ORLANDO, Fla.—A prospective phase 2 study of the low-molecular-weight heparin (LMWH) tinzaparin for initial treatment and secondary prophylaxis of venous thromboembolism (VTE) associated with cancer treatment found the agent to be safe and efficacious, with the recurrent VTE event rate comparing favorably with that reported for another LMWH, dalteparin.
VTE, a major complication in patients with cancer, is associated with a higher risk of recurrent VTE and bleeding when treated with unfractionated or low-molecular-weight heparin (LMWH) followed by warfarin. Recently, a randomized trial found that initial treatment and secondary prophylaxis with LMWH was associated with a lower recurrence of VTE compared with secondary prophylaxis with warfarin.
To evaluate the efficacy and safety of once-daily tinzaparin for initial treatment and extended prophylaxis in patients with cancer, Scott T. Tagawa, MD, Weill Medical College of Cornell University, New York, and colleagues initiated a single-arm phase 2 study that included a prospective analysis of plasma biomarkers to assess whether any could predict treatment failure or be predictive of patient survival.
Patients eligible for the study included those with objectively confirmed symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or unexpected PE detected on staging CT scans using O’Connell criteria (J Clin Oncol. 2006;24:4928-32), ECOG score ≤2, and an estimated survival of 6 months. Planned enrollment was 100 patients. Treatment was initiated with tinzaparin 175 U/kg for 6 months; those who completed the 6-month study could continue tinzaparin for an additional 6 months if clinically appropriate. All patients who received at least one injection of tinzaparin were evaluable for safety and efficacy. Study end points were objectively confirmed DVT, PE, or major bleeding events.
Of 93 patients treated, 40 (43%) completed 6 months; 6 (6.5%) remained on active treatment, and 45 (48%) had died before 6 months. Study withdrawals included 8 (8.8%) for hospice care and 1 for poor compliance. Ten patients (10.7%) continued on treatment after 6 months and 2 patients transitioned to treatment with warfarin.
Eleven patients (11.8%) had a recurrent VTE (8 DVT, 3 PE), 2 of which occurred within the first 4 weeks on treatment and 9 before month 3. No recurrent VTE occurred after 12 weeks. These findings are comparable to the 8% reported for dalteparin. In addition, 3 patients (3%) who had major bleeding events compared favorably with those in the Comparison of Low Molecular Weight Heparin versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism (CLOT) trial (Lee et al. N Engl J Med. 2003;349:146-53.), Dr. Tagawa reported in a poster presentation during the 52nd American Society of Hematology Meeting and Exposition. No patients had fatal thrombotic or bleeding events and all deaths were considered to be due to progressive cancer, although a possible fatal VTE may have occurred in patients who died at home or in hospice.
Serial blood samples were obtained pretreatment, at 1 week, and at 1, 3, and 6 months. D-dimer, thrombin-antithrombin complex, interleukin-6, interleukin-8, and plasma tissue factor were analyzed in patients who had blood samples collected at pretreatment, 1 week, and 1 month.
Seventy-seven patients (82.7%) were evaluable for biomarker assessment. Biomarker data failed to show a correlation between D-dimer, thrombin-antithrombin complex, or interleukin-6 levels and survival from time of thrombotic event. In those who developed recurrent VTE after 1 month, D-dimer level at month 1 was higher than the pretreatment level in 4 of 6 patients (66.7%) vs 10 of 71 patients (14%) without VTE recurrence. The reason for failure of tinzaparin to suppress thrombin generation effectively in these patients remains unexplained, the investigators concluded.