RESUMO
INTRODUCTION: VTE is a major complication in cancer patients. Despite treatment with low molecular weight heparin (LMWH), 9% will have recurrent VTE within 6 months. Measurement of plasma biomarkers in cancer patients receiving LMWH may be predictive of recurrent VTE or overall survival (OS). AIM: We conducted a single arm phase 2 study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis of VTE in cancer patients. The study included a prospective analysis of plasma biomarkers D-dimer and IL-6 to assess whether these were predictive of recurrent VTE or OS. MATERIALS AND METHODS: Consecutive patients with active cancer diagnosed with a pulmonary embolism (PE) and/or proximal deep venous thrombosis (DVT) at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles County Medical Center, or New York Presbyterian - Weill Cornell Medical Center were invited to participate in this study with a target enrollment of 100 patients. Key eligibility criteria included: age ≥18, ECOG score ≤2, adequate organ function, and ≥6 month estimated survival. Patients were treated with daily subcutaneously tinzaparin 175 U/kg for 6 months on study. Tinzaparin could be continued ≤1 year at the discretion of the treating physician. All patients who received ≥1 dose were evaluable for efficacy and safety. Primary study endpoints were recurrent VTE or major bleeding. Secondary outcome measures included OS and plasma biomarkers. Biomarkers were measured at baseline, 7 days, 1 month and 6 months after tinzaparin initiation. Patients who had baseline and 1 week or 1 month samples collected were included in the biomarker analysis. RESULTS: 97 patients were enrolled. 2 patients were ineligible. 8 patients did not have baseline or follow-up biomarkers completed. 87 patients were included in the analysis. 28 (32%) of patients completed≥6 months of tinzaparin. Major bleeding occurred in 2 patients. 11 patients had recurrent VTE at 6 months (3 PE, 7 DVT, 1 central venous thrombosis not associated with a catheter). Median baseline D-dimer level was 2759 ng/mL (range: 375-37,591). Median baseline IL-6 level was 9.4 pg/mL (range: 0.8-20.9). Baseline D-dimer>median was predictive of VTE recurrence at 6 months (p=.006). Baseline IL-6>median was not predictive of VTE recurrence at 6 months. Neither 1 month D-dimer or IL-6 levels were predictive of VTE recurrence at 6 months. D-dimer and IL-6 at baseline and at 1 month were not predictive of OS. CONCLUSIONS: In patients with active cancer and VTE treated with tinzaparin, baseline D-dimer levels above the median value were predictive of VTE recurrence at 6 months.
