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OC-09 Usual care compared with long-term low-molecular-weight heparin in patients with cancer and proximal venous thrombosis
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4th Int. Conf. on Thrombosis and Hemostasis Issues in Cancer / Thrombosis Research 120 Suppl. 2 (2007) S145–S178
essential that LMWH plasma levels are high at the time of cancer cell inoculation. Administration of LMWH at 30 min prior to inoculation of B16 melanoma cells to the tail vein and LMWH treatment for the following 24 h reduced the number of lung metastases after 3 weeks with 75%. All other treatment regimes did not have any effect. Furthermore, we found that B16 melanoma cells but not K1735 melanoma cells expressed CD24, the ligand for P-selectin. It is concluded on the basis of our animal experiments that LMWHs inhibit cancer progression in particular when cancer cells are present in the circulation possibly by interfering with cancer cell-platelet interactions. It is unlikely that processes such as angiogenesis are involved because of the small time frame of LMWH effects when cancer cells are present in the ciruclation. Reference(s) [1] Falanga A, Piccioli A (2005) Curr Opin Pulm Med 11:403 407. [2] Niers TMH et al. (2007) Crit Rev Oncol Hematol 61:195 207. [3] Collen A et al. (2000) Cancer Res 60:6196 6200. [4] Marchetti M et al. (2007) Thromb Res: in press. (PMID: 17692905).
Plenary Session VII: Antithrombotics and cancer (II): prophylaxis and treatment of venous thromboembolism OC-09 Usual care compared with long-term low-molecular-weight heparin in patients with cancer and proximal venous thrombosis R.D. Hull *. University of Calgary, Calgary, Alta, Canada Background: Patients with cancer and venous thromboembolism are at high risk for recurrent venous thromboembolism. Lowmolecular-weight heparin, body-weight adjusted, avoids the need for anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy. A substantial clinical need exists for an alternative to long-term vitamin-K-antagonists. Objective: To evaluate the efficacy of long-term therapeutic dose low-molecular-weight heparin. Design: A multicentre randomized open-label clinical trial using objective outcome measures. Setting: Multicentre trial in Canada. Patients: Of 200 patients with cancer and acute proximal deep-vein thrombosis, 100 received usual care and 100 received tinzaparin. Intervention: Patients were randomized to receive long-term therapeutic tinzaparin or usual care with initial low-molecularweight heparin overlapped with long-term vitamin-K-antagonist therapy for 3 months. Measurements: Outcomes were assessed at 3 and 12 months. Results: Of 200 patients, 100 received usual care and 100 received tinzaparin. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P = 0.044; risk ratio = 0.44; absolute difference 9.0; 95% confidence interval [CI], 21.7 to 0.7). Bleeding occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference 3.0; 95% CI, 9.1 to 15.1). Bleeding was largely minor. In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 1 of 48 patients (2.1%) receiving usual care and 0 of 51 patients (0%) receiving tinzaparin. Mortality at 1 year was high; 47% in each group died, reflecting the severity of the cancers. Limitations: Because of the limited database in the literature, we also performed a systematic review. Conclusions: Our findings confirm the limited but benchmark data in the literature that low-molecular-weight heparin is more effective than usual care. A systematic review of the
literature showed that the summary treatment effect for recurrent venous thromboembolism favoured long-term low-molecular-weight heparin therapy, further emphasizing the superiority of long-term low-molecular-weight heparin therapy for preventing recurrent venous thromboembolism as compared with usual care. OC-10 Anticoagulant effects after termination of therapy using once weekly subcutaneous injections of idraparinux in patients with acute venous thromboembolism J. Harenberg1 *, C.H. Weiss2 , I. Joerg1 , T. Fenyvesi1 , G. Mikus3 . 1 IV. Department of Medicine, University Hospital Mannheim, Mannheim; 2 Department of Biometry and Medical Statistics, University Hospital Mannheim, Mannheim; 3 Department of Clinical Pharamcology and Pharmacoepidemiology, University of Heidelberg, Germany Introduction: Prophylaxis of recurrent venous thromboembolism (VTE) in patients with initial acute VTE has been investigated using fixed dose of once a week subcutaneous injection of Idraparinux. The Van Gogh DVT and PE studies compared Idraparinux versus INRadjusted Warfarin and the Van Gogh Extension study Idraprinux versus placebo. Treatment was performed without coagulation monitoring. Aim: Analysis of the anticoagulant effects after termination of the studies, because the anticoagulant effects of idraparinux may be required for patients in acute clinical settings. Methods: The anticoagulant effects of Idraparinux were analysed every 3 months upt to 15 months in 23 patients using anti-factor-Xa inhibition method (chromogenic substrate S2222 method), Heptest coagulation method, and prothrombin induced clotting time (PiCT) assay. The local ethics board accepted the study and patients gave written informed consent. Results: The Heptest and PiCT methods were prolonged in all patients’ blood for 9 to 15 months after therapy termination. The chromogenic assay method showed factor-Xa inhibition for the same period of follow-up. The elimination half-life of Idraparinux was calculated at 60.2 days using the aXa-assay and 107.7 days using Heptest (p < 0.0001). Activities of idraparinux were higher after 12 compared to 6 months of therapy using aXa and Heptest assays. Conclusion: Steady state condition of idraparinux are reached between 6 and 12 months of therapy. Heptest and PiCT determine anticoagulant activites in addition to the AT-mediated factor Xa inhibiton of idraparinux. Polymethylation of idraparinux leads to less negative charged sulfate groups compared to the parent compound and may lead in binding to non-antithrombin proteins.
4th Int. Conf. on Thrombosis and Hemostasis Issues in Cancer / Thrombosis Research 120 Suppl. 2 (2007) S145–S178
essential that LMWH plasma levels are high at the time of cancer cell inoculation. Administration of LMWH at 30 min prior to inoculation of B16 melanoma cells to the tail vein and LMWH treatment for the following 24 h reduced the number of lung metastases after 3 weeks with 75%. All other treatment regimes did not have any effect. Furthermore, we found that B16 melanoma cells but not K1735 melanoma cells expressed CD24, the ligand for P-selectin. It is concluded on the basis of our animal experiments that LMWHs inhibit cancer progression in particular when cancer cells are present in the circulation possibly by interfering with cancer cell-platelet interactions. It is unlikely that processes such as angiogenesis are involved because of the small time frame of LMWH effects when cancer cells are present in the ciruclation. Reference(s) [1] Falanga A, Piccioli A (2005) Curr Opin Pulm Med 11:403 407. [2] Niers TMH et al. (2007) Crit Rev Oncol Hematol 61:195 207. [3] Collen A et al. (2000) Cancer Res 60:6196 6200. [4] Marchetti M et al. (2007) Thromb Res: in press. (PMID: 17692905).
Plenary Session VII: Antithrombotics and cancer (II): prophylaxis and treatment of venous thromboembolism OC-09 Usual care compared with long-term low-molecular-weight heparin in patients with cancer and proximal venous thrombosis R.D. Hull *. University of Calgary, Calgary, Alta, Canada Background: Patients with cancer and venous thromboembolism are at high risk for recurrent venous thromboembolism. Lowmolecular-weight heparin, body-weight adjusted, avoids the need for anticoagulant monitoring and has been shown to be more effective than vitamin-K-antagonist therapy. A substantial clinical need exists for an alternative to long-term vitamin-K-antagonists. Objective: To evaluate the efficacy of long-term therapeutic dose low-molecular-weight heparin. Design: A multicentre randomized open-label clinical trial using objective outcome measures. Setting: Multicentre trial in Canada. Patients: Of 200 patients with cancer and acute proximal deep-vein thrombosis, 100 received usual care and 100 received tinzaparin. Intervention: Patients were randomized to receive long-term therapeutic tinzaparin or usual care with initial low-molecularweight heparin overlapped with long-term vitamin-K-antagonist therapy for 3 months. Measurements: Outcomes were assessed at 3 and 12 months. Results: Of 200 patients, 100 received usual care and 100 received tinzaparin. At 12 months, the usual-care group had an excess of recurrent venous thromboembolism; 16 of 100 (16%) versus 7 of 100 (7%) receiving low-molecular-weight heparin (P = 0.044; risk ratio = 0.44; absolute difference 9.0; 95% confidence interval [CI], 21.7 to 0.7). Bleeding occurred in 27 patients (27%) receiving tinzaparin and 24 patients (24%) receiving usual care (absolute difference 3.0; 95% CI, 9.1 to 15.1). Bleeding was largely minor. In patients without additional risk factors for bleeding at the time of randomization, major bleeding occurred in 1 of 48 patients (2.1%) receiving usual care and 0 of 51 patients (0%) receiving tinzaparin. Mortality at 1 year was high; 47% in each group died, reflecting the severity of the cancers. Limitations: Because of the limited database in the literature, we also performed a systematic review. Conclusions: Our findings confirm the limited but benchmark data in the literature that low-molecular-weight heparin is more effective than usual care. A systematic review of the
literature showed that the summary treatment effect for recurrent venous thromboembolism favoured long-term low-molecular-weight heparin therapy, further emphasizing the superiority of long-term low-molecular-weight heparin therapy for preventing recurrent venous thromboembolism as compared with usual care. OC-10 Anticoagulant effects after termination of therapy using once weekly subcutaneous injections of idraparinux in patients with acute venous thromboembolism J. Harenberg1 *, C.H. Weiss2 , I. Joerg1 , T. Fenyvesi1 , G. Mikus3 . 1 IV. Department of Medicine, University Hospital Mannheim, Mannheim; 2 Department of Biometry and Medical Statistics, University Hospital Mannheim, Mannheim; 3 Department of Clinical Pharamcology and Pharmacoepidemiology, University of Heidelberg, Germany Introduction: Prophylaxis of recurrent venous thromboembolism (VTE) in patients with initial acute VTE has been investigated using fixed dose of once a week subcutaneous injection of Idraparinux. The Van Gogh DVT and PE studies compared Idraparinux versus INRadjusted Warfarin and the Van Gogh Extension study Idraprinux versus placebo. Treatment was performed without coagulation monitoring. Aim: Analysis of the anticoagulant effects after termination of the studies, because the anticoagulant effects of idraparinux may be required for patients in acute clinical settings. Methods: The anticoagulant effects of Idraparinux were analysed every 3 months upt to 15 months in 23 patients using anti-factor-Xa inhibition method (chromogenic substrate S2222 method), Heptest coagulation method, and prothrombin induced clotting time (PiCT) assay. The local ethics board accepted the study and patients gave written informed consent. Results: The Heptest and PiCT methods were prolonged in all patients’ blood for 9 to 15 months after therapy termination. The chromogenic assay method showed factor-Xa inhibition for the same period of follow-up. The elimination half-life of Idraparinux was calculated at 60.2 days using the aXa-assay and 107.7 days using Heptest (p < 0.0001). Activities of idraparinux were higher after 12 compared to 6 months of therapy using aXa and Heptest assays. Conclusion: Steady state condition of idraparinux are reached between 6 and 12 months of therapy. Heptest and PiCT determine anticoagulant activites in addition to the AT-mediated factor Xa inhibiton of idraparinux. Polymethylation of idraparinux leads to less negative charged sulfate groups compared to the parent compound and may lead in binding to non-antithrombin proteins.