| Objective:The coronavirus disease 2019(COVID-19)pandemic has created an unprecedented burden on healthcare systems throughout the world and caused over 70 million infected people and 1.6 million deaths in over 200 countries/regions so far.The global epidemic situation is still serious,and could even progress in some countries and regions before the vaccines have been widely used.COVID-19 has often been considered as an acute respiratory infectious disease.However,emerging evidence shows that the injury of cardio-cerebrovascular system is an important and considerable extrapulmonary injury of COVID-19 which needs further research.Prior researches about the incidences,risk factors and contributions to poor prognosis of cardio-cerebrovascular events in COVID-19 patients have drawn controversial conclusions.The severities of disease and prognosis among different patients are highly heterogeneous,ranging from asymptomatic infection or mild disease to critical illness with multiple organ injuries.Therefore,early prediction,identifications,diagnoses and therapies are of great importance for COVID-19 patients.The current study was conducted aiming to identify incidences and risk factors,as well as develop and validate a prediction model for cardio-cerebrovascular events during hospitalizations of COVID-19 patients,and also to evaluate the impacts of cardiocerebrovascular events on prognosis among COVID-19 patients via original research and meta-analysis.Materials and Methods:Chapter One:This retrospective,multicenter,observational study of laboratoryconfirmed adult COVID-19 patients was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee(No.2020-272).Clinical data of hospitalized patients from two major COVID-19 designated hospitals(Wuhan Red Cross hospital and People’s Hospital of Wuhan University)in Wuhan city,Hubei province and 36 COVID-19 designated hospitals in Sichuan province,China between January 14 and March 9,2020 were collected and analyzed,including baseline data recorded at admission or within 24h after admission to hospitals and cardiocerebrovascular events during hospitalizations.All included patients were randomly divided into training set and testing set(70%percent vs.30%of patients).One of the primary outcomes was occurrence of composite cardio-cerebrovascular events which was considered if any of the following appeared during hospitalizations:(1)acute myocarditis;(2)acute myocardial infarction(AMI);(3)new or worsening heart failure(HF);(4)de novo arrhythmia;(5)deep vein thrombosis(DVT)or pulmonary embolism(PE);(6)cerebrovascular events;(7)cardiovascular death.The other primary outcome was major adverse cardiovascular events(MACE),including cardiovascular death,non-fatal myocardial infarction or non-fatal stroke.The secondary outcome was each cardio-cerebrovascular event,which was analyzed individually to identify related risk factors.The risk factors were identified by LASSO regression and multivariate Logistic regression analyses.And then,the nomogram was established and further evaluated by the C index,calibration curve and decision curve analysis.Data were analyzed by using IBM SPSS Statistics version 23.0 and R software 4.0.2.Chapter two:All included patients in training set and testing set were analyzed together.The primary outcome was in-hospital death,and the secondary outcomes included ICU admission,need for invasive mechanical ventilation,death within 14 days,death within 30 days,etc.The relationships between cardio-cerebrovascular events and clinical outcomes were explored through multivariate Cox regression analysis and survival curve analysis.In addition,all independent risk factors of poor prognosis were also identified.Data were analyzed by using IBM SPSS Statistics version 23.0.Chapter three:A systematic and comprehensive search was conducted in five databases:PubMed,Web of Science,Embase,Cochrane Library and medRxiv(https://www.medrxiv.org)from 1 December 2019 to 1 December 2020.Potentially relevant studies which reported the relationships between cardiovascular complications or events and ICU admission or death in patients with COVID-19 were identified.All related retrospective or prospective,observational or interventional,case-control or cohort studies were considered for inclusion.STATA software(version 12.0;Stata Corporation)was used for analysis,and the risk ratio(RR)and 95%confidence interval(95%CI)were calculated for dichotomous data.Results:Chapter One:A total of 1206 patients confirmed with COVID-19 were retrospectively enrolled in the study.Among them,844 patients were randomized to training set and 362 patients were included in the testing set.In the training set,91 patients(10.8%)were found to have composite cardio-cerebrovascular events.According to the results of regression analyses and the clinical practice,eight variables were included in the nomogram,including age,hemoptysis,consciousness,diastolic blood pressure,oxygenation index under 300,chronic heart disease(except for hypertension),neutrophil counts and blood urea nitrogen at admission.The C indexes were 0.827(0.783,0.872)in training set and 0.755(0.675,0.834)in testing set.The calibration curve and decision curve analysis indicated that the nomogram had superior predictive efficiency and clinical value.All patients were divided into Wuhan and Sichuan subgroups in terms of regions,with C indexes of 0.770(0.720,0.820)and 0.906(0.857,0.954),respectively.Finally,the other results of subgroup analyses were similar to the overall analyses,which showed that our results were robust and stable.Similarly,48 patients(5.7%)developed MACE in the training set.The predictive nomogram for MACE consisted of six variables:age,consciousness,oxygenation index under 300,lymphocyte counts,neutrophil counts and blood urea nitrogen.The C indexes were 0.933(0.899,0.966)in training set,0.814(0.699,0.928)in testing set,0.889(0.842,0.935)in Wuhan subgroup and 0.970(0.920,1.019)in Sichuan subgroup.The performance of nomogram was verified via calibration curves,decision curve analysis and subgroup analyses.Chapter two:Finally,a total of 58 patients(4.8%)died in hospitals.The acute myocardial infarction(HR:2.778,95%CI:1.133,6.813),new or worsening HF(HR:2.666,95%CI:1.055,6.736),de novo arrhythmia(HR:2.384,95%CI:1.267,4.485)and composite cardio-cerebrovascular events(HR:1.610,95%CI:1.211,2.140)were all independent risk factors for in-hospital death.The other independent risk factors included age,respiratory rate,Glasgow Coma Score,lymphocyte count,blood urea nitrogen,serum creatinine,C-reactive protein,chronic heart disease(except for hypertension),D-dimer,white blood cells,etc.Survival curve analysis and Log rank test(P<0.001)showed that composite cardio-cerebrovascular events had significant adverse impacts on prognosis of COVID-19 patients.The subgroup analyses had similar results.As for the secondary outcomes,the cardio-cerebrovascular events were associated with ICU admissions,required for invasive mechanical ventilation,death within 14 days and death within 30 days.Chapter three:A total of 26 researches of 5511 patients with COVID-19 were included in the meta-analysis.Acute myocardial injury was significantly associated with in-hospital death(RR:4.93,95%CI:3.29,7.38,P<0.001;I2=93.9%,P<0.001)and ICU admission(RR:4.20,95%CI:2.29,7.69,P<0.001;I2=88.9%,P<0.001);new or worsening HF was associated with increased in-hospital mortality(RR:3.36,95%CI:2.80,4.02,P<0.001;I2=5.3%,P=0.366);DVT or PE was significantly associated with ICU admission(RR:3.09,95%CI:2.32,4.12,P<0.001;I2=10.1%,P=0.342);de novo arrhythmia increased the in-hospital mortality(RR:2.87,95%CI:1.23,6.73,P=0.015;I2=81.7%,P=0.001).According to the GRADE approach,these outcomes were all low certainty of evidence.The sensitivity analysis,subgroup analysis and meta-regression analysis did not identify specific sources of heterogeneity.Potential publication bias did not significantly change our conclusions.Conclusion:The current study developed and validated a prediction model with superior predictive efficiency and clinical value for composite cardio-cerebrovascular events and MACE during hospitalizations of COVID-19 patients.The significant adverse effects of individual and composite cardio-cerebrovascular events on prognosis among COVID-19 patients were confirmed through original research and meta-analysis.More studies are warranted to confirm or improve our conclusions in the future. |
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