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Meta-analysis of Effect of Statins in Patients with COVID-19

      Since the occurrence of novel coronavirus disease 2019 (COVID-19) pandemic, there have been many discussions on the repurposing of existing drugs for the treatment of COVID-19, one of which is the statins. However, there are two opposing views on the effects of statins on the clinical course of COVID-19. Dysregulation of the myeloid differentiation primary response protein (MYD) 88 pathway which results in overwhelming inflammation has been observed and associated with poor prognosis in other coronavirus infections; this could be the case for COVID-19 but has not been conclusively proven
      • Yuan S
      Statins May Decrease the Fatality Rate of Middle East Respiratory Syndrome Infection.
      ,
      • Yuan X
      • Deng Y
      • Guo X
      • Shang J
      • Zhu D
      • Liu H
      Atorvastatin attenuates myocardial remodeling induced by chronic intermittent hypoxia in rats: partly involvement of TLR-4/MYD88 pathway.
      . Statins are known inhibitors of MYD88 and could stabilize MYD88 levels in the presence of external stressors, which thus suggest their roles in protecting COVID-19 patients from the development of overwhelming inflammatory responses
      • Totura AL
      • Whitmore A
      • Agnihothram S
      Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection.
      . Besides, statins are known to experimentally up-regulate ACE2 expression, and therefore might be protective towards lung injury induced by coronavirus
      • Li YH
      • Wang QX
      • Zhou JW
      Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats.
      . On the other hand, statins cause deficiency of endogenous cholesterol content in the cells, leading to upregulation of low-density lipoprotein receptors, which in turn results in constant incorporation of exogenous cholesterol onto the cell membrane and the subsequent formation of multiple lipid rafts, thus enhancing accessibility for coronaviruses
      • Shresta S
      Statin drug therapy may increase COVID-19 infection.
      . Some researchers
      • Thorp EB
      • Gallagher TM
      Requirements for CEACAMs and cholesterol during murine coronavirus cell entry.
      have also argued that statins might promote the development of a more severe course of COVID-19 due to activation of the inflammasome pathway in acute respiratory distress syndrome, leading to increased pro-inflammatory interleukin-18 (IL-18) levels and subsequent cytokine storm
      • Goldstein MR
      • Poland GA
      • Graeber CW
      Are certain drugs associated with enhanced mortality in COVID-19?.
      ,
      • Rogers A
      • Guan J
      • Trtchounian A
      • Hunninghake G
      • Kaimal R
      • Desai M
      Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome.
      . Individual observational studies
      • Yan H
      • Valdes AM
      • Vijay A
      Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China. Preprint.
      • Zhang XJ
      • Qin JJ
      • Cheng X
      In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.
      • Rodriguez-Nava G
      • Trelles-Garcia DP
      • Yanez-Bello MA
      • Chung CW
      • Trelles-Garcia VP
      • Friedman HJ
      Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study.
      • Grasselli G
      • Greco M
      • Zanella A
      • et al.
      Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.
      have since reported on this area and we carried out a meta-analysis to summarise the existing evidence on the effect of statins on the clinical outcomes of COVID-19 from adjusted analyses.
      We searched PubMed, Google Scholar, and medRxiv (preprint repository) databases, up to 27 July 2020, for studies evaluating the risk of severe illness and/or mortality in COVID-19 among statin users compared to non-statin users, with the following keywords and their MeSH terms: “COVID-19”, “statin”, and “HMG-CoA reductase” without language restrictions. The reference lists of reviews and retrieved articles were also screened for additional pertinent papers. Studies were included if they are of cohort or case-control design, included patients with confirmed COVID-19, and with data available to compare the risk of severe illness and/or mortality among statin users compared to non-statin users in adjusted analyses. Each included article was independently evaluated by two authors (CSK and SSH) who extracted the study characteristics and measures of effect. In case of discrepancies in data extraction, the consensus was achieved through discussion. The quality of observational studies was evaluated using the Newcastle-Ottawa Scale

      Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed July 27, 2020)

      . Adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model using Meta XL, version 5.3 (EpiGear International, Queensland, Australia). The Cochran’s Q heterogeneity test and I2 statistic were performed to estimate the heterogeneity.
      Our literature search yielded 274 potential studies. After deduplication and application of the eligibility criteria, four studies with a total of 8,990 COVID-19 patients were included for meta-analysis. Except for Yan et al. which is of moderate quality (5/9), other studies are of good quality (at least 7/9). Study characteristics are provided in Table 1. The pooled analysis revealed a significantly reduced hazard for fatal or severe disease with the use of statins (Figure 1; pooled HR=0.70; 95% CI 0.53-0.94) compared to non-use of statins in COVID-19 patients. Since our meta-analysis included a fairly large total number of COVID-19 patients from four studies in which 3 are large-scale studies that adjusted extensively for multiple potential confounding factors, the findings can be considered reliable. Current preliminary findings suggested a reduction in fatal or severe disease by 30% and discredited the suggestion of harms with the use of statins in COVID-19 patients. Much left to be determined on the regimen of statin for the treatment of COVID-19 though available evidence suggests that statin therapy of moderate-to-high intensity could be effective. Nevertheless, we await more data from prospective studies to substantiate our findings. Future well-designed randomized controlled trials are also needed to confirm the benefits of statins in COVID-19 patients.
      Table 1
      StudyCountryDesignTotal number of patientsAgeStatin regimenMortalitySevere disease
      The definition of severe disease in the study by Yan et al. is based on the definition given in Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia by Chinese National Health Commission while in the study by Zhang et al. is based on the admission into intensive care unit.
      Adjustment of CovariatesNOS
      Statin users (n/N; %)Non-statin users (n/N; %)Adjusted estimateStatin users (n/N; %)Non-statin users (n/N; %)Adjsuted estimate
      Yan et alChinaRetrospective, multicenter61048.8 (14.2)N/A---5/16; 31.3123/594; 20.7HR=0.98

      (0.32-2.99)
      Age, sex, body mass index5/9
      Zhang et alChinaRetrospective, multicenter4,305Statin=66.0 (59.0–72.0)

      Non-statin=57.0 (45.0–67.0)
      Atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, pitavastatin

      Median duration: 22.0 days,

      Median dose (atorvastatin equivalent): 20.0 mg per day
      45/861; 5.2325/3444; 9.4HR=0.58

      (0.43-0.80)
      --HR=0.69

      (0.56-0.85)
      Mortality: Age, gender, and oxygen saturation at admission

      Severity: Age, gender, blood pressure, pre-existing comorbidities, indicators of disease severity and organ injuries, low-density-lipoprotein-cholesterol increase, total cholesterol increase
      8/9
      Rodriguez-Nava et alUSARetrospective, single center8768 (58-75)Atorvastatin 40 mgN/AN/AHR=0.38

      (0.18-0.77)
      ---Age, hypertension, cardiovascular disease, invasive mechanical ventilation, severity according to the National Institutes of Health criteria, number of comorbidities, and adjuvant therapies7/9
      Grasselli et alItalyRetrospective, multicenter3,98863 (56-69)N/AN/AN/AHR=0.98

      (0.81-1.20)
      ---Age, gender, type of respiratory support, comorbidities, angiotensin-converting enzyme inhibitor therapy, angiotensin receptor blocker, diuretic, positive end-expiratory pressure at admission, fraction of inspired oxygen at admission, arterial partial pressure of oxygen/fraction of inspired oxygen at admission7/9
      HR=hazard ratio; NOS=Newcastle-Ottawa Scale.
      a The definition of severe disease in the study by Yan et al. is based on the definition given in Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia by Chinese National Health Commission while in the study by Zhang et al. is based on the admission into intensive care unit.
      Figure 1:
      Figure 1Pooled mortality and/or disease severity risk in COVID-19 patients using or not using statins. (Heterogeneity: I2=71%; p = 0.01)

      Declaration of interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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