Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study

Background We have reported previously that, compared with use of second-ge neration oral contraceptives, the use of third-generation oral contraceptiv es is associated with increased resistance to the anticoagulant action of a ctivated protein C (APC). Owing to the cross-sectional design of that study , these observations may have been subject to unknown bias or uncontrolled effects of the menstrual cycle. We aimed to overcome these sources of bias by doing a cycle-controlled randomised cross-over trial. Methods The response to APC in plasma was assessed in 33 women who received two consecutive cycles of a second-generation oral contraceptive (150 mu g levonorgestrel and 30 mu g ethinyloestradiol) or a third-generation oral c ontraceptive (150 mu g desogestrel and 30 mu g ethinyloestradiol), and who switched preparations after two pill-free cycles. Normalised APC sensitivit y ratios were calculated by measurement of the effect of APC on thrombin ge neration in the plasma of these women and in pooled plasma from 90 controls . Findings Of the 33 women,five were excluded because not all required plasma samples were available. in the remaining 28 women, the normalised APC sens itivity ratio increased during treatment with both preparations. Compared w ith levonorgestrel, desogestrel-containing oral-contraceptive treatment cau sed a highly significant (p<0.0001) additional increase in normalised APC s ensitivity ratio (0.51 [95% CI 0.37-0.66]). Normalised APC sensitivity rati os during oral-contraceptive treatment correlated with the values before or al-contraceptive use. Interpretation Oral-contraceptive treatment diminishes the efficacy with wh ich APC down-regulates in-vitro thrombin formation. This phenomenon, design ated as acquired APC resistance, is more pronounced in women using desogest rel-containing oral contraceptives than in women using levonorgestrel-conta ining preparations. Whether acquired APC resistance induced by oral contrac eptives explains the increased risk of venous thromboembolism in oral-contr aceptive users remains to be established.