The association between statin and COVID-19 adverse outcomes: national COVID-19 cohort in South Korea

Introduction

On March 11, 2020, the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) outbreak a global pandemic (1,2). Over a year later, there has now been more than 250 million cases, and more than 5 million deaths worldwide (3).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 disease, and its pathophysiology involves an overproduction of an early response proinflammatory cytokines, specifically tumor necrosis factor (TNF), interleukin (IL)-6 and IL-1β (4). If unabated, this cytokine storm subsequently places COVID-19 patients at increased risk of vascular hyperpermeability, multiorgan failure, and death (5).

As a result, statins have been suggested for use as a therapy for COVID-19. It is reported that statin agents can stabilize MYD88 at normal levels and reduce an ensuing cytokine storm (6). Statins may also up-regulate angiotensin-converting enzyme 2 (ACE2), which is typically downregulated by SARS-CoV-2, and thus potentially facilitate the infiltration of SARS-CoV-2 (7).

There currently exist limited and conflicting clinical data on the use of statins amongst COVID-19 patients. While many studies (8-15) reported that statin medications reduced the risk of disease severity and/or mortality, several other studies (16-20) reported no significant difference between statin users and non-users. As well, one study (21) reported an increased mortality among statin users. Meanwhile, a recent systematic review and meta-analysis of 110,078 patients reported a reduced risk of mortality among those administered statins after their COVID-19 hospitalization, but no difference in patients who were administered statins before hospitalization (22). Although there is a lack of consensus among data on efficacy and safety of statins amongst COVID-19 patients, the current recommendation is for COVID-19 patients to continue any antecedent statin use (23).

Given the limited and conflicting data, there is a need for further and more rigorous investigation into the relationship between statin use and COVID-19 outcomes. The aim of this analysis was to compare hospitalized patients with COVID-19 who did and did not receive statins before hospitalization, in terms of COVID-19 outcomes. Our hypothesis was that antecedent statin use is associated with decreased incidence of all-cause death, intensive care unit (ICU) admission, mechanical ventilation use and cardiovascular outcomes [myocardial infarction (MI), transient cerebral ischemic attacks (TIA) or ischemic stroke]. We present the following article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-21-3464/rc).

Methods

Data source and study population

We used the database from project #OpenData4Covid19, an international collaborative research project hosted by the Ministry of Health and Welfare (MoHW) of South Korea and the Health Insurance Review and Assessment Service (HIRA). The HIRA is a nationwide governmental agency providing a review of health insurance claims and a fee-for-service reimbursement (24), covering 98% of the Korean population (approximately 50 million people). The database consists of history of claims for 234,427 consecutive individuals for SARS-CoV-2 infection from January 1^st to May 15^th, 2020 in South Korea. Specifically, information gathered in the dataset includes sociodemographic characteristics, healthcare utilization history, diagnosis results [International Classification of Diseases, 10^th Revision (25); ICD-10] and prescription from both inpatient and outpatient settings.

Between January 1^st and May 15^th, 2020, 7,590 individuals tested positive for COVID-19. A positive COVID-19 result was defined as a positive result from a diagnostic test that used a reverse-transcription polymerase chain reaction method approved by the South Korean Ministry of Food and Drug Safety per WHO recommendation (26). Individuals were excluded if they were younger than 40 years old, since younger patients are less likely to experience severe adverse outcomes after COVID-19 infection regardless of statin use and therefore inclusion of younger patients may undermine the effects of statins. As well, statin use is less common in these younger patients and its use might be associated with higher risk features that are less generalizable to the general public. We also excluded individuals who were not hospitalized for precise outcome assessment. As a result, 4,349 individuals were included in the sample cohort (Figure 1). Cohort entry was defined as the date of admission for COVID-19 hospitalization. Most of these patients were hospitalized until fully recovery. A full recovery was defined as cessation of fever without medication use, and two consecutive negative test results within a 24-hour period (27).

Figure 1 Population-based cohort study design using the HIRA and KDCA database of South Korea. HIRA, Health Insurance Review and Assessment Service; COVID-19, coronavirus disease 2019; CDC, Centers for Disease Control and Prevention; KDCA, Korean Disease Control and Prevention Agency.

This study was approved by the Human Investigation Review Board of Public Institutional Bioethics Committee designated by the South Korean MoHW, which waived the requirement of informed consent due to retrospective study design and anonymity of the HIRA database (IRB # P01-2020-1262-001). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Endpoints

We set the primary endpoint as a composite of all-cause death, ICU admission, mechanical ventilation use and cardiovascular outcomes (MI, TIA or ischemic stroke). As secondary endpoints, we measured the components of the composite endpoint individually. All endpoints were defined using in-hospital ICD-10 diagnostic codes and the national procedure coding system (Table S1). We measured study endpoints between the date of cohort entry and the earliest of the date of hospital discharge or end of study period (May 15, 2020), whichever occurred earlier.

Exposures

We defined exposure by using inpatient and outpatient prescription records of statin medications from the HIRA database. Patients prescribed statins within 240 days prior to cohort entry were regarded as statin users, and otherwise patients were defined as non-users. The prescription of statin was defined by Anatomical Therapeutic Chemical (ATC) codes (Table S1). Our definition follows an intention-to-treat approach.

Statistical analysis

For descriptive statistics, we presented mean and standard deviation for continuous variables and frequency and percentage for categorical variables. We compared baseline characteristics for statin users and non-users with absolute standardized difference (aSD). aSD ≤0.1 was preferred for indicating balance while aSD ≤0.2 was deemed acceptable.

For outcome analysis, we estimated odds ratio (OR) from a logistic regression analysis incorporated with the inverse probability of treatment weighting (IPTW). First, we estimated the propensity score (PS) of prescribing statin from a logistic regression, where the predictors include age in years, square of age, sex, and health insurance type at cohort entry, 20 pre-exposure comorbidities and 12 pre-exposure co-medications (Appendix 1). We defined comorbidity variables from in-hospital ICD-10 diagnostic codes and co-medications from in/out-hospital ATC codes (Table S1). We assigned the inverse probability of treatment (IPT) weight to each individual in the cohort, 1/PS to the statin users, and 1/(1−PS) to the non-users, to construct a balanced pseudo-population. Then, weighted univariable logistic regressions were fitted to estimate the effect of statin use on primary and secondary endpoints. We reported the estimated OR and its 95% confidence interval (CI). For comparison, we also considered unweighted logistic regression: both univariable and multivariable, adjusted for age, sex, insurance type, history of diabetes mellitus and history of hypertension.

To study the association effect per subgroups, we conducted outcome analysis stratified the cohort by (I) age (<65 and ≥65 years) and (II) sex for the risk of the primary endpoint. We also considered stratification by the history of (III) hyperlipidemia, (IV) hypertension, and (V) diabetes mellitus. To examine the effect modification, P value for interaction from each stratification was assessed (P for interaction).

We performed several sensitivity analyses. We re-estimated the OR with modified data where all confirmed positive individuals of at least 40 years of age were included into the study population regardless of their hospitalization record. The time window for ascertaining exposure extended from 240 to 360 days to include statin users who get statin prescription annually. In addition, we considered alternative choices of statistical methods: (I) conducting the main IPTW analysis with discarding individuals with extreme PS values (IPTW with trimming); (II) including the estimated PSs as an additional predictor to other covariates (outcome adjustment model); (III) the stabilized mortality ratio weighting (SMRW) instead of IPTW; and (IV) PS matching instead of IPTW.

Results

A total of 4,349 adults of at least 40 years of age were hospitalized with COVID-19 in South Korea between January 1, 2020 and May 15, 2020 and included this analysis. Of these, 1,115 (26%) were statin users. Statin users were older than non-users on average (65.9±11.2 vs. 58.3±12.3 years). Among statin users, 39.6% were males, whereas 36.1% of non-users were male. A larger proportion of statin users had comorbidities of coronary artery disease (16.8% vs. 3.6%), chronic lung disease (50.6% vs. 24.6%), diabetes mellitus (40.3% vs. 10.7%), hyperlipidemia (65.4% vs. 18.1%), and hypertension (53.5% vs. 17.7%), relative to non-users. Statin users also used more antidiabetic (35.6% vs. 6.4%) and antiplatelet (37.7% vs. 7.9%) medications (Table 1). All variables after the adjustment achieved aSD ≤0.1 except for anxiolytics (aSD =0.12).

Among 530 primary composite events of all-cause death, ICU admission, mechanical ventilation use and cardiovascular adverse outcomes, 362 occurred in non-users (11.2%; 362/3,234) and 168 (15.1%; 168/1,115) in statin users. No significant difference was noted between statin users and non-users in the IPTW weighted analysis (IPTW adjusted OR 0.82; 95% CI: 0.60–1.11). Similarly, there was no difference between statin users and non-users for the individual components of all-cause death, mechanical ventilation, ICU admission, and cardiovascular adverse outcome (Table 2).

In the subgroup analyses, there existed a significant effect modification by hypertension status (P for interaction =0.0087). Statin users who had hypertension experienced lower odds for the composite (IPTW OR 0.40, 95% CI: 0.23–0.69). There was no effect modification by age, sex, hyperlipidemia and diabetes mellitus (Table 3).

The results from the sensitivity analyses remained generally consistent with the main analysis with no harmful effects of statin use on the endpoints. When redefining the study population, changing the exposure ascertainment window and applying other statistical methods, the primary endpoint, all-cause death, ICU admission and cardiovascular outcomes, showed generally similar results. For example, statins showed protective effects on the primary endpoint (SMRW adjusted OR 0.64, 95% CI: 0.45–0.93; PS matching OR 0.74, 95% CI: 0.56–0.98). The protective effects of statins persisted for primary endpoint, when including all confirmed patients with COVID-19 (SMRW adjusted OR 0.58, 95% CI: 0.40–0.88; PS matching OR 0.76, 95% CI: 0.57–0.99). For all-cause deaths, statins showed protective effects (SMRW adjusted OR 0.56, 95% CI: 0.35–0.89; PS matching OR 0.67, 95% CI: 0.45–0.98). The protective effects of statins persisted for all-cause deaths, when including all confirmed patients with COVID-19 (SMRW adjusted OR 0.49, 95% CI: 0.29–0.84). For ICU admission, statin showed protective effects when redefining exposure window to 360 days (IPTW-trimming adjusted OR 0.67, 95% CI: 0.47–0.97) (Tables S2,S3).

Discussion

This study reported on one of the largest investigations of COVID-19 patients with hospitalization in South Korea. It utilized a nationwide and completely enumerated dataset and applied a PS-based weighting to control for potential confounding variables. In the main analysis, there was no significant difference between baseline (pre-hospitalization) statin users and non-users with respect to the composite endpoint of mortality, ICU admission, mechanical ventilation use and cardiovascular outcomes.

Although results of our main analysis showed statistically insignificant association between statin and primary endpoint, it is possible that we missed detecting a real protective association of statin in the main analysis, especially since some of sensitivity analysis showed protective association of statin for primary endpoint, all cause death and ICU admission based on varying statistical methods such as SMR weighting and PS matching, changing the exposure window change to 360 days, and inclusion of non-hospitalized COVID-19 patients. These results are in contrast to the findings from the two recently published randomized controlled trials (28,29). In the Effectiveness and Safety of Medical Treatment for SARS-CoV-2 (COVID-19) in Colombia: A Pragmatic Randomized Controlled Trial (29), the combined use of rosuvastatin 40 mg once daily with colchicine and emtricitabine/tenofovir reduced the risk of 28-day mortality and the need for invasive mechanical ventilation in hospitalized patients with pulmonary compromise from COVID-19. In the Intermediate vs. Standard-Dose Prophylactic Anticoagulation in Critically-ill Patients With COVID-19: An Open Label Randomised Controlled Trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) (28) of patients admitted to ICU, a subgroup of patients who presented within 7 days of symptom onset showed lower odds of the primary efficacy outcome (venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality) when they had received atorvastatin 20 mg once daily, compared with patients who got placebo. Both studies report a potentially beneficial effect of antecedent statin use, and suggests that statin use may have a protective effect in the early inflammatory phase.

In our prespecified subgroup analysis, statin use showed lower odds of the primary endpoint in hypertensive patients. As hypertensive COVID-19 patients are known to have poorer prognosis than normotensive patients (30), this result is encouraging; statins may have greater protective effects among patients with hypertension. Daniels et al. (31) reported similar findings of a protective association for severe COVID-19 outcomes among statin users, in patients with hypertension and/or cardiovascular disease. These pronounced protective association of statin among hypertensive patients could be from statin’s effect on treating underlying cardiovascular disease, as Daniels et al. Proposed. However, Lohia et al. (12) reported no protective association between statin and severe COVID-19 outcome among hypertensive patients, but did report a protective association among patients with diabetes mellitus. No similar finding was found in our cohort, but this may be due to our cohort’s much lower event rate (7.7% mortality rate among statin user), which could have decreased the power to detect the effect of statin in our cohort’s subgroups. Furthermore, our cohort’s ethnic composition may play a role here—the majority of individuals in our cohort were Korean, compared to the majority being Black in Lohia et al.’s study (12). Of final note, our cohort had a much lower event rate that other hospitalization cohorts, as most of the COVID-19 patients in Korea were hospitalized according to a national policy to contain infection, regardless of patient’s symptoms. Among all confirmed COVID-19 patients ≥40 years of age (n=4,610), 94.3% were hospitalized (n=4,349) regardless of symptom presence in our population.

Further investigation is needed since statins may be cost-effective with the potential benefit outweighing any potential toxicities (32). Mechanistically, statins are postulated to upregulate ACE2, countering the effect of SARS-CoV-2, where ACE2 is downregulated and thereby facilitates the infiltration of SARS-CoV-2 (7). Although statins can cause rare muscle and liver side effects, discontinuation of statins treatment is a known way to reverse these side effects, alleviating concerns of significant and irreversible adverse effects. As of January 19, 2022, 12 randomized clinical trials to assess the effect of statins in COVID-19 patients were registered on the clinicaltrials.gov website (NCT02735707, NCT04952350, NCT04904536, NCT04900155, NCT04801940, NCT04631536, NCT04472611, NCT04466241, NCT04380402, NCT04348695, NCT04333407, NCT02344290) which may help elucidating true effect of statin among COVID-19 patients.

This study has several strengths. First, we used a nationwide cohort of all hospitalized patients with COVID-19 in South Korea between January 1^st and May 15^th, 2020. Since South Korea maintained a strict patient management system during this period with mandatory admission requirement for the majority the confirmed COVID-19 patient, the use of this population-based cohort mitigated any potential sampling bias issue. In addition, our study design further mitigated healthy user bias by including chronic co-medications as confounders, which may have adjusted for past adherence (33). Furthermore, our main findings of no harmful effects of statin on COVID-19 outcomes were reaffirmed by our sensitivity analyses. In fact, they showed protective effects when we redefined the study population, extended the ascertainment period of the statin use, and considered various statistical approaches. Given these neutral to protective effects of statin on COVID-19 outcomes, our findings endorse the current guideline to continue statin in COVID-19 patients who have previously been treated with statins (23).

There are also several limitations of this study. First, there may have been outcome misclassification in cardiovascular outcomes (MI, stroke, and TIA), because we defined our cardiovascular outcome variables by diagnostic codes in admirative claim data. The HIRA reported that 82% of primary diagnosis codes in claims coincide with electronic medical records (34), so more than 18% of outcome misclassification can occur while trying to capture all the diagnostic codes other than primary diagnosis codes. However, we expect a greater validity for MI, stroke, and TIA since our study population focused on hospitalized patients under careful management. Other outcomes such as all-cause death seem to be well classified because the HIRA COVID-19 database was linked to the national death records and outcomes defined from procedure codes (ICU admission and mechanical ventilation use) are also expected to be valid since the codes are mandatory in the reimbursement review process. Second, statin exposure was defined based on inpatient and outpatient prescriptions. We were not aware of detailed information on the exposure, for example, adherence to the prescription. Lastly, although we performed IPTW and thorough sensitivity analyses, there might still be a residual confounding by potential unmeasured confounders typically used in clinical studies (e.g., body weight, body mass index, baseline blood pressures, laboratory test values) due to the inherent limitation of claims data.

In conclusion, our analysis of a nationwide sample of South Korean, hospitalized COVID-19 patients found that statin users overall did not experience poorer COVID-19 outcomes relative to non-users. However, in hypertensive patients, protective effects of statin use on COVID-19 outcomes were shown, which warrants further investigation.

Acknowledgments

The authors thank healthcare professionals dedicated to treating COVID-19 patients in South Korea, the Ministry of Health and Welfare, the Health Insurance Review & Assessment Service (HIRA) and Ye-Jin Sohn (HIRA) for sharing invaluable national health insurance claims data.

Funding: YGC’s work was supported, in part, by 2020R1G1A1A01006229 awarded by the National Research Foundation of Korea.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-21-3464/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-21-3464/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-21-3464/coif). CBS serves as an unpaid Editor-In-Chief of Annals of Palliative Medicine. YGC’s work was supported, in part, by 2020R1G1A1A01006229 awarded by the National Research Foundation of Korea. The other authors have no conflicts of interest to declare.

Ethical Statement:The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Human Investigation Review Board of Public Institutional Bioethics Committee designated by the South Korean Ministry of Health and Welfare, which waived the requirement of informed consent due to retrospective study design and anonymity of the HIRA database (IRB # P01-2020-1262-001). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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