Effect of raloxifene therapy on venous thromboembolism in postmenopausal women: A meta-analysis

Summary

Raloxifene, a selective estrogen receptor modulator, is indicated for the prevention of osteoporosis in postmenopausal women. However, its effect on the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) is unclear. Therefore, we conducted a meta-analysis to evaluate the effect of raloxifene on these outcomes. To identify randomized controlled trials of raloxifene, a systematic search of PubMed, EMBASE, and Cochrane Collaboration databases was performed from the date of inception of these databases to October 2007. Search was limited to trials that were published in peer-reviewed English-language medical journals. Articles were included in the meta-analysis if they had reported on DVT, PE, or thromboembolic events. Nine trials, including 24,523 postmenopausal women, (median age 59.4 years, range 55 to 67 years; median follow-up 24 months, range 3 to 67 months) met inclusion criteria. Therapy with raloxifene was associated with a 62% increase in odds of either DVT or PE (odds ratio = 1.62; 95% confidence interval = 1.25 to 2.09; p-value < 0.001). Similarly, raloxifene therapy was associated with 54% increase in odds of DVT (odds ratio = 1.54; 95% confidence interval = 1.13 to 2.11; p-value = 0.006) and 91% increase in odds of PE alone (odds ratio = 1.91;95% confidence interval = 1.05 to 3.47; p-value = 0.03). Raloxifene increases the risk of DVT and PE in postmenopausal women.

Keywords

Raloxifene - deep venous thrombosis - pulmonary embolism - venous thromboembolism

• References

• 1 Thiebaud D, Secrest RJ. Selective estrogen receptor modulators: mechanism of action and clinical experience. Focus on raloxifene. Reprod Fertil Dev 2001; 13: 331-336.
• 2 Delmas PD, Bjarnason NH, Mitlak BH. et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337: 1641-1647.
• 3 Bevers TB. Raloxifene and the prevention of breast cancer. Expert Opin Pharmacother 2006; 7: 2301-2307.
• 4 Eilertsen AL, Sandvik L, Mowinckel MC. et al. Differential effects of conventional and low dose oral hormone therapy (HT), tibolone, and raloxifene on coagulation and fibrinolysis. Thromb Res 2007; 120: 371-379.
• 5 Azevedo GD, Franco RF, Baggio MS. et al. Procoagulant state after raloxifene therapy in postmenopausal women. Fertil Steril 2005; 84: 1680-1684.
• 6 Cosman F, Baz-Hecht M, Cushman M. et al. Shortterm effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res 2005; 116: 1-13.
• 7 Delmas PD, Ensrud KE, Adachi JD. et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002; 87: 3609-3617.
• 8 Barrett-Connor E, Mosca L, Collins P. et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355: 125-137.
• 9 Egger M, Davey Smith G, Schneider M. et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634.
• 10 Duval S, Tweedie R. Trim and fill: A simple funnelplot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455-463.
• 11 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12.
• 12 Martino S, Cauley JA, Barrett-Connor E. et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004; 96: 1751-1761.
• 13 Johnston Jr. CC, Bjarnason NH, Cohen FJ. et al. Long-term effects of raloxifene on bone mineral density, bone turnover, and serum lipid levels in early postmenopausal women: three-year data from 2 doubleblind, randomized, placebo-controlled trials. Arch Intern Med 2000; 160: 3444-3450.
• 14 de Valk-de Roo GW, Stehouwer CD, Meijer P. et al. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol 1999; 19: 2993-3000.
• 15 McClung MR, Siris E, Cummings S. et al. Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene. Menopause 2006; 13: 377-386.
• 16 Kessel B, Nachtigall L, Plouffe L. et al. Effect of raloxifene on sexual function in postmenopausal women. Climacteric 2003; 6: 248-256.
• 17 Palacios S, Farias ML, Luebbert H. et al. Raloxifene is not associated with biologically relevant changes in hot flushes in postmenopausal women for whom therapy is appropriate. Am J Obstet Gynecol 2004; 191: 121-131.
• 18 Reginster JY, Felsenberg D, Pavo I. et al. Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized, controlled trial. Osteoporos Int 2003; 14: 741-749.
• 19 US Department of Health and Human Services. Bone Health and Osteoporosis A Report of the Surgeon General. US Dept of Health and Human Services. Public Health Service, Office of the Surgeon General; Rockville, MD: 2004
• 20 Anderson GL, Limacher M, Assaf AR. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2004; 291: 1701-1712.
• 21 Grady D, Herrington D, Bittner V. et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). J Am Med Assoc 2002; 288: 49-57.
• 22 Santos ME. Hormone replacement therapy and venous disease. Acta Chir Belg 2006; 106: 659-661.
• 23 Walsh BW, Kuller LH, Wild RA. et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. J Am Med Assoc 1998; 279: 1445-1451.
• 24 Vogelvang TE, Mijatovic V, van der Mooren MJ. et al. Effect of raloxifene and hormone therapy on serum markers of brain and whole-body cholesterol metabolism in postmenopausal women. Maturitas 2005; 50: 312-320.
• 25 Dias Jr. AR, Melo RN, Gebara OC. et al. Effects of conjugated equine estrogens or raloxifene on lipid profile, coagulation and fibrinolysis factors in postmenopausal women. Climacteric 2005; 8: 63-70.
• 26 Andersson B, Johannsson G, Holm G. et al. Raloxifene does not affect insulin sensitivity or glycemic control in postmenopausal women with type 2 diabetes mellitus: a randomized clinical trial. J Clin Endocrinol Metab 2002; 87: 122-128.
• 27 Ozeren M, Karahan SC, Ozgur M. et al. The effects of short-term raloxifene therapy on fibrinolysis markers: TAFI, tPA, and PAI-1. Acta Obstet Gynecol Scand 2005; 84: 987-991.
• 28 Eilertsen AL, Liestol S, Mowinckel MC. et al. Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007; 97: 938-943.
• 29 Eilertsen AL, Qvigstad E, Andersen TO. et al. Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation. Maturitas 2006; 55: 278-287.
• 30 Dahm AE, Iversen N, Birkenes B. et al. Estrogens, selective estrogen receptor modulators, and a selective estrogen receptor down-regulator inhibit endothelial production of tissue factor pathway inhibitor 1. BMC Cardiovasc Disord 2006; 6: 40.
• 31 Egger M, Smith GD. Principles of and procedures for systematic reviews. Egger M, Smith GD, Altman DG. Systematic Reviews in Health Care.. Second BMJ Publishing Group; London: 2001: 23-42.