Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC) In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 +/- 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n = 17), 60 mg raloxifene (n = 23),150 mg raloxifene (n = 20) or placebo (n = 23) for 24 months. At baseline and after 6,12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 +/- 2.4 years) randomly received 120 mg raloxifene (n = 15) or placebo (n = 15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/ medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 +/- 0.82 to 2.87 +/- 0.86 at 24 months (P < 0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance. (C) 2004 Lippincott Williams Wilkins.