Long-term therapy with low-molecular-weight heparin in cancer patients with venous thromboembolism

Summary

Long-term therapy with low-molecular-weight heparin (LMWH) is the treatment of choice for cancer patients with venous thromboembolism (VTE). However, the ideal doses of LMWH have not been thoroughly studied. We used the RIETE Registry data to assess the influence of the daily LMWH dosage on outcome during the first three months after VTE. We used propensity score-matching to compare patients who received <150 vs. those receiving ≥150 UI/kg/day LMWH. Up to July 2010, 3,222 cancer patients with VTE received long-term therapy with fixed doses of LMWH. Of these, 1,472 (46%) received <150 IU/kg/day (mean, 112 ± 28), and 1,750 received ≥150 IU/kg/day (mean, 184 ± 32). Results of the propensity score matching involved 1269 matched pairs. During follow-up, the incidence of pulmonary embolism (PE) recurrences was similar (1.2% vs. 1.9%), but patients receiving <150 IU/kg/day LMWH had a lower incidence of fatal PE than those treated with ≥150 IU/kg/day (0.2% vs. 1.0%; p=0.004). Multivariate analysis confirmed that patients receiving <150 IU/kg/day LMWH had a lower risk for fatal PE (odds ratio [OR]: 0.2; 95% confidence interval [CI]: 0.06–0.8) and for major bleeding (OR: 0.6; 95% CI: 0.3–1.0) than those treated with ≥150 IU/kg/day. In real life, one in every two cancer patients with VTE received lower doses of LMWH than those used in randomised trials, with large variations from patient to patient. Unexpectedly, patients treated with <150 IU/kg/day LMWH had fewer fatal PE cases and fewer major bleeding events than those receiving ≥150 IU/kg/day LMWH. This finding, however, should be validated in prospective clinical trials.

Keywords

Cancer - heparins - venous thrombosis - pulmonary embolism

• References

• 1 Meyer G, Marjanovic Z, Valcke J. et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med 2002; 162: 1729-1735.
• 2 Lee AYY, Levine MN, Baker RI. et al. Low-molecular-weigh heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 34: 146-153.
• 3 Deitcher SR, Kessler CM, Merli G. et al. for the ONCENOX Investigators. Secondary prevention of venous thromboembolic events in patients with active cancer: Enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Haemost 2006; 12: 389-396.
• 4 Hull RD, Pineo GF, Brant RF. Et al. LITE Trial investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med. 2006; 119: 1062-1072.
• 5 Kearon C, Kahn SR, Agnelli G. et al. American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 454S-545S.
• 6 Wagman LD, Baird MF, Bennett CL. et al. National Comprehensive Cancer Network. Venous thromboembolic disease. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2008; 06: 716-753.
• 7 Lyman GH, Khorana AA, Falanga A. et al. American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490-5505.
• 8 Debourdeau P, Kassab Chahmi D. et al. 2008 SOR* French guidelines for the prevention and treatment of thrombosis associated with central venous catheters in patients with cancer: Report from the working group. Ann Oncol 2009; 20: 1459-1471.
• 9 Farge D, Kassab-Chahmi D, Bosquet L. et al. 2008 French national guidelines for the treatment of venous thromboembolism in patients with cancer: Report from the working group. Crit Rev Oncol Hematol 2010; 73: 31-46.
• 10 Khorana AA, Streiff MB, Farge D. et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. J Clin Oncol 2009; 27: 4919-4926.
• 11 Monreal M, Falgá C, Valdés M. et al for the RIETE Investigators. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: Findings from the RIETE Registry. J Thromb Haemost 2006; 04: 1950-1956.
• 12 Laporte S, Mismetti P, Découssus H. et al. RIETE investigators. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism; Findings from the registro informatizado de la enfermedad tromboembólica venosa (RIETE) Registry. Circulation 2008; 117: 1711-1716.
• 13 Trujillo-Santos Trujillo-Santos, Nieto JA, Tiberio G. et al. RIETE Registry. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100: 435-439.
• 14 Pini M, Aiello S, Manotti C. et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-197.
• 15 Das SK, Cohen AT, Edmonson RA. et al. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-527.
• 16 Lopaciuk S, Bielska-Falda H, Noszczyk W. et al. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999; 81: 26-31.
• 17 Gonzalez-Fajardo J, Arreba W, Castrodeza J. et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep vein thrombosis. J Vasc Surg 1999; 30: 283-292.
• 18 Veiga F, Escriba A, Maluenda M. et al. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep vein thrombosis in the elderly: a randomized trial. Thromb Haemost 2000; 84: 559-564.
• 19 Lopez-Beret P, Orgaz A, Fontcuberta J. et al. Low-molecular weight heparin versus oral anticoagulant in the long-term treatment of deep venous thrombosis. J Vasc Surg 2001; 33: 77-90.
• 20 Hull R, Pineo G, Mah AF. The LITE Investigators. Long-term low molecular weight heparin treatment versus oral anticoagulant therapy for proximal deep vein thrombosis. Blood 2000; 96: 1933 (Abstract).
• 21 Iorio A, Guercini F, Pini M. Low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism: meta-analysis of the randomized comparisons with oral anticoagulants. J Thromb Haemost 2003; 01: 1906-1913.
• 22 D’Agostino Jr. RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998; 17: 2265-2281.
• 23 Ruíz-Giménez N, Suárez C, González R. et al. RIETE Investigators. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100: 26-31.
• 24 Nieto JA, Solano R, Ruiz-Ribó MD. et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism. Findings from the RIETE Registry. J Thromb Haemost 2010; 08: 1216-1222.