Data Management And Sharing System of China National Clinical Research Center for Neurological Diseases

Journal：Journal of the American Heart Association

Publication type: Original Articles

IF(IF): 5.501

PMID: 33412918 Link To Pubmed Full text Download

Fibrinogen is a pleiotropic protein secreted from liver[1] with critical roles in coagulation, proinflammatory cascade and impeding tissue repair[2]. D-dimer is a fibrinogen degradation product that reflects thrombus formation and breakdown[3]. Development of immunological detection for fibrinogen and d-dimer[3, 4] has strengthened the application to measure plasma coagulation indicators, which are often quantified within 2 h of blood collection. For the limitation of blood sample storage, fibrinogen detection is lack of accuracy [5, 6], which causes few multicenter clinical data and very little clinical value of fibrinogen assay. Accurate centralized detection of plasma coagulation indicators enhances the potential clinical application of fibrinogen and d-dimer from risk stratification of cardiovascular disease (CVD) biomarkers in community-based studies[7, 8] to prediction of secondary prevention of stroke in clinical practices[9-12]. Furthermore, numerous studies have discussed the relationship between fibrinogen and d-dimer levels and incidence of stroke and CVD in general population [13-18]. Fibrinogen and d-dimer have been measured to explore the correlation with stroke outcome in patients with previous history of stroke or acute stroke[10, 19, 20]. Perhaps increased fibrinogen and d-dimer levels suggested poor clinical outcomes of stroke patients. Nevertheless, the results were limited and controversial. Especially in acute stroke studies, there were only single-central, small cohort studies. In our study, we measured fibrinogen and d-dimer in CNSRⅢ (Chinese National Stroke Registration-Ⅲ), a nationwide, multicentre, prospective registry for patients with ischemic cerebrovasular disease. We further evaluated whether acute-phase or stable-phase fibrinogen and d-dimer levels are associated occurrences of recurrent stroke, and combined vascular events, and fatal and disabling stroke.

Study population CNSRⅢ study (Chinese National Stroke Registration-Ⅲ) was a nationwide, consecutive, multicentre, prospective registry trail that enrolled 15166 patients with acute ischemic cerebral disease within 7 days of symptom onset from 171 centers. The study protocol was approved by the ethics committee at each study center. All participants or their legal proxies provided written informed consent. Participants were aged 18 years or older who were excluded with silent ischemic stroke with no symptoms or signs at study entry (2015-2017). Acute ischemic cerebral disease was diagnosed according to the World Health Organization criteria[21] and confirmed by brain computed tomography or magnetic resonance. All the participating centers were consistent with diagnostic criteria across with a standard protocol. The unique identifier of CNSRⅢ was NCT00979589. Biomarker Measurements EDTA plasma samples from CNSRⅢ were obtained at the time of enrollment and at 3-month follow-up and stored at -80℃. No freezing and thawing circle occurred before test. Fibrinogen and d-dimer were measured (from February 2018 to February 2019) in a core laboratory certified by the College of Amercian Pathologists with laboratory personnel blinded to clinical data. Both biomarkers were analyzed using an immunoturbidimetric assay which is a mass–based assay with international standards (Kamiya Biomedical, Seattle, Wash)[22] and were performed according to manufacturers’ recommendations. The coefficients of variation obtained from blinded simultaneously analyzed quality controls were ＜5% for fibrinogen and ＜3% for d-dimer. Patients Follow up and Outcomes Assessed Participants were followed up for 3 months and 1 year after enrollment from August 2015 and March 2018. All follow-up visits were face-to-face and end point event information was collected with assessment of modified Rankin Scale (mRS) score ranging from 0 to 6. The outcomes were recurrent stroke (ischemic or hemorrhagic), combined vascular evens (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death) and occurrence of fatal and disabling stroke defined as mRS of 3 to 6 during 3 months and 1 year follow-up period. Statistical Analysis The demographic and clinical characteristics were analyzed in accordance with quartiles of the fibrinogen with χ 2 statistics for categorical variables and analysis of variance or Kruskal–Wallis test for continuous variables, respectively. We analyzed fibrinogen and d-dimer as categorical and continuous variables. For the categorical analyses, individuals were classified according to quartiles of fibrinogen and d-dimer distribution and the lowest measurement group was used as the reference group. For the continuous analyses, fibrinogen and d-dimer values were log-transformed respectively. Cox proportional hazards models were used to investigate the crude and multivariable-adjusted hazard ratios (HRs) with their 95% CIs for recurrent stroke and combined vascular evens, while odds ratios (OR) with their 95% CIs for fatal and disabling stroke defined as mRS of 3 to 6 during 3 months and 1 year follow-up period were estimated by using a logistic regression model. All covariates in the univariable analysis were included in the multivariable model. Model 1 was adjusted for age, gender, BMI, homocysteine level, and history of smoking, drinking, atrial fibrillation, hypertension, diabetes, dyslipidemia, ischemic stroke, TIA, myocardial infarction, angina pectoris, heart failure and venous thrombotic events. When comparing mRS, baseline NIHSS score was adjusted at the same time. Model 2 was adjusted for all variables in model 1 plus d-dimer or fibrinogen. The fibrinogen or d-dimer was analyzed continuously and as quartiles to investigate a potential dose–response relationship with the outcome of ischemic cerebral disease. All statistical analyses were performed with SAS software, version 9.4 (SAS Institute Inc, Cary, NC). All P values were 2-sided, with P values <0.05 considered to indicate statistical significance.