Chronic Venous Disease as a Prognostic Factor for Venous Thromboembolism: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review aimed to evaluate chronic venous disease as a prognostic factor for subsequent venous thromboembolism. DATA SOURCES: PubMed, Scopus, and Web of Science were systematically searched. REVIEW METHODS: This systematic review was conducted according to Cochrane Prognosis Methods Group guidance and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The primary outcome was venous thromboembolism, defined as deep vein thrombosis and/or pulmonary embolism. Certainty of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: Seven longitudinal, prognostic factor studies including 3 760 257 participants were included, of whom 702 325 had chronic venous disease and 3 057 932 served as controls. Six studies evaluated varicose veins, whereas one more broadly evaluated chronic venous disease. Pooled unadjusted analysis identified an increased risk of venous thromboembolism (risk ratio [RR] 2.25, 95% confidence interval [CI] 2.09 - 2.43, I2 = 0%; p = .83) (moderate certainty of evidence) and deep vein thrombosis (RR 5.23, 95% CI 4.92 - 5.56, I2 = 64.6%; p = .059) (moderate certainty of evidence) among chronic venous disease individuals compared with controls. Crude time to event analysis replicated these findings, demonstrating an increased venous thromboembolism hazard among the chronic venous disease group (hazard ratio [HR] 2.52, 95% CI 1.88 - 3.37, I2 = 0%; p = .79) (moderate certainty of evidence). However, in the adjusted time to event analysis, which included two studies comprising 2 320 327 participants, the association was attenuated and fell marginally short of statistical significance (adjusted HR 1.76, 95% CI 0.97 - 3.19, I2 = 74.0%; p = .050) (very low certainty of evidence). CONCLUSIONS: Although the available evidence, predominantly derived from studies evaluating varicose veins, consistently indicated higher unadjusted venous thromboembolism estimates among chronic venous disease individuals, adjusted prognostic data were limited and heterogeneous, resulting in very low certainty. Chronic venous disease may represent a clinically relevant marker of subsequent venous thromboembolism, but the magnitude and independence of this prognostic effect remain uncertain, highlighting the need for adequately adjusted longitudinal studies.