The Clinical Effects And Efficacy Of Statins In Patients With COVID-19

Part 1 Clinical characteristics and treatment information of patients with COVID-19Objective The Coronavirus disease 2019(COVID-19)outbreak began in December2019 and spread rapidly all over the world.Cardiometabolic diseases are common comorbidities among COVID-19 patients,and can significantly increase the severity and mortality of disease.Statins are commonly used drugs for cardiometabolic diseases,but the use of statins in COVID-19 population is unclear.This study will analyze the use information of statins among COVID-19 patients and the clinical characteristics of the statins users,to lay the foundation for further exploring the effect of statin in COVID-19 patients.Methods Medical records of 13,981 COVID-19 patients admitted to 21 hospitals in Hubei Province from December 30,2019 to April 17,2020 were collected.According to the use of statins in hospital,the study population was categorized as statin group and non-statin group.Nonnormally distributed continuous variables were displayed in median(IQR),and the difference statistics adopt the Mann-Whitney U test.Categorical variables were expressed as number and percentage(%),and the difference statistics adopt Fisher's exact test or chi-square test.Results The median age of 13,981 COVID-19 patients was 58 years old,and 48.9%were men among the study population.Hypertension(34.8%)was the most common comorbidity in the COVID-19 patients.In the study population,there were 1219(8.7%)statin users.Compared with the non-statin group,patients in the statin group were older(66.0 vs.57.0 years,P<0.001),and had a higher proportion of hypertension,diabetes,coronary heart disease and cerebrovascular disease.In the statin group,increased neutrophil count,procalcitonin,alanine aminotransferase,aspartate aminotransferase,low density lipoprotein,total cholesterol,and D-dimer,and decreased estimated glomerular filtration rate were more common than those in the non-statin group.Atorvastatin was the most commonly used in the statin group.Conclusions Statins were commonly used drugs in patients with COVID-19.Patients with in-hospital use of statins showed more severe inflammation and organ dysfunction on admission than those without.Part 2 Efficacy and safety evaluation of statins in patients with COVID-19Objective Previous clinical studies have indicated that statins may have a therapeutic effect on pneumonia and acute respiratory distress syndrome(ARDS).Meanwhile,statins have been confirmed to have anti-inflammatory and potential anti-viral infection effects.Therefore,it has been proposed that statins may be used to treat COVID-19.However,the up-regulation effect of statins on angiotensin-converting enzyme 2 suggests that statins use may bring a greater risk of COVID-19 infection and worsening.To address the current controversy regarding the prognostic effects of statins in the COVID-19 population,this study will evaluate the relationship between the in-hospital use of statins and death,organ damage and adverse effects of COVID-19.Methods The study population included 13,981 COVID-19 patients.The end of follow-up time was set to 28 days after admission.The primary outcome was death,and the secondary outcomes including acute organ damege(ARDS,septic shock,acute liver injury,acute kidney injury,acute heart injury),and clinical outcomes representing worsening of the disease(intensive care unit(ICU)management and invasive mechanical ventilation.The adverse effects associated with statins were defined as abnormal elevations in ALT and CK.Mixed-effect Cox model,Time-varying Cox model and marginal structure Cox proportional hazard model(MSM)were applied to evaluate the relationship between statin use and clinical outcomes.Results During the follow-up period,there were 938 deaths among 13,981COVID-19 patients,of which 67 deaths in the statin group(mortality 5.5%),and 871 deaths in the non-statin group(mortality 6.8%).Compared with the non-statin group,the 28-day all-cause mortality in the statin group was significantly lower(incidence rate ratio,0.78,95%CI,0.61-0.996;P=0.046).The results analyzed by mixed-effect Cox model(adjusted HR,0.50,95%CI,0.38-0.65;P<0.001),Time-varying Cox model(adjusted HR,0.63,95%CI,0.48-0.84;P=0.001)and MSM(adjusted HR,0.72,95%CI,0.54-0.97;P=0.032)all indicated that the risk of death in the statin group was significantly lower than that in the non-statin group.The conclusion of the sensitivity analysis on the relationship between statin use and death risk was consistent with the above.In addition,the mixed-effect Cox model shows that ARDS in the statin group (adjusted HR,0.83,95%CI,0.72-0.97;P=0.015),ICU management(adjusted HR,0.69,95%CI,0.56-0.85;P=0.001)and invasive mechanical ventilation(adjusted HR,0.37,95%CI,0.26-0.53;P<0.001)were significantly lower than the non-statin group.The risk of adverse effects of statin determined by CK increase above upper limit of normal or ALT increase above 3-folds of upper limit of normal showed no significant difference between the two groups.Conclusion In-hospital use of statins was associated with a reduced risk of mortality among individuals with COVID-19,and did not increase the risk of organ damage or adverse effects.These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19,and also provide a low-cost and highly accessible potential treatment strategy for COVID-19 globally.Part 3 The clinical effects of statins in patients with COVID-19Objective The clinical pleiotropic effects of statins include lipid regulation,anti-inflammation and cardiovascular protective effects.Meanwhile,lipid metabolism alterations,inflammation and cardiac injury have been confirmed as important pathophysiological mechanisms of COVID-19.This study will analyze the dynamic changes of lipids profiles,inflammatory indicators and myocardial enzymes in COVID-19 patients with and without statins use to reveal the clinical effects of statins in COVID-19.This study will provide mechanistic evidence for the use of statins in COVID-19 patients.Methods The statin group and the non-statin group in the retrospective cohort were matched through the propensity matching scoring method(PSM),with the matching factors of the imbalanced variables at admission between the two groups.Locally weighted regression and smoothing scatterplot(Lowess)model was used to delineate the dynamic curves of blood lipid profile(total cholesterol,triglycerides,high-density lipoprotein,low-density lipoprotein),inflammation indicators(interleukins-6,C-reactive protein,neutrophils)and cardiac injury markers(creatine kinase(CK),creatine kinase MB isoenzyme(CKMB),high-sensitivity cardiac troponin I(hs-c Tn I),myoglobin)within 28 days after admission.Results Using PSM,861 participants from the statin group were matched at a 1:4ratio to 3,444 participants from the non-statin group.As shown in the Lowess model diagram,there was no significant difference in the dynamic changes of blood lipid profile between the statin group and the non-statin group.The inflammatory indicators levels of interleukin-6,C-reactive protein,and neutrophils count in the statin group were significantly lower than those in the non-statin group,and showed a more obvious downward trend.The level of hs-c Tn I was more stable and lower in the statin group than that in the non-statin group during the whole process.However,there was no significant difference in the dynamic fitting curves of CK,CKMB and myoglobin levels between the two groups.Conclusion The use of statins in COVID-19 patients can significantly reduce inflammation.This result provides mechanistic evidence for the use of statins in COVID-19 patients.Part 4 The effect of the combination therapy of statins and ACEI/ARB on the prognosis of patients with hypertension and COVID-19Objective Hypertension is a risk factor for the mortality of COVID-19.Statins are often combined with Angiotensin Converting Enzyme Inhibitor(ACEI)or Angiotensin Receptor Blocker(ARB)for the treatment of hypertension in clinical practice.The combination of statins and ARB has been used to treat Ebola virus infection and has shown certain efficacy.However,for COVID-19,the clinical application of ACEI/ARB and statins have similar dilemma in increasing the expression of angiotensin-converting enzyme 2.This study aimed to evaluate the association of the combination therapy of statins and ACEI/ARB and the prognosis of patients with hypertension and COVID-19.Methods The study population included patients with hypertension and COIVD-19 which use statins and antihypertensive drugs during hospitalization.According to the type of antihypertensive drugs,the study population were divided into statin+ACEI/ARB group(N=319)and statin+non ACEI/ARB group(N=603).The primary outcome was all-cause death within 28 days after admission.The secondary outcomes included acute respiratory distress syndrome(ARDS),septic shock,acute liver injury,acute kidney injury,acute heart injury,ICU management and invasive mechanical ventilation.The mixed-effect Cox model,Time-varying Cox model and marginal structure Cox proportional hazard model(MSM)were used to evaluate the risk of clinical outcomes.The mixed-effect Cox model was also used to calculate the risk of the primary and secondary endpoints between the matched statin+ACEI/ARB group and statin+non ACEI/ARB group.Results The mixed-effect Cox model,Time-varying Cox model and MSM model analysis suggested that there was no significant correlation between statin combined with ACEI/ARB treatment and the 28-day all-cause mortality of patients with hypertension and COVID-19.However,the matched statin+ACEI/ARB group showed lower risk of death than that in the matched statin+non ACEI/ARB group(adjusted HR,0.32,95%CI,0.12-0.82;P=0.018).There was no significant difference in the risk of secondary outcomes between the two groups before matching.After matching,the risk of ARDS(adjusted HR,0.59;95%CI,0.37-0.92;P=0.020)and acute cardiac injury(adjusted HR,0.61,95%CI,0.38-0.97;P=0.038)was significantly lower in the matched statin+ACEI/ARB than that in the matched statin+non ACEI/ARB group.Conclusion The combined application of statins and ACEI/ARB did not increase the risk of poor prognosis in patients with COVID-19 and hypertension.It is safe to use statins combined with ACEI/ARB in patients with hypertension and COVID-19.