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-generation oral contraceptives, the use of third-generation oral contraceptives is associated with increased resistance to the anticoagulant action of activated protein C (AFC). 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 AFC in plasma was assessed in 33 women who received two consecutive cycles of a second-generation oral contraceptive (150 μg levonorgestrel and 30 μg ethinyloestradiol) or a third-generation oral contraceptive (150 μg desogestrel and 30 μg ethinyloestradiol), and who switched preparations after two pill-free cycles. Normalised AFC sensitivity ratios were calculated by measurement of the effect of AFC on thrombin generation 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 AFC sensitivity ratio increased during treatment with both preparations. Compared with levonorgestiel, desogestrel-containing oral-contraceptive treatment caused a highly significant (p<0•0001) additional increase in normalised AFC sensitivity ratio (0•51 [95% CI 0•37–0•66]). Normalised AFC sensitivity ratios during oral-contraceptive treatment correlated with the values before oral-contraceptive use. Interpretation Oral-contraceptive treatment diminishes the efficacy with which AFC down-regulates in-vitro thrombin formation. This phenomenon, designated as acquired AFC resistance, is more pronounced in women using desogestrel-containing oral contraceptives than in women using levonorgestrel-containing preparations. Whether acquired AFC resistance induced by oral contraceptives explains the increased risk of venous thromboembolism in oral-contraceptive users remains to be established.