Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial

Abstract

To cite this article: Raps M, Rosendaal F, Ballieux B, Rosing J, Thomassen S, Helmerhorst F, van Vliet H. Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial. J Thromb Haemost 2013; 11: 855-61.Summary. Background: The use of combined oral contraceptives is associated with a 3-to 6-fold increased risk of venous thrombosis. This increased risk depends on the estrogen dose as well as the progestogen type of combined oral contraceptives. Thrombin generation-based activated protein C resistance (APC resistance) and sex hormone-binding globulin (SHBG) levels predict the thrombotic risk of a combined hormonal contraceptive. Recently, a four-phasic oral contraceptive containing dienogest (DNG) and estradiol valerate (E2V) has been marketed. The aim of this study was to evaluate the thrombotic risk of the DNG/E2V oral contraceptive by comparing APC resistance by measuring normalized APC sensitivity ratios (nAPCsr) and SHBG levels in users of oral contraceptives containing dienogest and estradiol valerate (DNG/E2V) and oral contraceptives containing levonorgestrel and ethinyl estradiol (LNG/EE). Methods: We conducted a single-center, randomized, open label, parallel-group study in 74 women using DNG/E2V or LNG/ EE, and measured nAPCsr and SHBG levels in every phase of the regimen of DNG/E2V. Results: During the pill cycle SHBG levels did not differ between DNG/E2V users and LNG/EE users. nAPCsr levels were overall slightly lower in DNG/E2V users than in LNG/EE users, mean difference À0.44 (95% CI, À1.04 to 0.17) for day 2, À0.20 (95% CI, À0.76 to 0.37) for day 7, À0.27 (95% CI, À0.81 to 0.28) for day 24 and À0.34 (95% CI, À0.91 to 0.24) for day 26. Conclusion: No statistical significant differences in nAPCsr and SHBG levels were found between users of the oral contraceptive containing DNG/E2V and LNG/EE, suggesting a comparable thrombotic risk Keywords: activated protein C resistance, natural estrogen, oral contraceptives, sex hormone binding globulin, thrombotic risk. IntroductionUse of combined oral contraceptives is associated with a 3-to 6-fold increased risk of venous thrombosis. This increased risk depends on the estrogen dose as well as the progestogen-type of combined oral contraceptives [1]. Socalled 'high-dose' combined oral contraceptives containing 50 lg or more ethinyl estradiol (EE) are associated with a 2-fold higher risk of thrombosis than 'low-dose' combined oral contraceptives containing 20-30 lg EE [2,3]. Furthermore, combined oral contraceptives containing the progestogens gestodene (GTD), desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP) increase the risk of venous thrombosis by a factor two compared with combined oral contraceptives containing levonorgestrel (LNG) [1][2][3][4][5][6][7][8][9][10].The differences in the risk of venous thrombosis can at least partially be explained by the different effects of various combined oral contraceptives on the resistance to activated protein...

Use of oral contraceptives for management of acne vulgaris and hirsutism in women of reproductive and late reproductive age

“…The relative risk of thrombosis during the use of norethisterone, levonorgestrel, and norgestimate is 2-3 with NNH: 2381-4762 [ 25 ]. Dienogest has a similar risk profile to levonorgestrel [ 38 ]. The relative risk of thrombosis during the use of desogestrel, gestodene, drospirenone, and contraceptive intravaginal rings was 4-6 with NNH: 952-1587 [ 39 ].…”

Noncontraceptive benefits of the estradiol valerate/dienogest combined oral contraceptive: a review of the literature

“…Of the other publications, one was a pooled study summarizing menstrual blood loss (MBL) data across two individual studies previously identified, and was included as appropriate 23. The other seven articles reported on outcomes that were not the focus of this review but were included, where appropriate, as supportive references 11,19–21,25–27. Ten other pertinent articles were identified from published manuscripts known to the authors or from unpublished manuscripts that were available to them and were included for discussion,14,29–37 but three others were not included as the outcomes reported were not the focus of this review 38–40.…”

Overview of the therapeutic possibilities of combined oral contraceptive containing estradiol valerate and dienogest

“…Так, в проспективном когортном исследовании INAS-SCORE, включавшем 50 203 участницы, доказано, что прием КОК, содержащих ЭВ и ДНГ, ассоциирован со схожим или более низким риском развития кардиоваскулярных осложнений в сравнении с КОК, содержащими левоноргестрел, и другими оральными контрацептивами [7]. В других исследованиях также показано, что препарат, содержащий ЭВ и ДНГ, имеет аналогичное или меньшее влияние на гемостаз по сравнению с монофазными КОК, содержащими этинилэстрадиол и левоноргестрел [8,9]. Авторы отмечают, что прием ЭВ/ ДНГ сопровождался значительно меньшим увеличением уровня D-димера (37% против 88% для ЭВ/ДНГ и этинилэстрадиола/левоноргестрела соответственно) и менее выраженным ростом уровня протромбина и фибриногена [9].…”