Dynamic assessment of venous thromboembolism risk in patients with cancer by longitudinal D‐Dimer analysis: A prospective study

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of cancer. Elevated D‐dimer is associated with an increased risk of cancer‐associated VTE. Whether changes in D‐dimer over time harbor additional prognostic information that may be exploited clinically for dynamic prediction of VTE is unclear. OBJECTIVES: To explore the potential role of longitudinal D‐dimer trajectories for personalized prediction of cancer‐associated VTE. PATIENTS/METHODS: A total of 167 patients with active malignancy were prospectively enrolled (gastrointestinal: n = 59 [35%], lung: n = 56 [34%], brain: n = 50 [30%], others: n = 2 [1%]; metastatic disease: n = 74 [44%]). D‐dimer (median = 0.8 µg/mL [25th‐75th percentile: 0.4‐2.0]) was measured at baseline and during 602 monthly follow‐up visits. Joint models of longitudinal and time‐to‐event data were implemented to quantify the association between D‐dimer trajectories and prospective risk of VTE. RESULTS: VTE occurred in 20 patients (250‐day VTE risk = 12.1%, 95% confidence interval [CI], 7.8‐18.5). D‐dimer increased by 34%/month (0.47 µg/mL/month, 95% CI, 0.22‐0.72, P < .0001) in patients who developed VTE, but remained constant in patients who did not develop VTE (change/month = −0.06 µg/mL, 95% CI, −0.15 to 0.02, P = .121). In joint modeling, a doubling of the D‐dimer trajectory was associated with a 2.8‐fold increase in the risk of VTE (hazard ratio = 2.78, 95% CI, 1.69‐4.58, P < .0001). This finding was independent of established VTE risk factors. Highly personalized, dynamic predictions of VTE conditional on individual patients’ D‐dimer trajectories could be obtained. CONCLUSIONS: D‐dimer increases before the onset of cancer‐associated VTE, but remains constant over time in patients without VTE. This study represents proof‐of‐concept that longitudinal trajectories of D‐Dimer may advance the personalized assessment of VTE risk in the oncologic setting.