# Improved COVID-19 Outcomes following Statin Therapy: An Updated Systematic Review and Meta-analysis

Authors: Amir Vahedian-Azimi; Seyede Momeneh Mohammadi; Maciej Banach; Farshad Heidari Beni; Paul C. Guest; Khalid Al-Rasadi; Tannaz Jamialahmadi; Amirhossein Sahebkar
Journal: BioMed Research International
 (2021)

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## Abstract

Background. Although vaccine rollout for COVID-19 has been effective in some countries, there is still an urgent need to reduce disease transmission and severity. We recently carried out a meta-analysis and found that pre- and in-hospital use of statins may improve COVID-19 mortality outcomes. Here, we provide an updated meta-analysis in an attempt to validate these results and increase the statistical power of these potentially important findings. Methods. The meta-analysis investigated the effect of observational and randomized clinical studies on intensive care unit (ICU) admission, tracheal intubation, and death outcomes in COVID-19 cases involving statin treatment, by searching the scientific literature up to April 23, 2021. Statistical analysis and random effect modeling were performed to assess the combined effects of the updated and previous findings on the outcome measures. Findings. The updated literature search led to the identification of 23 additional studies on statin use in COVID-19 patients. Analysis of the combined studies (n=47; 3,238,508 subjects) showed no significant effect of statin treatment on ICU admission and all-cause mortality but a significant reduction in tracheal intubation (OR=0.73, 95% CI: 0.54-0.99, p=0.04, n=10 studies). The further analysis showed that death outcomes were significantly reduced in the patients who received statins during hospitalization (OR=0.54, 95% CI: 0.50-0.58, p<0.001, n=7 studies), with no such effect of statin therapy before hospital admission (OR=1.06, 95% CI=0.82-1.37, p=0.670, n=29 studies). Conclusion. Taken together, this updated meta-analysis extends and confirms the findings of our previous study, suggesting that in-hospital statin use leads to significant reduction of all-cause mortality in COVID-19 cases. Considering these results, statin therapy during hospitalization, while indicated, should be recommended.


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## Body

## 1. Introduction

As of May 1, 2021, 152,038,419 people have been infected by the SARS-CoV-2 virus, the cause of Coronavirus Disease 2019 (COVID-19) [1, 2]. This translates to nearly 2% of the world population and accounts for a doubling in the number of cases over the last 6 months [3]. The number of people who have died in association with a COVID-19 diagnosis has now reached 3,194,337, which translates to a death rate that has held steady over the last 6 months at 2.1% of the cases. However, since December 2020, we have seen the rollout and administration of multiple vaccines against COVID-19 disease, due to an unprecedented and coordinated effort across the world. Although some countries with advanced vaccination programs have seen a reduction in COVID-19 case numbers, there is still an urgency to control disease spread and reduce its severity worldwide.While waiting for increased vaccinations across the globe, one way of achieving this is through repurposing existing therapeutics. We recently carried out a meta-analysis, which identified significant reductions in intensive care unit (ICU) admission and death outcomes in COVID-19 patients taking statins [4]. Most importantly, this analysis also found that mortality was reduced most profoundly in those patients who were administered statins in-hospital (by 60%), compared to those who were already taking statins prior to hospital admission (by 23%). If confirmed, this would represent an important step forward in the treatment of COVID-19 disease severity. However, this latter finding was accounted for by only three studies with significant heterogeneity between them [4]. In addition, a recent meta-analysis by Hariyanto and Kurniawan [5] indicated that statin use has nothing to do with the composite adverse outcomes of COVID-19, including the risk of mortality. However, the study showed that despite the presence of COVID-19 infection, patients with dyslipidemia should continue to take statins as this is beneficial for cardiovascular outcomes.Here, we provide an updated meta-analysis to further compare statin use on ICU admission, tracheal intubation, and death outcomes in COVID-19 patients. It was of particular interest to compare in-hospital vs. prehospital statin treatment on these outcomes.


## 2. Methods

### 2.1. Search Strategy

This meta-analysis was performed according to PRISMA guidelines. The searches were reconducted using Web of Science, PubMed, Scopus, and ProQuest databases for targeted articles up to April 23, 2021 (previous searches had been performed up to November 2, 2020). The population, intervention, comparison, and outcome (PICO) criteria were, respectively, patients infected with qPCR-confirmed SARS-CoV-2, statin therapy, SARS-CoV-2 patients who were not treated with statins, and intensive care unit (ICU) admission, tracheal intubation, and mortality.The main aim was to further elucidate if statin therapy is associated with the improvement of outcomes in COVID-19 patients. The keywords were chosen as described previously to account for the various names of SARS-CoV-2 and statins [4]. For comprehensive screening of target articles, we first carried out searches without consideration of specific outcomes. Next, we identified three outcomes (ICU admission, tracheal intubation, and mortality) that could be used in a well-powered meta-analysis.


### 2.2. Eligibility Criteria

The inclusion criteria were (1) observational studies and randomized clinical trials testing the effect of statins on COVID-19 and (2) studies including ICU admission, tracheal intubation, and mortality outcomes. Articles were excluded if they were (1) clinical case reports, literature reviews, and preclinical investigations and (2) studies which did not incorporate statin nonusers as controls.


### 2.3. Quality Assessment

Assessment of study quality was performed separately by two authors (FHB and AVA), applying the Newcastle-Ottawa Scale (NOS) for cohort studies, and disagreements were resolved as above. The assessment categories were (1) selection of study groups, (2) comparability of groups, and (3) ascertainment of either the exposure (case-control studies) or outcome (cohort studies) of interest. These were rated from 0 to 3 stars as an indication of quality. This translated to a total of 0 to 9 stars per article.


### 2.4. Statistical Analysis

The analyses were conducted as described previously [4]. Briefly, data extraction for the main outcomes was performed, and random effect meta-analysis was conducted, by applying the restricted maximum likelihood method [6], to account for unknown, unregistered, or unpublished studies. Heterogeneity between studies was determined using the Cochran Q test, tau-squared (τ2), H-squared (H2), and I-squared (I2) statistics. Significant results and I2 values higher than 75% were considered heterogeneous while H2=1 represented perfect homogeneity [7]. Publication biases were displayed using funnel plots, and regression-based Egger’s [8] and nonparametric rank correlation-based Begg’s [9] tests were applied as a measure of small-study effects. A nonparametric “trim and fill” method was used to account for publication bias, and modified effect sizes were estimated. Common effect sizes were displayed using an odds ratio (OR) with 95% confidence interval (CI) for the outcomes, and forest plots were used to illustrate the significance of the results. Subgroup analyses were performed for those studies reporting in- or prehospital use of statins.


## 2.1. Search Strategy

This meta-analysis was performed according to PRISMA guidelines. The searches were reconducted using Web of Science, PubMed, Scopus, and ProQuest databases for targeted articles up to April 23, 2021 (previous searches had been performed up to November 2, 2020). The population, intervention, comparison, and outcome (PICO) criteria were, respectively, patients infected with qPCR-confirmed SARS-CoV-2, statin therapy, SARS-CoV-2 patients who were not treated with statins, and intensive care unit (ICU) admission, tracheal intubation, and mortality.The main aim was to further elucidate if statin therapy is associated with the improvement of outcomes in COVID-19 patients. The keywords were chosen as described previously to account for the various names of SARS-CoV-2 and statins [4]. For comprehensive screening of target articles, we first carried out searches without consideration of specific outcomes. Next, we identified three outcomes (ICU admission, tracheal intubation, and mortality) that could be used in a well-powered meta-analysis.


## 2.2. Eligibility Criteria

The inclusion criteria were (1) observational studies and randomized clinical trials testing the effect of statins on COVID-19 and (2) studies including ICU admission, tracheal intubation, and mortality outcomes. Articles were excluded if they were (1) clinical case reports, literature reviews, and preclinical investigations and (2) studies which did not incorporate statin nonusers as controls.


## 2.3. Quality Assessment

Assessment of study quality was performed separately by two authors (FHB and AVA), applying the Newcastle-Ottawa Scale (NOS) for cohort studies, and disagreements were resolved as above. The assessment categories were (1) selection of study groups, (2) comparability of groups, and (3) ascertainment of either the exposure (case-control studies) or outcome (cohort studies) of interest. These were rated from 0 to 3 stars as an indication of quality. This translated to a total of 0 to 9 stars per article.


## 2.4. Statistical Analysis

The analyses were conducted as described previously [4]. Briefly, data extraction for the main outcomes was performed, and random effect meta-analysis was conducted, by applying the restricted maximum likelihood method [6], to account for unknown, unregistered, or unpublished studies. Heterogeneity between studies was determined using the Cochran Q test, tau-squared (τ2), H-squared (H2), and I-squared (I2) statistics. Significant results and I2 values higher than 75% were considered heterogeneous while H2=1 represented perfect homogeneity [7]. Publication biases were displayed using funnel plots, and regression-based Egger’s [8] and nonparametric rank correlation-based Begg’s [9] tests were applied as a measure of small-study effects. A nonparametric “trim and fill” method was used to account for publication bias, and modified effect sizes were estimated. Common effect sizes were displayed using an odds ratio (OR) with 95% confidence interval (CI) for the outcomes, and forest plots were used to illustrate the significance of the results. Subgroup analyses were performed for those studies reporting in- or prehospital use of statins.


## 3. Results

### 3.1. Literature Search

Supplementary Figure1 shows the flowchart of the study selection process. A total of 1,234 records were initially searched from PubMed (n=319), Scopus (n=206), Web of Science (n=652), and ProQuest (n=49), and 8 studies were identified through other sources. The full list of records was reviewed with 144 duplicate studies omitted from the study, leaving 1,090 records. Following this, articles were screened by titles and abstracts, and the full texts of the remaining 323 studies were evaluated for eligibility. This left 71 studies for the final stringent screen. Finally, 47 studies were included, which met the eligibility criteria. Odds ratios (ORs) were extracted to evaluate the effect of statin use in patients with COVID-19 on ICU admission (n=17), tracheal intubation (n=10), and death (n=41). The general characteristics of included studies are given in Table 1. In addition, quality assessment of studies was done by the Newcastle-Ottawa scale (Supplementary Table 1).Table 1
Characteristics of included studies.
ICU admissionAuthorStatinSampleSettingStudy designResultConclusionReferenceUserNonuserMasana et al.5811576Patients admitted to their hospitals because of SARS-CoV-2 infectionMembers of the Lipids and Arteriosclerosis Units Net (XULA) of Catalonia (Spain)Retrospective observationalN/AN/A[30]103 (17.7)233 (14.8)Zhang et al.121912762Patients with COVID-19Hubei Province, ChinaRetrospectiveaHR: 0.69, CI: 0.56-0.85,p=0.001Cox model analysis showed statin use associated with lower prevalence ICU admission[25]N/AN/ASong et al.123126Patients with COVID-19“Lifespan” healthcare system hospitalsRetrospective cohortOR: 0.90, CI: 0.49-1.67,p=0.756No significant associations between statin use and hospital death or ICU admission[31]N/AN/AArgenziano et al.325525Patients with laboratory-confirmed COVID-19 infectionNew York-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical centerRetrospective case seriesOR=1.07, CI: 0.79-1.46N/A[32]93143De Spiegeleer et al.31123Residents at two elderly care homes with COVID-19 diagnosisOne of two Belgian nursing homesRetrospective multicenter cohortOR: 0.75, CI: 0.24-1.87Statin use showed nonsignificant benefits[33]631Yan et al.N/AN/AConfirmed COVID-19 diagnosisHospitals in Zhejiang Province, ChinaCase-controlOR: 0.98, CI: 0.32-2.99,p=0.973N/A[34]N/AN/ADreher et al.1832COVID-19 patients with and without acute respiratory distress syndrome (ARDS)Aachen University HospitalRetrospective cohortOR: 1.13, CI: 0.36-3.60N/A[35]915Tan et al.40509717 patients admittedTertiary center in Singapore for COVID-19 infectionRetrospective cohortATET Coeff: − 0.12, CI: −0.23-0.01,p=0.028Statin use independently associated with lower requirement for ICU admission[36]1N/ADaniels et al.46124Patients hospitalized for treatment of COVID-19University of California San Diego Health (UCSDH), ascertained by data capture within system-wide electronic health record (EHR) system (Epic Systems, Verona, WI, USA)Retrospective cohortAdjusted OR: 0.29, CI: 0.11-0.71,p<0.01Inpatients hospitalized for COVID-19, use of statin medication prior to admission associated with reduced risk of severe disease[37]2070Vahedian-Azimi et al.326525Positive for SARS-CoV-2Baqiyatallah University of Medical SciencesProspective observationalOR: 1.00, CI: 0.58-1.74,p=0.736Statin use not associated with mortality[10]39243Butt et al.8433999Danish citizens had a primary or secondary diagnosis code for COVID-19 infectionA Danish hospital, including inpatient, outpatient, and emergency department visitsObservational cohort studyHR 2.41 (95% CI 2.04 to 2.85)Statin exposure was associated with a significantly higher risk of severe COVID-19 infection compared with no statin exposure)severe COVID-19 infection, defined as a hospital diagnosis of “COVID-19 severe acute respiratory syndrome” (ICD-10 code: B972A) or admission to an intensive care unit([38]204 (24.2%)419 (10.5%)Fan et al.2501897Patients with COVID-19Zhongnan Hospital of Wuhan University and Leishenshan Hospital in Wuhan, ChinaRetrospective studyAdjusted HR, 0.319; 95% CI, 0.270–0.945;p=0.032The risk was lower for intensive care unit (ICU) care in the statin group vs. the nonstatin group[39]N/AN/AHippisley-Cox et al.561613870Patients who had COVID-19 diseaseGeneral practices in England contributing to the QResearch database from which current data were available, EnglandProspective cohort studyHR=1.21 (1.02-1.43)OR=1.55 (1.38-1.75)For ICU admission, there was no significant associations with the statin[40]487 (8.7%)799 (5.8%)McCarthy et al.107140Patients hospitalized with confirmed SARS-CoV-2 infectionThree Partners Healthcare hospitals (Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital)Retrospective cohort studyAdmitted to ICU or diedOR: 1.18 (0.71-1.96)N/A[41]5161Mitacchione et al.179663Patients hospitalized for COVID-19Hospitals include Luigi Sacco Hospital, Milan; Policlinico Umberto I Hospital, Rome; Spedali Civili Hospital, Brescia; Humanitas Gavazzeni Hospital; Bergamo, ItaliaObservational multicenter studyp=0.162Our results did not confirm the supposed favorable effects of statin therapy on COVID-19 intensive care unit admission[42]6 (3%)40 (6%)Ahlström et al.N/AN/AICU COVID-19 patientsSwedenRetrospective cohort studyOR=0.95 (0.81-1.12)p=0.53We did not find a protective effect on ICU admission in statin-treated patients[43]5181466Izzi-Engbeaya et al.N/AN/APatients hospitalized with swab-positive COVID-19ICHNT, which includes three hospitals admitting patients with COVID-19 (Charing Cross Hospital, Hammersmith Hospital, and St. Mary’s Hospital), LondonRetrospective cohort studyPrimary outcome of death/ICU admissionEstimate: −0.105SE: 0.504p=0.835OR=1.49 (1.12-1.98)N/A[44]N/AN/ATracheal intubationAuthorStatinSampleSettingStudy designResultConclusionUserNonuserZhang et al.121912762Patients with COVID-19Hubei Province, ChinaRetrospectiveaHR: 0.37, CI: 0.26-0.53,p<0.001Cox model analysis showed statin use associated with a lower prevalence of using mechanical ventilation[25]N/AN/ASong et al.123126Patients with COVID-19“Lifespan” healthcare system hospitalsRetrospective cohortStatin use significantly associated with decreased risk for IMV OR: 0.45, CI: 0.20-0.99,p=0.048Data support continued use of statins in patients hospitalized with COVID-19 due to decreased risk for IMV[31]N/AN/AGupta et al.648648Positive for SARS-CoV-2Columbia University Irving Medical Center (CUIMC) and Allen Hospital sites of the New York-Presbyterian Hospital (NYPH)RetrospectiveNo significant difference in invasive mechanical ventilationN/A[45]130 (20.1%)158 (24.4%)Masana et al.5811576Patients admitted to hospitals due to SARS-CoV-2 infectionMembers of the Lipids and Arteriosclerosis Units Net (XULA) of Catalonia (Spain)Retrospective observationalN/AN/A[30]84 (14.46)191 (12.12)Cariou et al.11921257Patients with diabetes admitted with COVID-1968 French hospitalsNationwide observationalOR: 1.13, CI: 0.83-1.53Routine statin use not significantly associated with increased risk of tracheal intubation/mechanical ventilation[46]19.2%19.7%Tan et al.40509Patients admitted for COVID-19Tertiary center in Singapore for COVID-19 infectionRetrospective cohortATET Coeff: −0.08, CI: −0.19-0.02,p=0.114No significant differences in intubation[36]1N/APeymani et al.7575Hospitalized COVID-19 patientsSingle tertiary hospital in Shiraz, IranRetrospectiveOR: 0.96, CI: 0.61-2.99,p=0.942Nonsignificant association between statin use and reduction in mortality in COVID-19 patients[47]N/AN/AFan et al.2501897Patients with COVID-19Zhongnan Hospital of Wuhan University and Leishenshan Hospital in Wuhan, ChinaRetrospective studyN/AN/A[39]26 (10.4%)180 (9.4%)Mitacchione et al.179663Patients hospitalized for COVID-19Hospitals include Luigi Sacco Hospital, Milan; Policlinico Umberto I Hospital, Rome; Spedali Civili Hospital, Brescia; Humanitas Gavazzeni Hospital; Bergamo, ItaliaObservational multicenter studyp=0.258Our results did not confirm the supposed favorable effects of statin therapy on COVID-19 mechanical ventilation[42]6 (3%)36 (5%)Nicholson et al.511531Adult patients with laboratory-confirmed COVID-19 infectionFive hospitals in the Mass General Brigham healthcare system (Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), Newton Wellesley Hospital (NWH), Brigham and Women’s Faulkner Hospital (BWFH), and North Shore Medical Center, NSMC) in Boston, USARetrospective cohortOR=0.84 (0.65–1.09), p=0.182N/A[48]180224MortalityAuthorStatinSampleSettingStudy designResultConclusionStatin timeUserNonuserGupta et al.648648Positive for SARS-CoV-2Columbia University Irving Medical Center (CUIMC) and Allen Hospital sites of the New York-Presbyterian Hospital (NYPH)RetrospectiveUnivariate OR: 0.69, CI: 0.56-0.85. Multivariate adjusted OR: 0.49, CI: 0.38-0.63Antecedent statin use associated with significantly lower rates of in-hospital mortality within 30 days[45]112 (17.2%)201 (31.0%)Masana et al.581581Patients admitted to hospitals due to SARS-CoV-2 infectionMembers of the Lipids and Arteriosclerosis Units Net (XULA) of Catalonia (Spain)Retrospective observationalSignificant difference in mortality rate between groupsHR: 0.58, CI: 0.39-0.89, p=0.01A lower SARS-CoV-2 infection-related mortality observed in patients treated with statin therapy prior to hospitalization[30]115 (19.79)148 (25.40)Zhang et al.121912762Patients with COVID-19Hubei Province, ChinaRetrospectiveIndividuals with statin therapy had a lower crude 28-day mortality (incidence rate ratios (IRR): 0.78, CI: 0.61–1.00,p=0.046)Statin use in hospitalized COVID-19 patients associated with lower risk of all-cause mortality and favorable recovery profile[25]0.21%0.27%Rossi et al.4229Patients with preexisting chronic cardiovascular disease, with COVID-19N/AObservationalMortality rates of patients taking statins were 21.4% (9/42) and 34.5% (10/29) in those not taking statins (p<0.05)Statin use significantly reduced risk of mortality in COVID-19 patients[19]9 (21.4%)10 (34.5%)Cariou et al.11921257Patients with diabetes admitted with COVID-1968 French hospitalsNationwide observationalMortality rates significantly higher in statin users in 28 days (23.9% vs. 18.2%,p<0.001). OR: 1.46, CI: 1.08-1.95Routine statin treatment significantly associated with increased mortality in T2DM patients hospitalized for COVID-19[46]23.9%18.2%Saeed et al.9831283Patients with diabetes mellitus hospitalized with COVID-19Montefiore Medical Center, Bronx, New YorkObservational retrospectivePatient with diabetes on statins had lower cumulative in-hospital mortality (24% vs. 39%,p<0.01). HR: 0.51, CI: 0.43-0.61, p<0.001Statin use associated with reduced in-hospital mortality from COVID-19 in patients with diabetes[21]24%39%Saeed et al.3721614Patients without diabetes mellitus hospitalized with COVID-19Montefiore Medical Center in Bronx, New YorkObservational retrospectiveNo difference noted in patients without diabetes (20% vs. 21%,p=0.82)Statin use associated with reduced in-hospital mortality from COVID-19 inpatients with diabetes[21]20%21%Song et al.123126Patients with COVID-19“Lifespan” healthcare system hospitalsRetrospective cohortNo significant associations between statin use and in-hospital deathOR: 0.88, CI: 0.37-2.08, p=0.781No significant associations between statin use and hospital death[31]N/AN/ADe Spiegeleer et al.31123Residents at two elderly care homes with COVID-19 diagnosisOne of two Belgian nursing homesRetrospective multicenter cohortConsidering death as serious outcome, the effect sizes, OR: 0.61, CI: 0.15-1.71,p=0.380Statins not statistically significantly associated with death from COVID-19 in elderly adults in nursing homes[33]N/AN/ARodriguez-Nava et al.4740Laboratory-confirmed COVID-19Community hospital intensive care unit (ICU) located in Evanston, ILRetrospective cohortMultivariable Cox PH regression model showed atorvastatin nonusers had 73% chance of faster progression to death compared with users. HR: 0.38, CI: 0.18-0.77,p=0.008Slower progression to death associated with atorvastatin use in patients with COVID-19 admitted to ICU[26]23 (49%)25 (63%)Zenga et al.38993COVID-19 inpatientsTongji Hospital, Tongji Medical College of HUST (Wuhan, China)Retrospective cohortOR=0.79, CI=0.3-2.05N/A[49]5160Nguyen et al.90266African American population with COVID-19University of Chicago Medical Center (UCMC), serving south metropolitan ChicagoRetrospective observationalOR=0.81, CI=0.39-1.72N/A[50]1035Wang et al.2412Multiple myeloma patients with COVID-19Mount Sinai HospitalRetrospective cohortStatin use significantly associated with mortality. OR: 6.21, CI: 1.37-39.77,p=0.012N/A[49]113Grasselli et al.N/AN/APatients admitted to ICUs in Lombardy with suspected SARS-CoV-2 infectionOne of the network ICUs, MilanRetrospective, observational studyStatins associated with higher mortality in univariate analysis. HR: 0.98, CI: 0.81-1.2,p=0.87Long-term treatment with statins, before ICU admission associated with higher mortality unadjusted analysis only. Multivariate analysis did not confirm association between any home therapies and increased mortality[51]N/AN/AAyed et al.1093Intensive care unit- (ICU-) admitted COVID-19 patientsJaber Al-Ahmad Al Sabah Hospital, KuwaitRetrospective cohortOR: 0.49, CI: 0.11-2.08N/A[52]443Tan et al.40509717 patients admittedTertiary center in Singapore for COVID-19 infectionRetrospective cohortATET Coeff: −0.04, CI: −0.16-0.08,p=0.488No significant differences in mortality[36]2Peymani et al.7575Hospitalized COVID-19 patientsSingle tertiary hospital, Shiraz, IranRetrospectiveHR: 0.76, CI: 0.16-3.72,p=0.735Nonsignificant association between statin use and reduction in mortality in patients with COVID-19[47]N/AN/ANicholson et al.5115311042 people with COVID-19 symptoms admittedMass General Brigham HospitalsRetrospective cohortOR: 0.50, CI: 0.27-0.93,p=0.027Chronic statin use associated with reduced in-hospital mortality[53]N/AN/ALala et al.9841752Hospitalized COVID-19-positive patients1 of 5 Mount Sinai Health System hospitals in New York CityMultihospital retrospective cohortHR: 0.57, CI: 0.47-0.69,p<0.001Statin use associated with improved survival[54]N/AN/AKrishnan et al.8171Consecutive patients requiring mechanical ventilation from March 10 to April 15St. Joseph Mercy Oakland HospitalRetrospective observationalOR: 2.44, CI: 1.23-4.76,p=0.0080Statin use associated with increased mortality[55]N/AN/AVahedian-Azimi et al.326525Positive for SARS-CoV-2Baqiyatallah University of Medical SciencesProspective observationalOR: 0.18, CI: 0.06–0.49p=0.0001Statin use associated with decreased mortality[10]8282Butt et al.8433999Danish citizens had a primary or secondary diagnosis code for COVID-19 infectionA Danish hospital, including inpatient, outpatient, and emergency department visitsObservational cohort studyHR 2.87 (95% CI 2.39 to 3.46)Statin exposure was associated with a significantly higher risk of mortality compared with no statin exposure[38]177 (21.0%)311 (7.8%)Fan et al.2501897Patients with COVID-19Zhongnan Hospital of Wuhan University and Leishenshan Hospital in Wuhan, ChinaRetrospective studyAdjusted HR, 0.428; 95% CI, 0.169–0.907;p=0.029Statin use was associated with lower mortality[39]6 (2.4%)70 (3.7%)Israel et al.N/AN/AHospitalized COVID-19 patients were assigned to two distinct case-control cohorts. Control patients were taken from the general populationClalit Health Services (CHS) data warehouseRetrospective cohortOR95%CI=0.691 (0.444, 1.037), 0.072Rosuvastatin has protective effects in this large population analysis[56]N/AN/AIsrael et al.N/AN/AHospitalized COVID-19 patients were assigned to two distinct case-control cohorts. Case patients were nonhospitalized SARS-CoV-2-positive patientsClalit Health Services (CHS) data warehouseCase-control matched cohortOR (95% CI) 0.530 (0.360, 0.766)p<0.001Rosuvastatin has protective effects in this large population analysis[56]N/AN/AMughal et al.—abstract4476Adult patients who were hospitalized with RT-PCR-confirmed SARS-CoV-2 infectionN/ARetrospective cohortN/AN/A[57]14 (31.8%)7 (9.2%)Mallow et al.531316363COVID-19 patientDatabase of inpatient and hospital-based outpatient detailed claims across more than 300 acute care hospitals in the USRetrospective cohortOR 0.54, 95% CI, 0.49–0.60;p<0.001Our findings suggest that patients administered statins in the hospital had a 46% lower risk of death than those not receiving statins[28]N/AN/AMcCarthy et al.107140Patients hospitalized with confirmed SARS-CoV-2 infectionThree Partners Healthcare hospitals (Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital)Retrospective cohort studyAdmitted to ICU or diedOR: 1.18 (0.71-1.96)N/A[41]5161Alamdari et al.117342COVID-19 patientsPatients who were admitted to Shahid Modarres Hospital, which is a 279-bed tertiary referral center in Tehran, IranRetrospective cohortOR: 0.27 (0.11–0.64)Statin use history decreased the incidence of mortality dramatically[58]6 (9.5%)57 (16.7%)Soleimani et al.66188Patients with COVID-19Sina Hospital in Tehran, IranRetrospective observational studyOR: 0.93 (0.49–1.76)N/A[59]17 (25%)51 (27%)Ayeh et al.5943853Patients with a diagnosis of SARS-CoV-2 infectionJohns Hopkins Hospital and affiliated hospitals, Johns Hopkins Bayview Medical Center, Howard County General Hospital, Sibley Memorial Hospital, and Suburban Hospital, USARetrospective studyHR=0.92, 95% CI (0.53–1.59)The average treatment effect of statin use on COVID-19-related mortality in the matched groups was not statistically significant[60]N/AN/AAhlström et al.N/AN/AICU COVID-19 patientsSwedenRetrospective cohort studyOR=0.72 (0.53-0.98)p=0.034Statins were protective of ICU death[43]110N/AAn et al.10749160Patients diagnosed with COVID-19South KoreaNationwide cohortOR: 4.11 (3.07-5.51)N/A[61]69 (6.4%)159 (1.7%)Holman et al.118995142710COVID-19 people with type 1 diabetesThe National Diabetes Audit (NDA), UKPopulation-based cohort studyHR=0.82 (0.65-1.03)p=0.081Association of prescription of statins with mortality in type 1 diabetes was not significant[62]338120Holman et al.2099505752245COVID-19 people with type 2 diabetesThe National Diabetes Audit (NDA), UKPopulation-based cohort studyHR=0.72 (0.62-0.75)p<0.001In people with type 2 diabetes, prescription for statins was associated with reduced mortality[62]73553086Inciardi et al.2574Patients hospitalized for COVID-19 pneumoniaCivil Hospitals of Brescia, Lombardy, ItalyRetrospective cohortOR=1.89 (0.71-5.03)N/A[63]9 (36%)17 (23%)Luo et al.55228Patients with confirmed COVID-19Tongji Hospital in Wuhan, ChinaRetrospective studyOR=2.98 (0.65–13.76)p=0.16N/A[27]N/AN/AUllah et al.108104Confirmed COVID-19 patientsPrimary, secondary, and tertiary electronic healthcare records (EHRs) of HPB patients in East LondonRetrospective single-center cohort studyOR=2.39 (1.25-4.56)N/A[64]3618Ramachandran et al.114181Patients admitted with a principal diagnosis of COVID-19Tertiary care academic medical center in Brooklyn, New YorkRetrospective cohort studyOR=1.59 (0.84-3.02)p=0.157N/A[65]N/AN/AIzzi-Engbeaya et al.N/AN/APatients hospitalized with swab-positive COVID-19ICHNT, which includes three hospitals admitting patients with COVID-19 (Charing Cross Hospital, Hammersmith Hospital, and St. Mary’s Hospital), LondonRetrospective cohort studyPrimary outcome of death/ICU admissionEstimate: −0.105SE: 0.504p=0.835OR=1.49 (1.12-1.98)N/A[44]N/AN/ABifulco et al.117424COVID-19 patientsPatients admitted to Humanitas Clinical and Research Hospital (Rozzano, Milan, Italy)Retrospective cohortAdjusted odds ratio (aOR): 0.75; 95% confidence interval (CI): 0.26–2.17;p=0.593Deaths were lower, although not significantly, in statin users with respect to nonstatin users[66]N/AN/AOh et al.N/AN/APatients with COVID-19NHIS-COVID-19 cohort database, South KoreanRetrospective cohort studyOR (95% CI) 0.74, (0.52, 1.05),p=0.094We found that it did not affect the hospital mortality of patients who were diagnosed with COVID-19[29]N/AN/AMaric et al.22974594COVID-19 patientsCerner’s large COVID-19 EHR database, USARetrospective cohort studyp=0.0183We observed a small, but statistically significant, decrease in mortality among patients prescribed statins (16.1%) when compared with matched COVID-19-positive controls (18.0 to 20.6%)[67]369 (16.1%)845 (18.39%)Mitacchione et al.179663Patients hospitalized for COVID-19Hospitals include Luigi Sacco Hospital, Milan; Policlinico Umberto I Hospital, Rome; Spedali Civili Hospital, Brescia; and Humanitas Gavazzeni Hospital, Bergamo, ItaliaObservational multicenter studyp=0.006Statin users appeared to show higher mortality rates[42]52 (%29)130 (%20)N/A: not available.


### 3.2. ICU Admission

As shown in Figure1(a), the risk of ICU admission between statin and nonstatin users in patients with COVID-19 was not significant. The OR from 17 studies was 0.99 (95% CI: 0.77-1.27, p=0.930) with significant heterogeneity between studies τ2=0.21,I2=92.84%,H2=13.97,Qdf=16=180.87, p<0.001). Assessment for bias by Egger’s (p=0.066) and Begg’s (p=0.295) tests did not find significant small-study effects, and visual analysis of the funnel plot showed some publication bias effects (Figure 1(b)).Figure 1
(a) Forest plot showing the risk of ICU admission between statin and nonstatin users in patients with COVID-19. (b) Funnel plot showing publication bias on ICU admission risk between statin and nonstatin users in patients with COVID-19.
(a)(b)


### 3.3. Tracheal Intubation

As shown in Figure2(a), the risk of tracheal intubation between statin and nonstatin users in patients with COVID-19 was significantly different. The risk of tracheal intubation in patients with COVID-19 who used statins was significantly reduced by 27% compared with those who did not take statins. The OR from 10 studies was 0.73 (95% CI: 0.54-0.99, p=0.04), with significant heterogeneity between studies τ2=0.18,I2=88.99%,H2=9.09,Qdf=9=118.87,p<0.001). Small-study effects were not significant as shown by Egger’s (p=0.993) and Begg’s (p=0.236) tests, and the funnel plot suggested no publication bias (Figure 2(b)). Thus, the results were not extended to account for publication bias.Figure 2
(a) Forest plot showing the risk of tracheal intubation between statin and nonstatin users in patients with COVID-19. (b) Funnel plot showing publication bias on tracheal intubation risk between statin and nonstatin users in patients with COVID-19.
(a)(b)


### 3.4. Death

As shown in Figure3(a), the risk of mortality between statin and nonstatin users in patients with COVID-19 was not significant. The OR from the 41 studies which determined the effect of statins on mortality was 0.96 (95% CI: 0.77-1.18, p=0.67), with significant heterogeneity between studies τ2=0.39,I2=95.93%,H2=24.56,Qdf=43=699.49, p<0.001. Assessment for bias by Egger’s (p=0.953) and Begg’s (p=0.551) tests showed no significant small-study effects, and visual inspection of the funnel plot suggested no publication bias (Figure 3(b)). When the analysis was restricted to studies in populations with cardiovascular disease (n=3) and diabetes (n=4), total death was found to be reduced in the former (OR=0.62 (95% CI: 0.45-0.85, p<0.001)) but not the latter (OR=1.06 (95% CI: 0.46-2.41, p=0.890)).Figure 3
(a) Forest plot showing the risk of mortality between statin and nonstatin users in patients with COVID-19. (b) Funnel plot showing publication bias on mortality risk between statin and nonstatin users in patients with COVID-19.
(a)(b)The risk of mortality in patients with COVID-19 who used statins before hospital admission was not significantly different from those who did not take statins (OR=1.06, 95% CI=0.82-1.37, p=0.670, 29 studies) but with significant heterogeneity between studies τ2=0.41,I2=93.32%,H2=14.97,Qdf=30=485.28, p<0.001) (Figure 4(a)). Analysis using Egger’s (p=0.167) and Begg’s (p=0.316) tests found no significant small-study effects, and the funnel plot showed no publication bias (Figure 4(b)). In the subgroup of studies conducted in populations with cardiovascular disease (n=2; OR=0.66, 95% CI=0.43-1.02, p=0.060) or diabetes (n=3; OR=1.12, 95% CI=0.36-3.44, p=0.840), there was no significant effect of prehospital statin use on mortality.Figure 4
(a) Forest plot showing the risk of mortality in patients with COVID-19 who used statins prehospital compared with those who did not take statins. (b) Funnel plot showing publication bias on mortality risk in patients with COVID-19 who used statins prehospital compared with those who did not take statins.
(a)(b)We also analyzed mortality risk in COVID-19 patients who received statins only after hospital admission. This allowed analysis of a new total of 7 studies which found a significant reduction in mortality compared with those who did not take statins (OR=0.54, 95% CI=0.5-0.58, p<0.001), with no significant heterogeneity between studies (τ2=0.00,I2=0.00%,H2=1,Qdf=30=15.67, p=0.03) (Figure 5(a)). Egger’s (p=0.167) and Begg’s (p=0.316) testing showed no significant small-study effects, and the funnel plot suggested no publication bias (Figure 5(b)).Figure 5
(a) Forest plot showing the risk of mortality in patients with COVID-19 who used statins in-hospital compared with those who did not take statins. (b) Funnel plot showing publication bias on mortality risk in patients with COVID-19 who used statins in-hospital compared with those who did not take statins.
(a)(b)


## 3.1. Literature Search

Supplementary Figure1 shows the flowchart of the study selection process. A total of 1,234 records were initially searched from PubMed (n=319), Scopus (n=206), Web of Science (n=652), and ProQuest (n=49), and 8 studies were identified through other sources. The full list of records was reviewed with 144 duplicate studies omitted from the study, leaving 1,090 records. Following this, articles were screened by titles and abstracts, and the full texts of the remaining 323 studies were evaluated for eligibility. This left 71 studies for the final stringent screen. Finally, 47 studies were included, which met the eligibility criteria. Odds ratios (ORs) were extracted to evaluate the effect of statin use in patients with COVID-19 on ICU admission (n=17), tracheal intubation (n=10), and death (n=41). The general characteristics of included studies are given in Table 1. In addition, quality assessment of studies was done by the Newcastle-Ottawa scale (Supplementary Table 1).Table 1
Characteristics of included studies.
ICU admissionAuthorStatinSampleSettingStudy designResultConclusionReferenceUserNonuserMasana et al.5811576Patients admitted to their hospitals because of SARS-CoV-2 infectionMembers of the Lipids and Arteriosclerosis Units Net (XULA) of Catalonia (Spain)Retrospective observationalN/AN/A[30]103 (17.7)233 (14.8)Zhang et al.121912762Patients with COVID-19Hubei Province, ChinaRetrospectiveaHR: 0.69, CI: 0.56-0.85,p=0.001Cox model analysis showed statin use associated with lower prevalence ICU admission[25]N/AN/ASong et al.123126Patients with COVID-19“Lifespan” healthcare system hospitalsRetrospective cohortOR: 0.90, CI: 0.49-1.67,p=0.756No significant associations between statin use and hospital death or ICU admission[31]N/AN/AArgenziano et al.325525Patients with laboratory-confirmed COVID-19 infectionNew York-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical centerRetrospective case seriesOR=1.07, CI: 0.79-1.46N/A[32]93143De Spiegeleer et al.31123Residents at two elderly care homes with COVID-19 diagnosisOne of two Belgian nursing homesRetrospective multicenter cohortOR: 0.75, CI: 0.24-1.87Statin use showed nonsignificant benefits[33]631Yan et al.N/AN/AConfirmed COVID-19 diagnosisHospitals in Zhejiang Province, ChinaCase-controlOR: 0.98, CI: 0.32-2.99,p=0.973N/A[34]N/AN/ADreher et al.1832COVID-19 patients with and without acute respiratory distress syndrome (ARDS)Aachen University HospitalRetrospective cohortOR: 1.13, CI: 0.36-3.60N/A[35]915Tan et al.40509717 patients admittedTertiary center in Singapore for COVID-19 infectionRetrospective cohortATET Coeff: − 0.12, CI: −0.23-0.01,p=0.028Statin use independently associated with lower requirement for ICU admission[36]1N/ADaniels et al.46124Patients hospitalized for treatment of COVID-19University of California San Diego Health (UCSDH), ascertained by data capture within system-wide electronic health record (EHR) system (Epic Systems, Verona, WI, USA)Retrospective cohortAdjusted OR: 0.29, CI: 0.11-0.71,p<0.01Inpatients hospitalized for COVID-19, use of statin medication prior to admission associated with reduced risk of severe disease[37]2070Vahedian-Azimi et al.326525Positive for SARS-CoV-2Baqiyatallah University of Medical SciencesProspective observationalOR: 1.00, CI: 0.58-1.74,p=0.736Statin use not associated with mortality[10]39243Butt et al.8433999Danish citizens had a primary or secondary diagnosis code for COVID-19 infectionA Danish hospital, including inpatient, outpatient, and emergency department visitsObservational cohort studyHR 2.41 (95% CI 2.04 to 2.85)Statin exposure was associated with a significantly higher risk of severe COVID-19 infection compared with no statin exposure)severe COVID-19 infection, defined as a hospital diagnosis of “COVID-19 severe acute respiratory syndrome” (ICD-10 code: B972A) or admission to an intensive care unit([38]204 (24.2%)419 (10.5%)Fan et al.2501897Patients with COVID-19Zhongnan Hospital of Wuhan University and Leishenshan Hospital in Wuhan, ChinaRetrospective studyAdjusted HR, 0.319; 95% CI, 0.270–0.945;p=0.032The risk was lower for intensive care unit (ICU) care in the statin group vs. the nonstatin group[39]N/AN/AHippisley-Cox et al.561613870Patients who had COVID-19 diseaseGeneral practices in England contributing to the QResearch database from which current data were available, EnglandProspective cohort studyHR=1.21 (1.02-1.43)OR=1.55 (1.38-1.75)For ICU admission, there was no significant associations with the statin[40]487 (8.7%)799 (5.8%)McCarthy et al.107140Patients hospitalized with confirmed SARS-CoV-2 infectionThree Partners Healthcare hospitals (Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital)Retrospective cohort studyAdmitted to ICU or diedOR: 1.18 (0.71-1.96)N/A[41]5161Mitacchione et al.179663Patients hospitalized for COVID-19Hospitals include Luigi Sacco Hospital, Milan; Policlinico Umberto I Hospital, Rome; Spedali Civili Hospital, Brescia; Humanitas Gavazzeni Hospital; Bergamo, ItaliaObservational multicenter studyp=0.162Our results did not confirm the supposed favorable effects of statin therapy on COVID-19 intensive care unit admission[42]6 (3%)40 (6%)Ahlström et al.N/AN/AICU COVID-19 patientsSwedenRetrospective cohort studyOR=0.95 (0.81-1.12)p=0.53We did not find a protective effect on ICU admission in statin-treated patients[43]5181466Izzi-Engbeaya et al.N/AN/APatients hospitalized with swab-positive COVID-19ICHNT, which includes three hospitals admitting patients with COVID-19 (Charing Cross Hospital, Hammersmith Hospital, and St. Mary’s Hospital), LondonRetrospective cohort studyPrimary outcome of death/ICU admissionEstimate: −0.105SE: 0.504p=0.835OR=1.49 (1.12-1.98)N/A[44]N/AN/ATracheal intubationAuthorStatinSampleSettingStudy designResultConclusionUserNonuserZhang et al.121912762Patients with COVID-19Hubei Province, ChinaRetrospectiveaHR: 0.37, CI: 0.26-0.53,p<0.001Cox model analysis showed statin use associated with a lower prevalence of using mechanical ventilation[25]N/AN/ASong et al.123126Patients with COVID-19“Lifespan” healthcare system hospitalsRetrospective cohortStatin use significantly associated with decreased risk for IMV OR: 0.45, CI: 0.20-0.99,p=0.048Data support continued use of statins in patients hospitalized with COVID-19 due to decreased risk for IMV[31]N/AN/AGupta et al.648648Positive for SARS-CoV-2Columbia University Irving Medical Center (CUIMC) and Allen Hospital sites of the New York-Presbyterian Hospital (NYPH)RetrospectiveNo significant difference in invasive mechanical ventilationN/A[45]130 (20.1%)158 (24.4%)Masana et al.5811576Patients admitted to hospitals due to SARS-CoV-2 infectionMembers of the Lipids and Arteriosclerosis Units Net (XULA) of Catalonia (Spain)Retrospective observationalN/AN/A[30]84 (14.46)191 (12.12)Cariou et al.11921257Patients with diabetes admitted with COVID-1968 French hospitalsNationwide observationalOR: 1.13, CI: 0.83-1.53Routine statin use not significantly associated with increased risk of tracheal intubation/mechanical ventilation[46]19.2%19.7%Tan et al.40509Patients admitted for COVID-19Tertiary center in Singapore for COVID-19 infectionRetrospective cohortATET Coeff: −0.08, CI: −0.19-0.02,p=0.114No significant differences in intubation[36]1N/APeymani et al.7575Hospitalized COVID-19 patientsSingle tertiary hospital in Shiraz, IranRetrospectiveOR: 0.96, CI: 0.61-2.99,p=0.942Nonsignificant association between statin use and reduction in mortality in COVID-19 patients[47]N/AN/AFan et al.2501897Patients with COVID-19Zhongnan Hospital of Wuhan University and Leishenshan Hospital in Wuhan, ChinaRetrospective studyN/AN/A[39]26 (10.4%)180 (9.4%)Mitacchione et al.179663Patients hospitalized for COVID-19Hospitals include Luigi Sacco Hospital, Milan; Policlinico Umberto I Hospital, Rome; Spedali Civili Hospital, Brescia; Humanitas Gavazzeni Hospital; Bergamo, ItaliaObservational multicenter studyp=0.258Our results did not confirm the supposed favorable effects of statin therapy on COVID-19 mechanical ventilation[42]6 (3%)36 (5%)Nicholson et al.511531Adult patients with laboratory-confirmed COVID-19 infectionFive hospitals in the Mass General Brigham healthcare system (Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), Newton Wellesley Hospital (NWH), Brigham and Women’s Faulkner Hospital (BWFH), and North Shore Medical Center, NSMC) in Boston, USARetrospective cohortOR=0.84 (0.65–1.09), p=0.182N/A[48]180224MortalityAuthorStatinSampleSettingStudy designResultConclusionStatin timeUserNonuserGupta et al.648648Positive for SARS-CoV-2Columbia University Irving Medical Center (CUIMC) and Allen Hospital sites of the New York-Presbyterian Hospital (NYPH)RetrospectiveUnivariate OR: 0.69, CI: 0.56-0.85. Multivariate adjusted OR: 0.49, CI: 0.38-0.63Antecedent statin use associated with significantly lower rates of in-hospital mortality within 30 days[45]112 (17.2%)201 (31.0%)Masana et al.581581Patients admitted to hospitals due to SARS-CoV-2 infectionMembers of the Lipids and Arteriosclerosis Units Net (XULA) of Catalonia (Spain)Retrospective observationalSignificant difference in mortality rate between groupsHR: 0.58, CI: 0.39-0.89, p=0.01A lower SARS-CoV-2 infection-related mortality observed in patients treated with statin therapy prior to hospitalization[30]115 (19.79)148 (25.40)Zhang et al.121912762Patients with COVID-19Hubei Province, ChinaRetrospectiveIndividuals with statin therapy had a lower crude 28-day mortality (incidence rate ratios (IRR): 0.78, CI: 0.61–1.00,p=0.046)Statin use in hospitalized COVID-19 patients associated with lower risk of all-cause mortality and favorable recovery profile[25]0.21%0.27%Rossi et al.4229Patients with preexisting chronic cardiovascular disease, with COVID-19N/AObservationalMortality rates of patients taking statins were 21.4% (9/42) and 34.5% (10/29) in those not taking statins (p<0.05)Statin use significantly reduced risk of mortality in COVID-19 patients[19]9 (21.4%)10 (34.5%)Cariou et al.11921257Patients with diabetes admitted with COVID-1968 French hospitalsNationwide observationalMortality rates significantly higher in statin users in 28 days (23.9% vs. 18.2%,p<0.001). OR: 1.46, CI: 1.08-1.95Routine statin treatment significantly associated with increased mortality in T2DM patients hospitalized for COVID-19[46]23.9%18.2%Saeed et al.9831283Patients with diabetes mellitus hospitalized with COVID-19Montefiore Medical Center, Bronx, New YorkObservational retrospectivePatient with diabetes on statins had lower cumulative in-hospital mortality (24% vs. 39%,p<0.01). HR: 0.51, CI: 0.43-0.61, p<0.001Statin use associated with reduced in-hospital mortality from COVID-19 in patients with diabetes[21]24%39%Saeed et al.3721614Patients without diabetes mellitus hospitalized with COVID-19Montefiore Medical Center in Bronx, New YorkObservational retrospectiveNo difference noted in patients without diabetes (20% vs. 21%,p=0.82)Statin use associated with reduced in-hospital mortality from COVID-19 inpatients with diabetes[21]20%21%Song et al.123126Patients with COVID-19“Lifespan” healthcare system hospitalsRetrospective cohortNo significant associations between statin use and in-hospital deathOR: 0.88, CI: 0.37-2.08, p=0.781No significant associations between statin use and hospital death[31]N/AN/ADe Spiegeleer et al.31123Residents at two elderly care homes with COVID-19 diagnosisOne of two Belgian nursing homesRetrospective multicenter cohortConsidering death as serious outcome, the effect sizes, OR: 0.61, CI: 0.15-1.71,p=0.380Statins not statistically significantly associated with death from COVID-19 in elderly adults in nursing homes[33]N/AN/ARodriguez-Nava et al.4740Laboratory-confirmed COVID-19Community hospital intensive care unit (ICU) located in Evanston, ILRetrospective cohortMultivariable Cox PH regression model showed atorvastatin nonusers had 73% chance of faster progression to death compared with users. HR: 0.38, CI: 0.18-0.77,p=0.008Slower progression to death associated with atorvastatin use in patients with COVID-19 admitted to ICU[26]23 (49%)25 (63%)Zenga et al.38993COVID-19 inpatientsTongji Hospital, Tongji Medical College of HUST (Wuhan, China)Retrospective cohortOR=0.79, CI=0.3-2.05N/A[49]5160Nguyen et al.90266African American population with COVID-19University of Chicago Medical Center (UCMC), serving south metropolitan ChicagoRetrospective observationalOR=0.81, CI=0.39-1.72N/A[50]1035Wang et al.2412Multiple myeloma patients with COVID-19Mount Sinai HospitalRetrospective cohortStatin use significantly associated with mortality. OR: 6.21, CI: 1.37-39.77,p=0.012N/A[49]113Grasselli et al.N/AN/APatients admitted to ICUs in Lombardy with suspected SARS-CoV-2 infectionOne of the network ICUs, MilanRetrospective, observational studyStatins associated with higher mortality in univariate analysis. HR: 0.98, CI: 0.81-1.2,p=0.87Long-term treatment with statins, before ICU admission associated with higher mortality unadjusted analysis only. Multivariate analysis did not confirm association between any home therapies and increased mortality[51]N/AN/AAyed et al.1093Intensive care unit- (ICU-) admitted COVID-19 patientsJaber Al-Ahmad Al Sabah Hospital, KuwaitRetrospective cohortOR: 0.49, CI: 0.11-2.08N/A[52]443Tan et al.40509717 patients admittedTertiary center in Singapore for COVID-19 infectionRetrospective cohortATET Coeff: −0.04, CI: −0.16-0.08,p=0.488No significant differences in mortality[36]2Peymani et al.7575Hospitalized COVID-19 patientsSingle tertiary hospital, Shiraz, IranRetrospectiveHR: 0.76, CI: 0.16-3.72,p=0.735Nonsignificant association between statin use and reduction in mortality in patients with COVID-19[47]N/AN/ANicholson et al.5115311042 people with COVID-19 symptoms admittedMass General Brigham HospitalsRetrospective cohortOR: 0.50, CI: 0.27-0.93,p=0.027Chronic statin use associated with reduced in-hospital mortality[53]N/AN/ALala et al.9841752Hospitalized COVID-19-positive patients1 of 5 Mount Sinai Health System hospitals in New York CityMultihospital retrospective cohortHR: 0.57, CI: 0.47-0.69,p<0.001Statin use associated with improved survival[54]N/AN/AKrishnan et al.8171Consecutive patients requiring mechanical ventilation from March 10 to April 15St. Joseph Mercy Oakland HospitalRetrospective observationalOR: 2.44, CI: 1.23-4.76,p=0.0080Statin use associated with increased mortality[55]N/AN/AVahedian-Azimi et al.326525Positive for SARS-CoV-2Baqiyatallah University of Medical SciencesProspective observationalOR: 0.18, CI: 0.06–0.49p=0.0001Statin use associated with decreased mortality[10]8282Butt et al.8433999Danish citizens had a primary or secondary diagnosis code for COVID-19 infectionA Danish hospital, including inpatient, outpatient, and emergency department visitsObservational cohort studyHR 2.87 (95% CI 2.39 to 3.46)Statin exposure was associated with a significantly higher risk of mortality compared with no statin exposure[38]177 (21.0%)311 (7.8%)Fan et al.2501897Patients with COVID-19Zhongnan Hospital of Wuhan University and Leishenshan Hospital in Wuhan, ChinaRetrospective studyAdjusted HR, 0.428; 95% CI, 0.169–0.907;p=0.029Statin use was associated with lower mortality[39]6 (2.4%)70 (3.7%)Israel et al.N/AN/AHospitalized COVID-19 patients were assigned to two distinct case-control cohorts. Control patients were taken from the general populationClalit Health Services (CHS) data warehouseRetrospective cohortOR95%CI=0.691 (0.444, 1.037), 0.072Rosuvastatin has protective effects in this large population analysis[56]N/AN/AIsrael et al.N/AN/AHospitalized COVID-19 patients were assigned to two distinct case-control cohorts. Case patients were nonhospitalized SARS-CoV-2-positive patientsClalit Health Services (CHS) data warehouseCase-control matched cohortOR (95% CI) 0.530 (0.360, 0.766)p<0.001Rosuvastatin has protective effects in this large population analysis[56]N/AN/AMughal et al.—abstract4476Adult patients who were hospitalized with RT-PCR-confirmed SARS-CoV-2 infectionN/ARetrospective cohortN/AN/A[57]14 (31.8%)7 (9.2%)Mallow et al.531316363COVID-19 patientDatabase of inpatient and hospital-based outpatient detailed claims across more than 300 acute care hospitals in the USRetrospective cohortOR 0.54, 95% CI, 0.49–0.60;p<0.001Our findings suggest that patients administered statins in the hospital had a 46% lower risk of death than those not receiving statins[28]N/AN/AMcCarthy et al.107140Patients hospitalized with confirmed SARS-CoV-2 infectionThree Partners Healthcare hospitals (Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital)Retrospective cohort studyAdmitted to ICU or diedOR: 1.18 (0.71-1.96)N/A[41]5161Alamdari et al.117342COVID-19 patientsPatients who were admitted to Shahid Modarres Hospital, which is a 279-bed tertiary referral center in Tehran, IranRetrospective cohortOR: 0.27 (0.11–0.64)Statin use history decreased the incidence of mortality dramatically[58]6 (9.5%)57 (16.7%)Soleimani et al.66188Patients with COVID-19Sina Hospital in Tehran, IranRetrospective observational studyOR: 0.93 (0.49–1.76)N/A[59]17 (25%)51 (27%)Ayeh et al.5943853Patients with a diagnosis of SARS-CoV-2 infectionJohns Hopkins Hospital and affiliated hospitals, Johns Hopkins Bayview Medical Center, Howard County General Hospital, Sibley Memorial Hospital, and Suburban Hospital, USARetrospective studyHR=0.92, 95% CI (0.53–1.59)The average treatment effect of statin use on COVID-19-related mortality in the matched groups was not statistically significant[60]N/AN/AAhlström et al.N/AN/AICU COVID-19 patientsSwedenRetrospective cohort studyOR=0.72 (0.53-0.98)p=0.034Statins were protective of ICU death[43]110N/AAn et al.10749160Patients diagnosed with COVID-19South KoreaNationwide cohortOR: 4.11 (3.07-5.51)N/A[61]69 (6.4%)159 (1.7%)Holman et al.118995142710COVID-19 people with type 1 diabetesThe National Diabetes Audit (NDA), UKPopulation-based cohort studyHR=0.82 (0.65-1.03)p=0.081Association of prescription of statins with mortality in type 1 diabetes was not significant[62]338120Holman et al.2099505752245COVID-19 people with type 2 diabetesThe National Diabetes Audit (NDA), UKPopulation-based cohort studyHR=0.72 (0.62-0.75)p<0.001In people with type 2 diabetes, prescription for statins was associated with reduced mortality[62]73553086Inciardi et al.2574Patients hospitalized for COVID-19 pneumoniaCivil Hospitals of Brescia, Lombardy, ItalyRetrospective cohortOR=1.89 (0.71-5.03)N/A[63]9 (36%)17 (23%)Luo et al.55228Patients with confirmed COVID-19Tongji Hospital in Wuhan, ChinaRetrospective studyOR=2.98 (0.65–13.76)p=0.16N/A[27]N/AN/AUllah et al.108104Confirmed COVID-19 patientsPrimary, secondary, and tertiary electronic healthcare records (EHRs) of HPB patients in East LondonRetrospective single-center cohort studyOR=2.39 (1.25-4.56)N/A[64]3618Ramachandran et al.114181Patients admitted with a principal diagnosis of COVID-19Tertiary care academic medical center in Brooklyn, New YorkRetrospective cohort studyOR=1.59 (0.84-3.02)p=0.157N/A[65]N/AN/AIzzi-Engbeaya et al.N/AN/APatients hospitalized with swab-positive COVID-19ICHNT, which includes three hospitals admitting patients with COVID-19 (Charing Cross Hospital, Hammersmith Hospital, and St. Mary’s Hospital), LondonRetrospective cohort studyPrimary outcome of death/ICU admissionEstimate: −0.105SE: 0.504p=0.835OR=1.49 (1.12-1.98)N/A[44]N/AN/ABifulco et al.117424COVID-19 patientsPatients admitted to Humanitas Clinical and Research Hospital (Rozzano, Milan, Italy)Retrospective cohortAdjusted odds ratio (aOR): 0.75; 95% confidence interval (CI): 0.26–2.17;p=0.593Deaths were lower, although not significantly, in statin users with respect to nonstatin users[66]N/AN/AOh et al.N/AN/APatients with COVID-19NHIS-COVID-19 cohort database, South KoreanRetrospective cohort studyOR (95% CI) 0.74, (0.52, 1.05),p=0.094We found that it did not affect the hospital mortality of patients who were diagnosed with COVID-19[29]N/AN/AMaric et al.22974594COVID-19 patientsCerner’s large COVID-19 EHR database, USARetrospective cohort studyp=0.0183We observed a small, but statistically significant, decrease in mortality among patients prescribed statins (16.1%) when compared with matched COVID-19-positive controls (18.0 to 20.6%)[67]369 (16.1%)845 (18.39%)Mitacchione et al.179663Patients hospitalized for COVID-19Hospitals include Luigi Sacco Hospital, Milan; Policlinico Umberto I Hospital, Rome; Spedali Civili Hospital, Brescia; and Humanitas Gavazzeni Hospital, Bergamo, ItaliaObservational multicenter studyp=0.006Statin users appeared to show higher mortality rates[42]52 (%29)130 (%20)N/A: not available.


## 3.2. ICU Admission

As shown in Figure1(a), the risk of ICU admission between statin and nonstatin users in patients with COVID-19 was not significant. The OR from 17 studies was 0.99 (95% CI: 0.77-1.27, p=0.930) with significant heterogeneity between studies τ2=0.21,I2=92.84%,H2=13.97,Qdf=16=180.87, p<0.001). Assessment for bias by Egger’s (p=0.066) and Begg’s (p=0.295) tests did not find significant small-study effects, and visual analysis of the funnel plot showed some publication bias effects (Figure 1(b)).Figure 1
(a) Forest plot showing the risk of ICU admission between statin and nonstatin users in patients with COVID-19. (b) Funnel plot showing publication bias on ICU admission risk between statin and nonstatin users in patients with COVID-19.
(a)(b)


## 3.3. Tracheal Intubation

As shown in Figure2(a), the risk of tracheal intubation between statin and nonstatin users in patients with COVID-19 was significantly different. The risk of tracheal intubation in patients with COVID-19 who used statins was significantly reduced by 27% compared with those who did not take statins. The OR from 10 studies was 0.73 (95% CI: 0.54-0.99, p=0.04), with significant heterogeneity between studies τ2=0.18,I2=88.99%,H2=9.09,Qdf=9=118.87,p<0.001). Small-study effects were not significant as shown by Egger’s (p=0.993) and Begg’s (p=0.236) tests, and the funnel plot suggested no publication bias (Figure 2(b)). Thus, the results were not extended to account for publication bias.Figure 2
(a) Forest plot showing the risk of tracheal intubation between statin and nonstatin users in patients with COVID-19. (b) Funnel plot showing publication bias on tracheal intubation risk between statin and nonstatin users in patients with COVID-19.
(a)(b)


## 3.4. Death

As shown in Figure3(a), the risk of mortality between statin and nonstatin users in patients with COVID-19 was not significant. The OR from the 41 studies which determined the effect of statins on mortality was 0.96 (95% CI: 0.77-1.18, p=0.67), with significant heterogeneity between studies τ2=0.39,I2=95.93%,H2=24.56,Qdf=43=699.49, p<0.001. Assessment for bias by Egger’s (p=0.953) and Begg’s (p=0.551) tests showed no significant small-study effects, and visual inspection of the funnel plot suggested no publication bias (Figure 3(b)). When the analysis was restricted to studies in populations with cardiovascular disease (n=3) and diabetes (n=4), total death was found to be reduced in the former (OR=0.62 (95% CI: 0.45-0.85, p<0.001)) but not the latter (OR=1.06 (95% CI: 0.46-2.41, p=0.890)).Figure 3
(a) Forest plot showing the risk of mortality between statin and nonstatin users in patients with COVID-19. (b) Funnel plot showing publication bias on mortality risk between statin and nonstatin users in patients with COVID-19.
(a)(b)The risk of mortality in patients with COVID-19 who used statins before hospital admission was not significantly different from those who did not take statins (OR=1.06, 95% CI=0.82-1.37, p=0.670, 29 studies) but with significant heterogeneity between studies τ2=0.41,I2=93.32%,H2=14.97,Qdf=30=485.28, p<0.001) (Figure 4(a)). Analysis using Egger’s (p=0.167) and Begg’s (p=0.316) tests found no significant small-study effects, and the funnel plot showed no publication bias (Figure 4(b)). In the subgroup of studies conducted in populations with cardiovascular disease (n=2; OR=0.66, 95% CI=0.43-1.02, p=0.060) or diabetes (n=3; OR=1.12, 95% CI=0.36-3.44, p=0.840), there was no significant effect of prehospital statin use on mortality.Figure 4
(a) Forest plot showing the risk of mortality in patients with COVID-19 who used statins prehospital compared with those who did not take statins. (b) Funnel plot showing publication bias on mortality risk in patients with COVID-19 who used statins prehospital compared with those who did not take statins.
(a)(b)We also analyzed mortality risk in COVID-19 patients who received statins only after hospital admission. This allowed analysis of a new total of 7 studies which found a significant reduction in mortality compared with those who did not take statins (OR=0.54, 95% CI=0.5-0.58, p<0.001), with no significant heterogeneity between studies (τ2=0.00,I2=0.00%,H2=1,Qdf=30=15.67, p=0.03) (Figure 5(a)). Egger’s (p=0.167) and Begg’s (p=0.316) testing showed no significant small-study effects, and the funnel plot suggested no publication bias (Figure 5(b)).Figure 5
(a) Forest plot showing the risk of mortality in patients with COVID-19 who used statins in-hospital compared with those who did not take statins. (b) Funnel plot showing publication bias on mortality risk in patients with COVID-19 who used statins in-hospital compared with those who did not take statins.
(a)(b)


## 4. Discussion

Our updated meta-analysis found no significant reductions in ICU admission and mortality outcomes in COVID-19 patients who used statins, compared to those who were not on these drugs. Interestingly, a significant reduction of all-cause mortality with statins was observed in patients with cardiovascular disease; however, due to the limited number of studies included, this still needs to be confirmed. The subgroup analysis also showed that administration of statins during hospitalization was associated with a significant 46% reduction in mortality, in line with the findings of our previous study [10]. Conversely, we found that use of statins prior to admission had no significant effect on the mortality outcomes. What is additionally important, statin therapy also reduced tracheal intubation by 27%.One possibility for these differences in mortality outcomes could be associated with the type of statin used across different studies. As the characteristic of the included studies were varied, this gives rise to bias which makes it difficult to draw firm conclusions. Expectedly, differential physiochemical characteristics of statins can affect the potency of their well-known pleiotropic actions [11–18]. For example, one study found that treatment with simvastatin or atorvastatin led to a reduction in mortality of COVID-19 patients, compared to cases given pravastatin or rosuvastatin [19]. In addition, the CORONADO study showed that treatment with statins was associated with increased mortality in COVID-19 patients with preexisting diabetes [20], although another study found that statin use reduced mortality in a similar patient group [21]. Again, this might have been due to the use of different statins as information regarding the statin type was not listed in the CORONADO study. Another possibility for the lack of effect of prehospital use of statins on mortality outcomes in COVID-19 patients could be due to the preexistence of diseases such as obesity, hypertension, cardiovascular disorders, and metabolic diseases, which are significant risk factors for severe outcomes [22–24]. This could be explained by the possibility that any potential benefit of statins could be nullified by the presence of comorbidities. Finally, the observed benefit in terms of reducing the incidence of tracheal intubation deserves further investigation. This benefit might imply that statin therapy is particularly beneficial in reducing the serious complications of COVID-19 like intubation which is closely related to death. This notion is in line with the observed mortality benefit in patients receiving statins during hospitalization.The currently updated meta-analysis had several limitations. First and foremost, only associations are given since it was not possible to investigate a cause-and-effect relationship involving statin use. Secondly, we do not have data from the included studies on the preparations of statins that were used in COVID-19 patients, which is a reason we cannot make any conclusions whether there are differences in the outcomes between hydrophilic and lipophilic ones. Thirdly, potential effects of preexisting or postdiagnosis development of comorbidities such as acute respiratory distress, coagulation disorders, or insulin resistance cannot be excluded. Fourthly, the findings were not adjusted for other medication use, which may also have affected outcomes. Finally, although the number of studies that we identified which investigated in-hospital use of statins was more than doubled in this updated meta-analysis [10, 21, 25–29], this was still likely to have been statistically underpowered.In conclusion, this updated meta-analysis further supports our previous finding that administration of statins during hospitalization is associated with reduced mortality of patients diagnosed with COVID-19 disease. Thus, further clinical studies are warranted to determine the timing of statin administration, recommended preparations, and doses, as well as potential effects of preexisting medical conditions and prescribed medications on clinical outcomes in COVID-19 patients. Most importantly, such studies will provide critical insights and outline strategic measures and patient-specific treatment approaches to successfully control the current devastating COVID-19 outbreak. It is hoped that such studies will help to pave the way for better preparedness in the likely event of future pandemics. However, more randomized clinical trial studies are needed to confirm these results.



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