs 25.0% for ivermectin and usual care, respectively; P <
.03) cohorts. Most of the studied patients received hydroxychloroquine
with or without azithromycin, and we are unable to determine whether
these medications had an added benefit or whether mortality would have
been better in both groups without these agents.
We
showed that ivermectin administration was associated significantly with
lower mortality among patients with COVID-19, particularly in patients
with more severe pulmonary involvement. Interpretation of these findings
are tempered by the limitations of the retrospective design and the
possibility of confounding. Appropriate dosing for this indication is
not known, nor are the effects of ivermectin on viral load or in
patients with milder disease. Further studies in appropriately designed
randomized trials are recommended before any conclusions can be made.
Uncited Reference
4
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro [published online ahead of print XX XX, 2020]. Antiviral Res. https://doi.org/10.1016/j.antivira1.2020.104787.
Acknowledgments
Author contributions:
J. C. R., lead author, had full access to all of the data in the study
and contributed to the study design, data collection and interpretation,
and writing of manuscript. M. S. S. provided data analysis and
interpretation and contributed to writing of the manuscript. N. F.
contributed to data collection and literature search. F. V. contributed
to the study design and data collection. J. S. contributed to data
collection and data organization. J.-J. R., corresponding author,
contributed substantially to the study design, data analysis and
interpretation, and the writing of the manuscript.
Financial/nonfinancial disclosures: None declared.
Other contributions:
The authors thank Edward Gracely, PhD, for his support and advice with
the statistical analysis, and Dr William Rifkin for reviewing the
manuscript.
References
- Safety of high-dose ivermectin: a systematic review and meta-analysis.J Antimicrobial Chemother. 2020; 75: 827-834
- Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond.Nat Rev Drug Discov. 2017; 16: 565-586
- Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus.Biochem J. 2012; 443: 851-856
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro [published online ahead of print XX XX, 2020]. Antiviral Res. https://doi.org/10.1016/j.antivira1.2020.104787.
- Safety and pharmacokinetic profile of fixed dose ivermectin with an innovative 18 mg tablet in healthy adult volunteers.PLoS Negl Trop Dis. 2018; 12e0006020
Richardson S, Hirsch JS, Narasimha M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area [published online ahead of print April 22, 2020]. JAMA. https://doi.org/10.1001/jama.2020.6775.5.
- Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062
- Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19.([published online ahead of print April 23, 2020])
Horby P, Lim WS, Emberson JR, et al. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19-preliminary report [published online ahead of print July 7, 2020]. N Engl J Med. https://doi.org/10.1056/NEJMoa2021426.
- Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464
Price CC, Altice FL, Shyr Y, et al. Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes [published online ahead of print 2020]. Chest. doi:https://doi.org/10.1016/j.chest.2020.06.006.
Article Info
Publication History
Published online: October 12, 2020
Publication stage
In Press Journal Pre-ProofFootnotes
FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.
Identification
Copyright
© 2020 The Authors. Published by Elsevier Inc under license from the American College of Chest Physicians.
User License
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Permitted
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
Not Permitted
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Elsevier's open access license policy
