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Scientific letter
DOI: 10.1016/j.rec.2021.01.005
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Available online 14 February 2021
Impact of statins in patients with COVID-19
Impacto de las estatinas en los pacientes con COVID-19
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Álvaro Aparisia,, Ignacio J. Amat-Santosa,b,,
Corresponding author
ijamat@gmail.com

Corresponding author:
, Diego López Oterob,c, Marta Marcos-Mangasa, José R. González-Juanateyb,c, J. Alberto San Romána,b
a Departamento de Cardiología, Hospital Clínico Universitario, Valladolid, Spain
b Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
c Departamento de Cardiología, Hospital Universitario de Santiago de Compostela, A Coruña, Spain
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Tables (2)
Table 1. Baseline characteristics and outcomes of statin vs nonstatin users infected with SARS-CoV-2
Table 2. Predictors of 30-day mortality in the study population
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To the Editor,

On November 11, 2020, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) had infected 9 187 237 people worldwide with an estimated mortality rate of 2.7%.1 Initial reports hinted that a dysregulated immune system might play a key role in its lethality.2 Patients with a prior history of cardiovascular disease (CVD) or risk factors are particularly at higher risk.3

Statins are common among high-risk patients and have been demonstrated to diminish the incidence of cardiovascular morbidity and mortality. Interestingly, it has previously been suggested that statins may confer a protective benefit in viral infections. In theory, statins might lessen the incidence of acute injury in coronavirus disease 2019 (COVID-19) by: a) decreasing L-mevalonate downstream mediators; b) through inhibition of protein prenylation; and c) upregulation of angiotensin-converting enzyme 2 levels.4 However, the greater use of statins in patients with a higher CVD burden might counterbalance a potential protective effect compared with nonstatin users. Our aim was to describe the characteristics and evaluate the impact of chronic statin treatment in the prognosis of patients admitted to hospital due to COVID-19.

We have performed a retrospective, observational study performed in 2 Spanish tertiary hospitals of all admitted patients between March 1 and April 30, 2020 with a definitive diagnosis of SARS-CoV-2 infection confirmed through positive reverse transcriptase polymerase chain reaction. We recorded prescribed therapy before admission and during hospital stay according to the protocols of our institutions and the discretion of the medical team. Clinical outcomes were also registered. Categorical variables are reported as absolute values and percentages. Continuous variables are expressed as mean±standard deviation; non normally distributed variables are reported as median [interquartile range]. The effect of statins on the primary outcome (in-hospital mortality) in the overall study population was evaluated with a multivariate logistic regression model after adjustment for the main cofounding factors. All the analyses were conducted using the statistical software IBM SPSS Statistics, Version 25.0. (IBM Corp, United States). Differences were considered statistically significant when P was <.05. The study was approved by the local ethics committee and informed consent was waived given its retrospective and observational nature.

Out of 840 patients admitted due to COVID-19, 295 (35.1%) were under statin therapy before hospital admission and 545 (64.9%) were not. Patients treated with statins were older (73.5±10.1 vs 65.7±15.9; P <.001) and had a higher prevalence of several comorbidities including hypertension (66.9% vs 41.3%; P <.001), diabetes mellitus (33% vs 12.1%; P <.001), and prior heart disease (13.9% vs 6.4%; P <.001). In parallel, those under statin therapy were more often receiving antihypertensive drugs, beta-blockers, and aspirin. Time from symptom onset to admission did not differ between groups. Statin users had a more prominent inflammatory profile at admission with higher C-reactive protein (92 vs 60.3mg/dL; P=.002), interleukin-6 (26.35 vs 19 pg/mL; P=.011), and D-dimer levels (954 vs 717; P=.001). Overall, patients in the statin cohort were more commonly treated with intravenous corticosteroids (66.7% vs 56.2%; P <.026) and anticoagulants (69.9% vs 59.7%; P=.033), but other empirical drugs for the treatment of COVID-19 were used in similar rates. Major in-hospital outcomes including acute respiratory failure (9.8%), intensive care admission (10.5%), and all-cause mortality (20.4%) were comparable. Main baseline characteristics according to lipid-lowering treatment at baseline are summarized in table 1.

Table 1.

Baseline characteristics and outcomes of statin vs nonstatin users infected with SARS-CoV-2

Variable  Overall COVID-19populationN=840  Statin usersn=295(35.1%)  Nonstatin usersn=545(64.9%)  P 
Baseline characteristics
Male sex  427/840 (50.8)  156/295 (52.9)  271/545 (49.7)  .382 
Age, y  68.15±14.73  73.47±10.08  65.66±15.93  <.001d 
CKDa  58/837 (6.9)  21/294 (7.1)  37/543 (6.8)  .858 
COPD  77/813 (9.5)  36/288 (12.5)  41/525 (7.8)  <.029d 
Diabetes  163/839 (19.4)  97/294 (33)  66/545 (12.1)  <.001d 
Dyslipidemia  343/836 (41)  247/292 (84.6)  96/544 (17.6)  <.001d 
Hypertension  421/838 (50.2)  196/293 (66.9)  225/545 (41.3)  <.001d 
Prior heart disease  73/810 (9)  39/281 (13.9)  34/529 (6.4)  <.001d 
Treatment prior to admission
Aspirin  128/837 (15.3)  100/295 (33.9)  28/542 (5.2)  <.001d 
ACEi  145/836 (17.3)  78/294 (26.5)  67/542 (12.4)  <.001d 
ARB  176/839 (21)  80/295 (27.1)  96/544 (17.6)  .001d 
Anticoagulants  98/838 (11.7)  44/294 (15)  54/544 (9.9)  .030d 
BB  155/839 (18.5)  88/295 (29.8)  67/544 (12.3)  <.001d 
Laboratory findings at admission
Hemoglobin, g/dL  13.3 [12-14.5]  13.1 [11.85-14.2]  13.4 [12.1-14.6]  .174 
eGFR, mL/min/1.73 m2b  82 [56-90]  73 [51-87]  85 [62-90]  .001d 
C-reactive protein, mg/L  66 [24-123.3]  92 [35.4-150.4]  60.3 [23-111.8]  .002d 
D-Dimer, ng/mL  760 [453-1475]  954 [534-1719]  717 [403-1301]  .001d 
ESR, mm/h  49 [30-66]  54 [39-73]  46 [28-58]  .067 
Ferritin, ng/mL  562 [287-1100]  592 [335-1100]  557 [264-1113]  .434 
GOT, UI/L  35 [24-52]  32.5 [24-52]  35.5 [24-52]  .575 
Interleukin-6, pg/mL  21.8 [11-42.2]  26.35 [15-50.6]  19 [9.7-37.9]  .011d 
LDH, UI/L  297 [225-403]  316 [244-421]  291 [218-396]  .006d 
Lymphocytes, cells/mm3  1000 [730-1375]  960 [720-1270]  1015 [730-1460]  .184 
Platelets, cells/mm3 x 103  205 [161-271,5]  202 [163,5-268,5]  206 [161-272]  .914 
Procalcitonine, ng/mL  0.1 [0.06-0.26]  0.1 [0.06-0.29]  0.09 [0.05-0.22]  .081 
hsTTn, pg/mL  15.2 [9-37]  15.8 [11.6-18.7]  15 [9-46.5]  .948 
Nonspecific COVID-19 treatment
Aspirin  60/513 (11.7)  45/162 (27.8)  15/351 (4.3)  <.001d 
ACEi  92/840 (11)  52/295 (17.6)  40/545 (7.3)  <.001d 
ARB  88/839 (10.5)  40/295 (13.6)  48/544 (8.8)  .033d 
BB  85/513 (16.6)  48/162 (29.6)  37/351 (10.5)  <.001d 
Statins  69/832 (8.3)  60/292 (20.5)  9/540 (1.7)  <.001d 
Anticoagulation  323/513 (63)  114/163 (69.9)  209/350 (59.7)  .026d 
Specific COVID-19 treatment
Azithromycin  749/798 (93.9)  271/286 (94.8)  478/512 (93.4)  .431 
Hydroxychloroquine  766/801 (95.6)  276/286 (96.5)  490/515 (95.1)  .368 
Betaferon  223/799 (27.9)  81/286 (28.3)  142/513 (27.7)  .846 
Lopinavir/ritonavir  701/802 (87.4)  250/287 (87.1)  451/515 (87.6)  .849 
Corticosteroids  293/492 (59.6)  106/159 (66.6)  187/333 (56.2)  .026 
Tocilizumab  44/796 (5.5)  13/284 (4.6)  31/512 (6.1)  .382 
Main in-hospital outcomes
Length of stay, d  9 [6-14]  9 [6-15]  9 [5-13]  .549 
Acute respiratory failurec  338/806 (41.9)  127/285 (44.6)  211/521 (40.5)  .264 
Heart failure  62/804 (7.7)  22/278 (7.9)  40/526 (7.6)  .876 
ICU admission  86/822 (10.5)  30/286 (10.5)  56/536 (10.4)  .985 
ICU LOS, d  13 [5.5-19]  13 [8-19]  12.5 [5.5-17]  .471 
Mechanical ventilation  72/738 (9.8)  23/261 (8.8)  49/477 (10.3)  .523 
All-cause overall mortality  171/840 (20.4)  64/295 (21.7)  107/545 (19.6)  .479 

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blockers; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; ESR, erythrocyte sedimentation rate; hsTTn, high-sensitivity T-troponin.

Values are expressed as mean±standard deviation, median [interquartile range], or No. (%).

a

Chronic kidney disease was defined as a glomerular filtration rate of <60mL/min or need for dialysis.

b

Estimated with the CKD-EPI formula.

c

Defined as pO2 <60mmHg, SO2 <92% or need for noninvasive or mechanical ventilation.

d

Significant P values.

A logistic regression model was used to study the association between chronic statin use with clinical outcomes in hospitalized COVID-19 patients. The following variables were included in the definitive model: age, sex, hypertension, dyslipidemia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, history of cigarette smoking, prior heart disease, and chronic adjuvant therapies (renin-angiotensin-aldosterone system inhibitors, beta-blockers, aspirin, and anticoagulation). In this model (see table 2), chronic statin treatment (adjusted odds ratio of 0.48, 95% confidence interval, 0.3-0.77; P=.002) was associated with lower in-hospital mortality compared with nonstatin users. In addition, elderly patients, male patients and diabetic patients were at a higher risk of death due to COVID-19.

Table 2.

Predictors of 30-day mortality in the study population

  UnivariateMultivariate
  OR (95%CI)  P  OR (95%CI)  P 
Male sex  2.03 (1.42-2.91)  <.001d  2.22 (1.43-1.64)  <.001d 
Age, y  1.09 (1.07-1.11)  <.001d  1.1 (1.08-1.12)  <.001d 
CKD  4.44 (2.59-7.64)  <.001d     
COPD  2.22 (1.35-3.64)  .002d     
Diabetes  2.82 (1.93-4.1)  <.001d  2.05 (1.27-3.29)  .003d 
Hypertension  2.86 (1.99-4.09)  <.001d     
Smokinga  1.55 (1.07-2.26)  .021d     
Previous heart disease  2.26 (1.35-3.78)  .002d     
Statins  1.13 (0.801-1.61)  .479  0.48 (0.3-0.77)  .002d 
Aspirin  2.35 (1.55-3.55)  <.001d  2.21 (1.26-3.87)  .006d 
RAAS inhibitorsb  1.76 (1.2-2.58)  .001d     
Anticoagulantsc  3.81 (2.45-5.93)  <.001d  1.98 (1.16-3.38)  .013d 
Beta-blockers  2.79 (1.90-4.09)  <.001d     
Diuretics  2.42 (1.55-3.79)  <.001d     

95%CI, 95% confidence interval; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; OR, odds ratio; RAAS, renin-angiotensin-aldosterone system inhibitors.

a

Includes active and former smokers.

b

Includes angiotensin converting enzyme inhibitors, angiotensin receptor blockers and spironolactone/eplerenone.

c

Vitamin K antagonist and new oral anticoagulants.

d

Significant P values.

Statins, with their pleiotropic properties, have the potential to reduce the severity of acute lung injury and mortality. Our findings are in agreement with those of a recent retrospective study that evaluated the impact of chronic statin treatment prior to COVID-19 hospitalization, in which statin use before hospital admission was associated with a 71% reduction for developing severe COVID-19.5 Likewise, Xiao-Jing Zhang et al.6 observed that in-hospital statin use was also associated with improved outcomes among COVID-19 patients.

This study has several limitations. Given the study design, we cannot infer causality of statins on mortality and it should be considered hypothesis generating. Our findings may be limited by the fact that we did not evaluate patients not admitted to hospital or under the effect of some unmeasured in-hospital confounders (eg, statin maintenance and impact of concomitant treatments). However, our results suggest that statin users with COVID-19 have a greater baseline risk mainly driven by more advanced age and a high burden of cardiovascular comorbidities, which might in theory disguise a potential protective effect of statins in this particular subset of patients. There is currently no evidence from any randomized controlled trial to show whether in-hospital statins may benefit patients with COVID-19, but we would like to draw the attention of the international community to this possibility until conclusive evidence is reported (STATCO19, NCT04380402).

Funding

This work was partially funded by the Gerencia Regional de Salud de Castilla y León (GRS COVID 111/A/20) and the Spanish Society of Cardiology (SEC/FEC-INVCLI 20/030).

Conflicts of interest

None conflicts of interest.

References
[1]
WHO. Coronavirus disease 2019 (COVID-19) situation report. Nov 11, 2020. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019. Accessed 11 Nov 2020.
[2]
D.M.D. Valle, S. Kim-Schulze, H.-H. Huang, et al.
An inflammatory cytokine signature predicts COVID-19 severity and survival.
Nat Med., 26 (2020), pp. 1636-1643
[3]
G. Grasselli, A. Zangrillo, A. Zanella, et al.
Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region.
Italy. JAMA., 323 (2020), pp. 1574-1581
[4]
S.P. Parihar, R. Guler, F. Brombacher.
Statins: a viable candidate for host-directed therapy against infectious diseases.
Nat Rev Immunol., 19 (2019), pp. 104-117
[5]
L.B. Daniels, A.M. Sitapati, J. Zhang, et al.
Relation of Statin Use Prior to Admission to Severity and Recovery Among COVID-19 Inpatients.
Am J Cardiol., 136 (2020), pp. 149-155
[6]
X.-J. Zhang, J.-J. Qin, X. Cheng, et al.
In-hospital Use of Statins is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.
Cell Metab., 32 (2020), pp. 176-187

Both authors contributed equally to this research.

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