Association Between Antecedent Statin Use and Decreased Mortality in Hospitalized Patients with COVID-19

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections and ARDS, but their benefit has not been assessed in COVID-19. Thus, we sought to determine whether antecedent statin use is associated with lower in-hospital mortality in patients hospitalized for COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1st through May 12th, 2020 with study period ending on June 11th, 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline socio-demographic and clinical characteristics, and outpatient medications. The primary endpoint included in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, demographic, baseline, and outpatient medication information were well balanced. Statin use was significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.48, 95% CI 0.36 – 0.64, p<0.001). We conclude that antecedent statin use in patients hospitalized with COVID-19 was associated with lower inpatient mortality. Randomized clinical trials evaluating the utility of statin therapy in patients with COVID-19 are needed.

endpoint included in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identi ed with 1:1 propensity-score matching, demographic, baseline, and outpatient medication information were well balanced. Statin use was signi cantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.48, 95% CI 0.36 -0.64, p<0.001).
We conclude that antecedent statin use in patients hospitalized with COVID-19 was associated with lower inpatient mortality. Randomized clinical trials evaluating the utility of statin therapy in patients with COVID-19 are needed.

Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal pathogen responsible for coronavirus disease 2019 (COVID- 19), enters human cells by engaging angiotensin-converting enzyme 2 (ACE2) 1 . This interaction may lead to an imbalance of the renin-angiotensin-aldosterone system (RAAS), a potential mechanism contributing to this pathogen's virulence 2 . A combination of direct viral toxicity and indirect effects such as untempered thromboin ammation and dysregulation of the RAAS may underlie severe presentations of COVID-19, which can manifest with acute respiratory distress syndrome (ARDS), myocardial injury, and micro-and macro-thrombotic events 3 . As such, several anti-in ammatory, immunomodulatory, and antithrombotic therapies may hold promise for prevention or treatment of patients with COVID-19 4 , and statins constitute one such class of medications.
Although statins have traditionally been administered to lower serum cholesterol, their pleiotropic effects, including anti-in ammatory and antithrombotic properties, make them an attractive class of drugs in the setting of COVID-19 [5][6][7][8] . Moreover, through effects on lipid rafts in cellular membranes [9][10][11][12] , statins may in uence viral transmission and infectivity. By these putative mechanisms, statins appear to have the potential to mitigate the impact of myocardial injury and thrombotic events that are associated with severe COVID-19 presentations 13 .
To date, a number of studies have evaluated the use of statins in the treatment of pneumonia and ARDS 5,[14][15][16][17][18][19][20] . While primary results of randomized clinical trials evaluating statins in ARDS have not indicated a bene t 19,20 , secondary analysis of 540 individuals from the HARP-2 (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary  trial demonstrated improved survival with statin treatment in patients with a hyperin ammatory phenotype 15 .
Therefore, we hypothesized that antecedent outpatient statin use may be associated with better clinical outcomes in patients hospitalized with COVID-19. In the current study, we sought to compare patient baseline and presentation characteristics as well as clinical outcomes, including in-hospital mortality, strati ed by antecedent statin use, in a cohort of patients admitted with COVID-19 to a quaternary academic medical center in New York City.

Methods
Patient population and data elements. For this retrospective study, we utilized data from the Columbia University Irving Medical Center (CUIMC) and Allen Hospital sites of the NewYork-Presbyterian Hospital (NYPH). Adult patients (≥18 years of age) who were hospitalized between February 1 st through May 12 th , 2020, and tested positive for SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) testing of nasopharyngeal or oropharyngeal specimens were included in the present analysis. All testing was conducted either by NYPH laboratories or the New York State Department of Health (in the period of time prior to when internal testing capabilities were available). Patients who were admitted for less than 24 hours were excluded from this analysis. The study period ended on June 11 th , 2020, allowing for a follow-up period of at least 30 days in all patients. The CUIMC Institutional Review Board approved this study and waived the requirement for obtaining informed consent. De-identi ed data will be made available on request to the corresponding authors.
Patient data were identi ed in the electronic medical record by using the institution's clinical data warehouse, which includes outpatient and inpatient information on individuals who receive care at our institution. No manual chart abstraction was performed. Follow-up for each patient continued until patients were discharged, died in-hospital, or the end of the study period was reached. Data analysis was limited to the index hospitalization in the event of readmissions. Baseline information including age, gender, race and ethnicity, insurance, New York City borough of residence, body mass index (BMI), comorbidities, and outpatient medications were recorded. Clinical comorbidities, including hypertension, diabetes, coronary artery disease, heart failure, stroke or transient ischemic attack, atrial arrhythmias (atrial brillation, atrial utter and supraventricular tachycardia), chronic lung disease, chronic kidney disease, and chronic liver disease were identi ed using ICD-10 medical billing codes (Supplemental Table  1). Outpatient medications, including statins, angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers, oral anticoagulants, and P2Y12 inhibitors were extracted from medication reconciliation elds in the electronic medical record, which are entries that are updated at the time of hospital admission.
We included features of the clinical presentation, including vital signs at presentation (i.e. temperature, heart rate, blood pressure, respiratory rate, and peripheral oxygen saturation). Several laboratory parameters at presentation were also collected from the electronic medical record, including white blood cell count, platelet count, creatinine, hepatic panel tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin, lactate, high-sensitivity troponin T, D-dimer, ferritin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Given that statins may act by lowering lipid levels, we collected lipid values for patients from inpatient and outpatient records at any dates after January 1 st 2018, and averaged them for each patient over the study period. As some patients did not have all laboratory studies of interest collected as part of clinical care, data are presented for only the patients in whom these were available. Details for missing laboratory values are provided in the Supplemental Table 2.
Study exposure. The exposure in this study was antecedent statin use. Antecedent statin use was de ned as record of statins as a home medication in the electronic medical record.
Study outcomes. The principal outcome was in-hospital mortality within 30 days of admission. The secondary outcome was a composite of in-hospital mortality or invasive mechanical ventilation within 30 days of admission. Other outcomes included in-hospital mortality at any time and invasive mechanical ventilation at any time, as some patients had a length of stay longer than 30 days. We also examined hospital length of stay (days), duration of invasive mechanical ventilation (days), renal replacement therapy with continuous veno-venous hemo ltration, and use of vasopressors.
Statistical analysis. We examined differences in socio-demographic, baseline clinical characteristics, and outpatient medications by antecedent statin use. Summary statistics are presented as numbers and percentages for categorical variables and medians and interquartile ranges for continuous variables. Differences between groups were examined using the 2-sided independent t-test and chi-squared test, as appropriate.
To address confounding by indication, we constructed a multivariable logistic regression model to predict the propensity of antecedent statin administration, adjusted for the following variables: age, sex, rst BMI assessment, race and ethnicity, insurance, New York City borough of residence, history of hypertension, diabetes, coronary artery disease, heart failure, stroke or transient ischemic attack, atrial arrhythmias, chronic lung disease, chronic kidney disease, and liver disease; outpatient use of beta-blockers, ACEi, ARBs, oral anticoagulants, and P2Y 12 receptor inhibitors. Propensity-score matching was implemented with the use of a nearest-neighbor strategy with speci cation of caliper width equal to 0.1 of the standard deviation of the logit of the propensity score. Descriptive analyses were performed for all baseline variables in the propensity-matched cohort.
For the primary and secondary endpoints, we performed logistic regression on the propensity-matched cohort. In addition, to examine whether the effect estimate remained consistent in the overall cohort, we performed logistic regression with multivariable adjustment on the overall cohort. We adjusted the multivariable models for variables that have been previously studied in association with mortality in COVID-19 including baseline socio-demographic and clinical characteristics and outpatient medications. 21,22 Sensitivity Analyses. We performed sensitivity analyses by de ning any recent statin use as either antecedent statin or inpatient statin use. Using this de nition, we evaluated the association of any recent statin use with the primary endpoint using multivariable logistic regression. We also performed subgroup analyses to assess the association of antecedent statin use with primary endpoint in a subset of patients with history of hypertension, coronary artery disease and stroke, conditions for which statins are usually prescribed.
Missing data. BMI and insurance information were missing in 19% and 15% of the patients, respectively, and multiple imputation with predictive mean matching was utilized to adjust the models for BMI and insurance. We imputed one hundred datasets, tted the logistic regression models for the primary and secondary endpoints for each imputed dataset, estimated the hazard ratios on each imputed dataset, and then averaged the one hundred estimated values to obtain the pooled estimates. Model estimates and standard errors were calculated with Rubin's rules 11 . Race and ethnicity were missing in 30% of the patients and were classi ed as 'others/missing' while adjusting in the models. Lipid levels were available for only 32% of the cohort. As such, we have presented them only at baseline. The remaining variables were missing in fewer than 5% of the study cohort.
P-values <0.05 were considered signi cant for the analysis. We did not adjust for multiple comparisons as this was an exploratory analysis. All analyses were performed using version 3.5.1 of the R programming language (R Project for Statistical Computing; R Foundation, mice, MatchIt, cobalt, rms packages). Furthermore, patients using statins were signi cantly more likely to have hypertension (74.0% vs. 43.3%), diabetes (55.8% vs. 26.1%), coronary artery disease (22.5% vs. 6.9%), heart failure (17.0% vs. 6.7%), and chronic kidney disease (22.0% vs. 9.6%) compared with patients not receiving statins (p<0.001 for all). Similarly, patients receiving statins had higher rates of history of stroke/transient ischemic attack (13.9% vs. 5.6%) and atrial arrhythmias (11.0% vs. 5.6%), p<0.001 for both. There were no signi cant differences in liver disease between the two groups.
Patients on statins were signi cantly more likely to be prescribed angiotensin-converting enzyme inhibitors (19.7% vs. 4.2%), angiotensin-receptor blockers (13.1% vs. 3.7%), P2Y12 inhibitors (11.9% s. 1.1%), oral anticoagulants (20.3% vs. 12.3%), and beta-blockers (44.0% vs. 12.7%) as outpatients compared to those not taking statins (p<0.001 for all). Of note, 77.0% of patients who were on antecedent statins and 8.6% of patients who were not on antecedent statins, received statins during hospitalization. Propensity-Matched Cohort Characteristics. Using 1:1 matching, a propensity-matched cohort of 1296 patients (648 patients on statins, 648 patients not on statins) was identi ed. No signi cant differences in demographics, comorbidities, or home medications remained in the propensity-matched cohort ( Table 1). The distribution of the estimated propensity scores for receipt of statins among patients who did and did not receive outpatient statins is shown in Supplemental Figure 1. In the matched analytic sample, the differences between pre-hospitalization variables were attenuated in the propensity-score-matched samples as compared with the unmatched samples (Supplemental Figure 2).
At the time of initial presentation, patients receiving statins were less likely to present with tachypnea (22.1% vs. 28.7%, p<0.01). There were no signi cant differences in presence of fever, tachycardia, peripheral desaturation or hypotension on initial assessment (Table 2).
In the propensity-matched cohort, patients on statins had signi cantly lower white blood cell count at presentation [7.6 (5.5 -10.3) vs. 8 Multivariable Adjustment in Overall Cohort. Statin use was signi cantly associated with a reduction in the primary endpoint (in-hospital mortality within 30 days) in the overall cohort in univariate (OR 0.69, 95% CI 0.56-0.85) and multivariable adjusted analysis (OR 0.49, 95% CI 0.38-0.63) ( Table 4). Other factors associated with increased odds of the primary endpoint included age, male sex, history of atrial arrhythmias, and diabetes ( Figure 1). Outpatient prescriptions of oral anticoagulants and P2Y12 inhibitor were also protective. These results were in agreement with sensitivity analyses performed within the dataset restricted to patients with hypertension, coronary artery disease and stroke/transient ischemic attack, and in the dataset with modi ed de nition of antecedent statin use (Supplemental Figures 3 and  4).
In addition, statin use was associated with reduced hazards of the secondary endpoint in the overall cohort in univariate (OR 0.75, 95% CI 0.63-0.89) and multivariable adjusted analysis (OR 0.54, 95% CI 0.44 -0.67) ( Table 4). Other factors associated with increased odds of secondary endpoint included male sex, age, history of atrial arrhythmias, diabetes, and stroke/TIA (Figure 2).

Discussion
The principal ndings of this detailed analysis regarding antecedent statin use in hospitalized patients with COVID-19 are 1) antecedent statin use was common in our cohort, as 36% of patients admitted to our institution were prescribed statins prior to their index admission; 2) patients receiving statins were older, with a higher burden of cardiovascular comorbidities, 3) patients receiving statins tended to present with lower levels of CRP, and 4) antecedent statin use was associated with signi cantly lower odds of patients experiencing the primary endpoint of in-hospital mortality within 30 days as well as the secondary endpoint of in-hospital mortality or invasive mechanical ventilation requirement within 30 days in a propensity-matched analysis.
In addition to respiratory failure due to pneumonia and ARDS, COVID-19 is known to result in a number of extrapulmonary manifestations 23 . Posited mechanisms explaining the multiorgan dysfunction that can result from severe COVID-19 presentations include but are not limited to direct effects of SARS-CoV-2 infection as well as indirect effects of a dysregulated immune response and hyperin ammatory state 23 . This is supported by clinical and laboratory markers of in ammation, as well as histopathologic and post-mortem data, which demonstrate extensive in ammation and endothelialitis as well as isolation of viral RNA in tissues from several organ systems in patients with COVID-19 [23][24][25][26][27] . Cardiovascular complications, speci cally myocardial injury and thrombotic complications, are common and relate closely to prognosis 13 . Therefore, identifying treatment strategies to prevent serious sequelae of this viral infection may have the potential to improve prognosis. The current analysis suggests that statins merit further evaluation as prophylactic and treatment agents for patients with COVID-19 given their pleiotropic properties and potentially disease-modifying effects in the setting of this viral illness.
There are many potential explanations as to how statins may have contributed to lower 30-day inhospital mortality and invasive mechanical ventilation in our cohort, despite high prevalence of cardiovascular comorbidities in patients with antecedent statin use. Statins, which target HMG-CoA (3hydroxy-3-methylglutaryl coenzyme A) reductase, confer a signi cant mortality bene t in patients with atherosclerotic cardiovascular disease 5,28,29 , who are overrepresented in hospitalized patients with COVID-19. In addition to hyperlipidemia and a number of other cardiovascular risk factors, in ammation has been identi ed as a key modulator of atherogenesis and can contribute considerably to adverse cardiovascular events 5,30,31 . The potential bene ts from statins extend beyond cholesterol-lowering properties, as there is a robust literature supporting the anti-in ammatory properties of statins in the preclinical and clinical arenas, suggesting that these drugs can stabilize and restore endothelial function, and lower rates of circulating in ammatory biomarkers such as CRP 5,32 . Patients receiving statins presented with signi cantly lower CRP levels in this cohort compared with those who were not on statins.
Plaque stabilization 33,34 and anti-thrombotic properties 35 are also favorable characteristics of this class of drugs. It has previously been demonstrated in several series of COVID-19 patients that pre-existing cardiovascular disease is associated with risk for clinical decompensation and severe disease 13,36 . Therefore, it is conceivable that antecedent statin use may confer bene t by preventing myocardial injury and infarction as well as thrombotic events, both of which may have in uenced mortality and endotracheal intubation rates, due to their multitude of effects. Similar mechanism may plausibly explain the association of outpatient use of antiplatelet agents and anticoagulants with lower mortality in patients with COVID-19, although these were not the focus of our study.
Other mechanisms, which may explain the effects of statin use in patients with COVID-19, have also been suggested. Functional membrane microdomains or lipid rafts consist of cholesterol and sphingolipids [9][10][11] , and viruses may gain entry to cells via receptors which are concentrated in these regions of the plasma membrane 12 . Thus, it has been theorized that statin-mediated reduction in cholesterol levels may su ciently alter the makeup of these lipid rafts 12 , potentially preventing or reducing likelihood for viral infection or replication, and hence disease severity. Though lipid levels were not available for our entire cohort, we did nd lower levels of total cholesterol and low-density lipoprotein in patients receiving statins. Additionally, a recent computational docking analysis was performed to assess the interaction between an important SARS-CoV-2 protease (Mpro) 37 and statins 38 . Interestingly, these authors found that several statins demonstrated stronger interactions with Mpro than some protease inhibitors, implicating a potential mechanism by which statins may be able to interfere with SARS-CoV-2 replication. Preclinical evidence suggests that statin use (as with ACEi and ARBs) can contribute to increased ACE2 expression and epigenetic modi cation 39 . As ACE2 serves as the entry point for SARS-CoV-2 to human hosts, it remains to be completely understood how the modulation and modi cation of ACE2 levels may impact viral replication and infectivity.
In addition to the mechanisms above, studies prior to the current COVID-19 era evaluated the use of statins to prevent progression of ARDS and limit severity of illness 5,15,19,40,41 , and evidence in this space is incomplete. While the primary results of the randomized SAILS (Statin for Acutely Injured Lungs From Sepsis) and HARP-2 trials did not demonstrate any bene t to statin use in ARDS 19,20 , a secondary analysis of HARP-2 suggested improved survival with statin use in a hyperin ammatory phenotype 15 .
Subphenotype analysis of SAILS did not replicate these results 42 . In light of these dissimilar ndings, it is important to note that these trials administered different drugs and were characterized by different inclusion criteria 43 . Whether speci c statins confer greater bene t due to higher bioavailability in lung tissue or more profound pleiotropic effects remains to be completely understood. However, the bene t noted from statins in our cohort may share mechanisms with some of the prior positive statin studies in the ARDS literature.
The limited evidence available regarding statins in the COVID-19 literature con rms the ndings presented in the present manuscript. In a separate study which evaluated the prevalence and impact of myocardial injury in 2,736 hospitalized patients to the Mount Sinai Hospital System in New York City, 36% of this cohort was receiving statins prior to admission 44 . In their multivariable model, while not the focus of their analysis, statin use was associated with signi cantly lower rates of in-hospital mortality (OR 0.57, 95% CI 0.47-0.69) 44 . Additionally, a separate study of 154 elderly individuals (mean age 86 years) suggested that statin use prior to admission was associated with less severe symptoms, but they did not assess in-hospital mortality 45 . Most recently, an analysis from the Wuhan, China demonstrated signi cantly lower 28-day mortality in patients who received inpatient statins compared with non-statin users (adjusted hazard ratio 0.58 [0.43-0.80) 46 . In this study, however, less than 10% of hospitalized patients received statins, and may not be representative of Western populations with higher burden of cardiovascular comorbidities. Moreover, their focus on in-hospital statin use in an observational setting may be subject to immortal time bias. With these studies as well as the ndings of the present analysis in mind, the results of ongoing randomized clinical trials and registries will be crucial, as they may provide important prospective data regarding the potential bene ts of statin therapy in COVID-19 (Clinicaltrials.gov Identi ers: NCT04407273, NCT04390074, NCT04348695, NCT04426084, NCT04333407, and NCT04380402).
Limitations. Our study has important limitations. As a retrospective analysis of electronic medical record data, there remains the potential for unmeasured confounders. However, we performed propensity matched analysis and multivariable adjustment with logistic regression to control for a number of demographic and clinical characteristics to minimize the likelihood for confounding. Additionally, we also performed a number of sensitivity analyses, including assessing outcomes in patients who received either outpatient or inpatient statins, and analyses restricted to cohort with cardiovascular disease, and ndings remained consistent. Additionally, medication reporting and reconciliation in the electronic medical record, especially in the setting of the ongoing pandemic, may have been subject to errors on the part of individual clinicians. Moreover, given this mechanism of assessing antecedent statin use, it was not possible to verify patient adherence with statin therapy despite evidence of prescription in the electronic medical record. However, patients in the antecedent statin group had better lipid pro les, suggestive of medication effect. Additionally, errors with data entry are unlikely to affect the primary endpoint, inpatient mortality. To increase the capacity for critical care interventions, multiple temporary intensive care units (ICU) were created in previously non-ICU patient care areas at our institution. Thus, assessment for need for ICU level-of-care or outcomes in ICU patients was not possible. We did, however, assess need for invasive mechanical ventilation as part of the key secondary endpoint, a therapy which was almost exclusively used in ICU settings. Further, patients who are receiving statins may re ect overall better outpatient care, and possibly a low-risk cohort. However, patients on statins were much older, and had a more severe burden of comorbidities in our study. Moreover, we examined proxy variables for socioeconomic status, including NYC borough of residence and medical insurance, and these were not signi cantly different between the two groups. Lastly, a small proportion of patients (2.5%) included in this analysis remained hospitalized at the end of study period, and so reporting on in-hospital outcomes in such patients remains incomplete at this time.

Conclusions
In this large analysis from a quaternary academic medical institution in an epicenter of the COVID-19 pandemic, we demonstrated that antecedent statin use was associated with signi cantly lower rates of in-hospital mortality within 30 days. These results indicate the important need for randomized controlled trials evaluating the bene ts of statin therapy in patients affected by COVID-19. Deidenti ed data will be made available upon request to the corresponding authors.

Code availability
The analysis code utilized for this study will me made available upon request to the corresponding authors.

Disclosures
Dr. Gupta received payment from the Arnold & Porter Law Firm for work related to the Sano clopidogrel litigation and from the Ben C. Martin Law Firm for work related to an inferior vena cava lter litigation; received consulting fees from Edward Lifesciences; and holds equity in the healthcare telecardiology startup Heartbeat Health. Dr. Madhavan has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to a speci c type of IVC lter. Dr. Cummings reports being a co-investigator for clinical trials evaluating the e cacy and safety of Remdesivir (Gilead Sciences) and convalescent plasma (Amazon) in hospitalized patients with COVID-19. Support for this work, which is unrelated to the current study, is paid to Columbia University. Dr. Brodie receives research support from ALung Technologies, he was previously on their medical advisory board. He has been on the medical advisory boards for Baxter, BREETHE, Xenios and Hemovent. Dr. Stone reports speaker or other honoraria from Cook, Terumo, QOOL  Data presented as N (%) or median (IQR). ALT = alanine transaminase, AST = aspartate transaminase, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, F = Fahrenheit, HR = heart rate, IQR = interquartile range, IL-6 = interleukin 6, SBP = systolic blood pressure.

Supplementary Files
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