Prevention of Venous Thrombosis in Cancer Patients: A randomized, Double-Blind Study Comparing Two Different Dosages of Low-Molecular Weight Heparin.

Background: Cancer patients are at increased risk of venous thrombosis (VT). In surgical cancer patients a dose of about 5000 anti factor Xa (aXa) units of low molecular weight heparin (LMWH) prevents VT at acceptable safety with regard to bleeding. We hypothesize that non-surgical cancer patients at risk of VT could benefit from a higher LMWH dose.

Methods: We conducted a randomized, double-blind trial in 49 hospitalised non-surgical cancer patients with risk factors of VT. Patients received either enoxaparin 40 mg or 80 mg once daily subcutaneously. Outcome variables were markers of coagulation activation (D-Dimer), thrombin generation (peak thrombin level) and aXa levels determined in venous blood before enoxaparin on day 1 to 4 and 2, 4, and 6 hours after enoxaparin on day 1. D-Dimer was determined by enzyme immunoassay (Asserachrom® D-Di, Roche, Germany), and thrombin generation by use of a commercially available fluorogenic assay (Technothrombin TGA, Vienna, Austria).

Results: 22 patients were randomized to enoxaparin 40 mg and 27 to 80 mg. On day 1, D-dimer levels [median (range)] before administration of enoxaparin (=baseline) were elevated in both groups [40 mg: 957.0 ng/ml (254.1–4419.6); 80 mg: 1054.9 ng/ml (197.0–14761.0)]. D-Dimer levels only slightly decreased 6 hours after enoxaparin in both groups (p=0.001). D-Dimer baseline levels in the 80 mg group were significantly lower on day 4 [1785.6 ng/ml (128.4–13742.5)] than on day 1 (p=0.01), while in the 40 mg group no difference was seen. In patients receiving enoxaparin 40 mg, peak thrombin levels (mean±SD) at baseline were 434.8±29.7 nM and significantly decreased over time. Trough levels (171.8±30.9 nM) were reached after 4 hours. The decrease of peak thrombin levels was significantly more pronounced in the enoxaparin 80 mg group. Compared with baseline (407.8±18.9 nM), peak thrombin levels were 138.7±19.6, 86.6±19.9 and 82.8±19.9 nM after 2, 4 and 6 hours, respectively. Compared with baseline on day 1, peak thrombin levels in the 80 mg group were significantly lower on day 4 (317.5±28.3 nM; p=0.005), while no significant difference was seen in patients receiving 40 mg (p=0.5). aXa levels significantly increased with maximum levels at 4 hours in patients receiving enoxaparin 40 mg and at 6 hours in the 80 mg group. In none of the patients receiving enoxaparin 40 mg and in 3 of those receiving 80 mg, peak aXa levels exceeded 1.0 IU/ml. None of the patients had thrombotic or bleeding complications.

Conclusion: Non-surgical cancer patients exhibit a state of hypercoagulability. Compared with enoxaparin 40 mg, the extent of coagulation activation and thrombin generation can be significantly reduced by doubling the dose. These findings support the hypothesis that thromboprophylaxis with a standard dose of enoxaparin 40 mg once daily might be too low to provide optimal protection from VT in non-surgical cancer patients at high thrombotic risk. Interventional studies are needed to investigate safety and efficacy of a more intense thromboprophylactic regimen in these patients.