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Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7248-7250 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.7897
Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Long-Term Treatment of Symptomatic Venous Thromboembolism: Is There Any Difference in Cancer-Related Mortality?
Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy To the Editor: Patients affected by advanced cancer are likely to develop venous thromboembolism (VTE). Its onset can increase comorbidities, diminishing the patient's quality of life and often compromising the regular administration of chemotherapy. Patients with malignancy treated with oral anticoagulant therapy (OAT) have a higher rate of bleeding, and possibly, an increased risk of recurrent VTE compared with patients without malignancy.1 Secondary prophylaxis with low-molecular-weight heparin (LMWH) may be a more effective and practical alternative to OAT in cancer patients. Lee et al reported the results of a large multicenter prospective trial in which 672 cancer patients were randomly assigned to receive LMWH or OAT for 6 months.2 No differences were found between the two arms regarding death for all causes (P = .53). The results of a meta-analysis of nine randomized trials demonstrated a statistically significant difference (approximately 40%) in the 3-month mortality in favor of LMWH, relative to unfractionated heparin, when given as the initial treatment for VTE in cancer patients.3 Lee et al4 have hypothesized that, in patients with solid tumors who were not known to have metastatic disease at the time of their thromboembolic event, impairing the establishment of tumor-related vasculature by a putative antiangiogenic agent such as LMWH could exert an inhibitory effect on tumor growth even beyond the time of drug exposure. However, the statistically significant improvement associated with dalteparin over OAT demonstrated in overall survival (death for any cause) in patients affected by nonmetastatic disease (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03) was not actually explored in specific cancer-related mortality as well. By these perspectives, we performed a literature-based pooled analysis to summarize the results of the randomized trials concerning cancer-related death during anticoagulant therapy and follow-up in cancer patients receiving LWMH or OAT. Event-based relative risk ratios with 95% CIs were derived. Combined-effect estimation was computed with both random- and fixed-effect models. A heterogeneity test was applied as well. We found two randomized clinical trials2,5 and one meta-analysis6 in which cancer-related death in cancer patients during anticoagulant therapy and follow-up was analyzed. Considering all the 944 patients eligible for this analysis, no difference was found in cancer-related death between cancer patients receiving LWMH and those given OAT (risk ratio, 0.92; 95% CI, 0.79 to 1.08; P = .35; Fig 1). No difference was observed applying both the fixed- and the random-effect model. This result resembles that reported by CLOT investigators concerning the probability of death from all causes (P = .53).2
None of these studies was primarily designed to investigate the effect of LMWH or OAT on cancer-related mortality. The drawbacks of a published-based meta-analysis, the discrepancies among studies in anticoagulant therapy dosage and duration must be taken into account. However, the absence of a significant heterogeneity (P = .42) suggests the consistency of these results. In our opinion, although prolonged treatment with LMWH in cancer patients has been reported to be more effective2 and safer4,7 than OAT, the potential advantage in survival remains still controversial. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Palareti G, Legnani C, Lee A, et al: A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 84:805-810, 2000[Medline]
2. Lee AY, Levine MN, Baker RI, et al: Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146-153, 2003 3. Hettiarachchi RJ, Smorenburg SM, Ginsberg J, et al: Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb Haemost 82:947-952, 1999[Medline]
4. Lee AYY, Rickles FR, Julian JA, et al: Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:2123-2129, 2005
5. 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: A randomized controlled study. Arch Intern Med 162:1729-1735, 2002 6. 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 1:1906-1913, 2003[CrossRef][Medline] 7. Hull RD, Pineo GF, Mah AF, et al: A randomized trial evaluating long-term low-molecular-weight heparin therapy for three months versus intravenous heparin followed by warfarin sodium. Blood 100:148a, 2002 (abstr 556)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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