key: cord-1051730-gjtcx3vq
authors: Lee, Hae-Young; Ahn, Juhee; Park, Juhong; Kyung Kang, Chang; Won, Sung-Ho; Wook Kim, Dong; Park, Jong-Heon; Chung, Ki-Hyun; Joh, Joon-Sung; Bang, Ji Hwan; Hee Kang, Cheong; Bum Pyun, Wook; Oh, Myoung-don
title: Beneficial Effect of Statins in COVID-19–Related Outcomes—Brief Report: A National Population-Based Cohort Study
date: 2021-02-04
journal: Arterioscler Thromb Vasc Biol
DOI: 10.1161/atvbaha.120.315551
sha: 71f8182df5ff8c117d34d264c0beafee7dc42ce1
doc_id: 1051730
cord_uid: gjtcx3vq

OBJECTIVE: Although statins are widely prescribed lipid-lowering drugs, there are concerns about the safety of their use in the context of coronavirus disease 2019 (COVID-19), since statins increase the expression of ACE2 (angiotensin-converting enzyme 2). This study aimed to disclose the association between statins and 60-day COVID-19 mortality. APPROACH AND RESULTS: All patients hospitalized with laboratory-confirmed COVID-19 were enrolled in this study from January 19 to April 16, 2020, in Korea. We evaluated the association between the use of statins and COVID-19–related mortality in the overall and the nested 1:2 propensity score–matched study. Furthermore, a comparison of the hazard ratio for death was performed between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. The median age of the 10 448 COVID-19 patients was 45 years. Statins were prescribed in 533 (5.1%) patients. After adjusting for age, sex, and comorbidities, Cox regression showed a significant decrease in hazard ratio associated with the use of statins (hazard ratio, 0.637 [95% CI, 0.425–0.953]; P=0.0283). Moreover, on comparing the hazard ratio between COVID-19 patients and the retrospective cohort of hospitalized pneumonia patients, the use of statins showed similar benefits. CONCLUSIONS: The use of statins correlates significantly with lower mortality in patients with COVID-19, consistent with the findings in patients with pneumonia.

C oronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, Hubei, China, in December 2019 and since then became a pandemic, as declared by the World Health Organization on March 11, 2020. 1 As of October 20, >40 118 333 confirmed cases and 1 114 749 deaths have been reported worldwide. 2 Although the fatality rate associated with SARS-CoV-2 is lower than that in the context of SARS-CoV or Middle East respiratory syndromerelated coronavirus, the elderly and people experiencing chronic conditions are prone to serious outcomes. 1 The most common comorbidities among COVID-19 patients include hypertension, diabetes, and coronary artery disease 1 ; therefore, frequently, such patients are treated with HMG-CoA (hydroxy-methyl-glutaryl-coenzyme A) reductase inhibitors, known as statins. Of note, statin treatment was reported to increase the expression of ACE2 (angiotensin-converting enzyme 2) in the heart of experimental models via epigenetic histone modifications. 3 Given that SARS-CoV-2 enters the target cell via ACE2 cell surface receptors, 4 

expression of ACE2 was shown to facilitate infection with SARS-CoV 5 ; therefore, statins might increase the risk of COVID-19. In contrast, besides their lipid-lowering activity, statins are well known for pleiotropic effects on inflammation, contributing to their beneficial impact in patients with conditions other than cardiovascular diseases, including autoimmune diseases, 6 community-acquired pneumonia, and sepsis. 7, 8 The immunomodulatory effect of statins depends on the inhibition of the production of isoprenoids and the consequent downregulation of redox-sensitive proinflammatory transcription factors such as NF-κB (nuclear factor-κB). 6 Moreover, statins were suggested to potentially inhibit the SARS-CoV-2 main protease-a key coronavirus enzyme-thus exerting antiviral activity. 9 Of note, previously, statins were effective in targeting the host response and preventing endothelial barrier damage in patients infected with the Ebola virus during the recent Ebola outbreak in West Africa. 10 Therefore, some hospitals included stains in the COVID-19 treatment protocol. 11 Korea has registered all SARS-CoV-2-infected patients and managed them either in hospitals or in community treatment centers; therefore, follow-up information is available for all patients. 12 Therefore, Korea offers the ideal scenario to comprehensively evaluate the association between the use of statins and the severity of COVID-19. Therefore, in the present study, we investigated the association between the use of statins and COVID-19-related deaths in all COVID-19 patients in Korea. Moreover, the hazard ratio (HR) was compared between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea.

We report a population-based cohort study supported by the Korea Disease Control and Prevention Agency, the National Health Insurance Service, and the Korean Society of Hypertension. The study was approved by the Institutional Review Board of Seoul National University Hospital (No. 2003 (No. -102-1109 . Informed consent was waived by the institutional review board. All authors reviewed the manuscript for the accuracy and completeness of the data.

Data related to all of the 10 448 patients, with laboratoryconfirmed infection with SARS-CoV-2 since the first case on January 19 up to April 16, 2020, in Korea, were retrieved from the compiled information available at the National Health Insurance Service. A case designated confirmed for COVID-19 was defined as one whose nasal and pharyngeal swab specimens tested positive in the context of high-throughput sequencing or real-time reverse transcriptase polymerase chain reaction assays. 13, 14 Diagnoses, prescription records, and information related to medical utilization were extracted from the national health information database-a public database compiled by the National Health Insurance Service. 15 Furthermore, for the National Health Insurance Service claim data analysis, operational definitions using the ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) codes were applied ( Table I in the Data Supplement) .

The association between the use of statins and the severity of pneumonia in hospitalized Korean patients between January and June 2019 was investigated using the information retrieved from the national health information database. 15 Of note, the national health information database holds information related to health care utilization, health screening, sociodemographic variables, and mortality of the entire Korean population; overall, the information available refers to data gathered during the process of claiming health care services. It includes information related to the records of inpatient and outpatient usage (diagnosis, length of stay, treatment costs, and services received) and prescription records (drug code, days prescribed, and daily dosage). Importantly, in our analysis, all potential identifiers in the national health information database data were removed, and the information was linked with new unidentifiable codes representing individual patients.

In the present study, the association between the use of statins and COVID-19-related mortality within 60 days was investigated. All commercially available statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) in Korea were included in the analysis. Dichotomous variables were created to identify the use of statins defined as a filled prescription with >60% of the proportion of days covered during 3 months before the diagnosis of COVID-19. 16 

The association of the clinical characteristics with mortality within 60 days was tested using bivariate statistics. (Table 2) . Even in the context of multivariate regression analysis, old age (>65 years) was by far the most important predictor of COVID-19-related mortality in patients. After adjusting for age, sex, and the history of comorbidities (hypertension, diabetes, cancer, COPD, stroke, coronary artery disease, heart failure, and chronic renal disease) before the diagnosis of COVID-19, Cox regression showed a significant decrease in HR associated with the use of statins (HR, 0.637 [95% CI, 0.425-0.953]; P=0.0283; Figure 1A ). Next, the association of statins was stratified by age, sex, and comorbidities. A decreased risk of death with statin use was consistent across all subgroups ( Figure 2 ). After PSM, Cox regression showed a more significant decrease in HR by 45% associated with the use of statins (HR, 0.553 [95% CI, 0.360-0.852]; P=0.0071; Table III in the  Data Supplement) .

Then, the HR of COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 was compared. Importantly, in 2019, there was no viral pneumonia epidemic in Korea, for example, due to severe acute respiratory syndrome or Middle East respiratory syndrome infection. Therefore, the 2019 pneumonia cohort was composed of bacterial and viral pneumonia patients combined. This retrospective cohort included 179 265 patients with a mean age of 39 years, of whom 49.4% were women. The most common comorbidity in the cohort was hypertension (33.3%), followed by COPD (25.1%), diabetes (23.4%), and any cancer (6.9%; Table IV in the Data Supplement). The mortality rate at 60 days was 7.4% and sharply increased among elderly patients (≥60 years); of note, it was even higher than that in the context of COVID-19 ( Figure 1B) . Moreover, after considering secondary factors, the results of the present study indicated a significantly lower risk of 60-day mortality in the context of the use of statins ( 

In the present study, we showed that statins are not associated with COVID-19-related fatal outcomes. In fact, the use of statins correlated with significantly lower mortality in COVID-19 patients (by 36%).

Higher event rates in elderly patients with comorbidities are a common finding reported previously. 17 Of note, in this study, patients with comorbidities were much older than those without comorbidities. For example, the mean age of hypertensive patients was >20 years older than that of nonhypertensive patients. In fact, after adjusting 

for secondary factors such as age and sex, our results revealed that the association between comorbidities and mortality was much reduced. However, still, patients with hypertension, diabetes, chronic kidney disease, or heart failure showed higher mortality compared with those without comorbidities. The most important finding of our study was that prior use of statins was significantly associated with lower mortality in COVID-19 patients. There are a few recently published studies investigating the effect of the use of statins on COVID-19, 18, 19 showing results consistent with those in our study. Moreover, this finding was consistent with previous meta-analyses in pneumonia patients 16, 20 and also with pneumonia patients in Korea, in 2019, evaluated in this study. Lastly, this protective effect was supported by the potential inhibitory effect in the context of the SARS-CoV-2 main protease-a key coronavirus enzyme. 9 In spite of the controversy regarding the role ACE2, the detailed effect of statins has not been comprehensively evaluated. 21, 22 As a result, the prescription of statins was reportedly reduced during the COVID-19 pandemic in the United States. 23 The concern is that the use of statins in COVID-19 patients may be further reduced due to possible drug interaction with antiviral/ antibacterial agents and lower cholesterol levels in the acute stress condition. 24, 25 However, our findings suggested that statins need not be discontinued during the COVID-19 treatment. 

The current study has several limitations. First, data related to drug exposure were measured based on the claims data. Hence, detailed information about drug exposure, such as adherence to the medication or discontinuation during COVID-19 hospitalization, remains unknown. Second, the follow-up duration of the study was limited to a short period of time. However, most outcomes (86%) occurred within 2 weeks of the COVID-19 treatment. Third, although we evaluated a total of 10 448 COVID-19 patients who were hospitalized in Korea from January 19, 2020, through April 15, 2020, the interpretation of our findings is influenced by the limited sample size. To overcome this limitation, we compared the results with those obtained with a retrospective cohort of >170 000 pneumonia patients hospitalized from January to June 2019. The results indicated similar trends in COVID-19 and pneumonia cases. Lastly, although we performed PSM and multivariate analyses, there might be still a healthy user bias, for example, due to the healthy adherer effect or selective prescribing, 26 potentially influencing the association between the use of statins and lower mortality in COVID-19 patients. The healthy adherer effect might affect the observational study result, which reported that patients who showed complete compliance to antihypertensive medication regardless of either calcium channel blockers or angiotensin II receptor blockers had a lower risk of COVID-19. 27 Therefore, we cannot exclude the possibility that the healthy adherer effect confounded the report's finding.

Statins were associated with significantly lower mortality of COVID-19, consistent with usual pneumonia patients. Overall, the findings of this article suggest that statins might be considered as a part of the supportive regimen during the treatment of COVID-19. The prospective randomized studies might be warranted to confirm the benefit of statins in COVID-19.

Received August 30, 2020; accepted January 12, 2021. 

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in china: Summary of a report of 72314 cases from the chinese center for disease control and prevention

World Health Organization. Coronavirus disease (COVID-2019) situation reports

Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications

Mental health care for medical staff in china during the COVID-19 outbreak

The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines

Immune modulatory effects of statins

Treating influenza with statins and other immunomodulatory agents

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults -A systematic review and meta-analysis

Statins and the COVID-19 main CLINICAL AND POPULATION STUDIES -AL protease: in silico evidence on direct interaction

Hiding in plain sight: an approach to treating patients with severe COVID-19 infection

Massachusetts general hospital (mgh) COVID-19 treatment guidance

Out-of-hospital cohort treatment of coronavirus disease 2019 patients with mild symptoms in Korea: an experience from a single community treatment center

Virus isolation from the first patient with SARS-CoV-2 in Korea

Detection of 2019 novel coronavirus (2019-ncov) by real-time RT-PCR

Data resource profile: the National health information database of the National Health Insurance Service in South Korea

The association of cardioprotective medications with pneumonia-related outcomes

China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China

Meta-analysis of effect of statins in patients with COVID-19

Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study

Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia

Cardiovascular disease, drug therapy, and mortality in COVID-19

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis

Prescription fill patterns for commonly used drugs during the COVID-19 pandemic in the United States

Review of emerging pharmacotherapy for the treatment of coronavirus disease 2019

Decreased serum level of lipoprotein cholesterol is a poor prognostic factor for patients with severe community-acquired pneumonia that required intensive care unit admission

Healthy user and related biases in observational studies of preventive interventions: a primer for physicians

Compliance of antihypertensive medication and risk of coronavirus disease 2019: a cohort study using big data from the korean national health insurance service

Oh contributed to data collection and interpretation. All authors critically revised the manuscript for relevant intellectual content and gave final approval for the version to be published. All authors agree to be accountable for all aspects of the work and will answer any questions related to the accuracy or integrity of the work. We declare no competing interests. We acknowledge all health care workers involved in the diagnosis and treatment of patients in Korea. We thank all the hospital staff members for their effort in collecting the information used in this study: Hongsang Oh, Junghan Kim 

None.