To the editor,
Since the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19)
a pandemic, the medical community started a race against time to find effective treatments
for this disease [1]. Atorvastatin as adjuvant immunomodulatory therapy is of particular
interest given its low cost, known safety profile, and availability. The severe acute
respiratory syndrome coronavirus (SARS-CoV) has been shown to interact with Toll-like
receptors on the host cell membrane, increasing the expression of the MYD88 gene,
ultimately activating NF-κB and triggering inflammatory pathways. Experimental models
have demonstrated that statins stabilize MYD88 levels after a pro-inflammatory trigger,
and, in a murine model, atorvastatin significantly attenuated NF-κB activation [2].
Furthermore, in the real world, two retrospective cohort studies reported a reduced
risk of influenza death among statin users [3, 4]. Therefore, we assessed whether
statin users at a dose of 40 mg daily had reduced inpatient mortality hazard from
COVID-19.
In this retrospective cohort study, we used a de-identified dataset that included
87 adult patients with laboratory-confirmed COVID-19 admitted to our community hospital
intensive care unit (ICU) located in Evanston, IL, from March to May 2020. We performed
a Cox proportional hazards (PH) regression model to examine the relationship between
adjuvant treatments and inpatient mortality. To minimize confounders, we adjusted
for age, hypertension, cardiovascular disease, invasive mechanical ventilation, severity
according to the National Institutes of Health criteria (respiratory rate > 30, SpO2 < 94%,
PaO2/FiO2 < 300 mmHg or lung infiltrates > 50%), number of comorbidities (as a continuous
variable), and other adjuvant therapies (including hydroxychloroquine, intravenous
steroids, azithromycin, tocilizumab, colchicine, and antibiotics), forcing these variables
into the model. We also performed a sensitivity analysis calculating the E value (with
the lower confidence limit) as described by VanderWeele et al. [5, 6] for the obtained
point estimate. The E value is defined as the minimum strength of association on the
risk ratio scale that an unmeasured confounder would need to have with both the exposure
and the outcome, conditional on the measured covariates, to explain away a specific
exposure-outcome association fully.
The median age was 68 years (interquartile range [IQR], 58–75 years), 56 (64.4%) were
males, and 50 (57.5%) were skilled nursing facility residents. Of these patients,
39 (44.8%) were ultimately discharged from the hospital, median length of stay 13 days
(IQR, 7 to 21 days), and 48 (55.2%) had died, median length of stay 9.5 days (IQR, 3 to 14.75 days),
a statistically significant difference (p = 0.032 by Mann-Whitney U test). A total
of 24 (61.5%) survivors received atorvastatin 40 mg daily compared to 23 (47.9%) of
non-survivors (p = 0.20 by chi-squared). In the multivariable Cox PH regression model,
atorvastatin non-users had a 73% chance of faster progression to death compared with atorvastatin
users (when probability = HR/HR + 1) (Table 1). The E value for the point estimate
was 3.29 and the E value for the lower confidence interval was 1.69, meaning that
a confounder not included in the multivariable Cox PH regression model associated
with atorvastatin use and inpatient mortality in patients with COVID-19 by a hazard
ratio of 1.69-fold each could explain away the lower confidence limit, but weaker
confounding could not.
Table 1
Multivariable Cox regression of target interventions for COVID-19
Intervention
Adjusted HR
a
95% CI
p
value
b
Atorvastatin
0.38
0.18–0.77
0.008
Steroids
1.93
0.81–4.59
0.136
Hydroxychloroquine
0.81
0.31–2.10
0.675
Colchicine
0.41
0.17–0.98
0.045
Tocilizumab
1.17
0.42–3.25
0.765
Azithromycin
0.49
0.20–1.23
0.132
Abbreviations: CI confidence interval, COVID-19 coronavirus disease 2019, HR hazard
ratio
aAdjusted for age, number of comorbidities, hypertension, cardiovascular disease,
severity, invasive mechanical ventilation, and antibiotics other than azithromycin
b
p < 0.05 was considered statistically significant
In conclusion, we found a slower progression to death associated with atorvastatin
in patients with COVID-19 admitted to our ICU. Given the observational nature of this
study, results should be taken with caution; randomized controlled trials are needed
to confirm this benefit (STATCO19, identifier NCT04380402). To date, supportive care
remains the mainstay of therapy, and the clinical efficacy for various treatments
is still under investigation.