[en] [en] OBJECTIVE: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC).
STUDY DESIGN: In this randomized, single centre, open-label, exploratory study, healthy women received either 15 mg estetrol/3 mg drospirenone (E4/DRSP) (n = 39), 30 mcg ethinylestradiol/150 mcg levonorgestrel (EE/LNG) (n = 30), or 20 mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (n = 32) for six 28-day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG).
RESULTS: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value <0.05 vs E4/DRSP), and +219% for EE/DRSP (p-value <0.05 vs E4/DRSP). Changes to prothrombin fragment 1 + 2 and SHBG for E4/DRSP, EE/LNG, and EE/DRSP were +23%, +71%, and +64% (p-value <0.05 vs E4/DRSP); and +55%, +74% and +251% (p-value <0.05 vs E4/DRSP), respectively. At cycle 6, changes to other hemostasis parameters for E4/DRSP were similar or smaller than for EE/LNG or EE/DRSP.
CONCLUSIONS: In this study, changes in hemostasis parameters after treatment with 6 cycles of E4/DRSP were smaller or similar to those observed for EE/LNG. Similar, but more pronounced changes were also observed versus EE/DRSP, which supports the hypothesis that the effect of COCs on hemostasis parameters is mainly mediated by the estrogenic component. Further studies are needed to provide more insight into the venous thromboembolic risk of E4/DRSP.
IMPLICATIONS STATEMENT: This study reports that the effects on hemostasis parameters of a COC containing 15 mg E4/3 mg DRSP are less or similar to those for EE/LNG or EE/DRSP. It also demonstrates that the choice of estrogen modulates the effects of COCs on hemostasis parameters.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Douxfils, Jonathan; Qualiblood SA, Namur, Belgium, Department of Pharmacy, Namur Thrombosis and Hemostasis Center, NAmur Research Institute for LIfe Sciences, University of Namur, Namur, Belgium
Klipping, Christine; Dinox BV, Groningen, the Netherlands
Duijkers, Ingrid; Dinox BV, Groningen, the Netherlands
Kinet, Virginie ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire ; Estetra SPRL, an affiliate's company of Mithra Pharmaceuticals, Liège, Belgium
Mawet, Marie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique (CHR) ; Estetra SPRL, an affiliate's company of Mithra Pharmaceuticals, Liège, Belgium
Maillard, Catherine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement ; Estetra SPRL, an affiliate's company of Mithra Pharmaceuticals, Liège, Belgium
Jost, Maud ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement ; Estetra SPRL, an affiliate's company of Mithra Pharmaceuticals, Liège, Belgium. Electronic address: mjost@mithra.com
Rosing, Jan; Department of Biochemistry, Maastricht University, Maastricht, the Netherlands
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques
Language :
English
Title :
Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters.
Conflict of interest: J. Douxfils is the director and founder of Qualiblood, a contract research organization that received funding from Mithra for the conduct of the study. He also reports personal fees from Daiichi-Sankyo, Diagnostica Stago, Portola, Roche and Roche Diagnostics. J. Rosing has provided expert witness testimony relating to effects of hormonal contraceptives on blood coagulation and his laboratory executed several industry-sponsored studies on the effects of female sex hormones on coagulation. He reports personal fees from Mithra and from Pantharei Bioscience and Oncology.C. Klipping and I. Duijkers are directors of Dinox BV, a contract research organization that received funding from Mithra for the conduct of the study. V. Kinet, M. Mawet, C. Maillard and M. Jost are employees of Mithra. JM Foidart is a member of the board at Mithra and received financial support for the supervision of this study.The study was sponsored by Estetra SPRL, an affiliate's company of Mithra Pharmaceuticals , Liège, Belgium. Medical writing support was provided by Mireille Gerrits PharmD, at Terminal 4 Communications, Hilversum, the Netherlands. Statistical support was provided by Pharmalex Belgium, Mont-Saint-Guibert, Belgium.
Dahlback, B., Carlsson, M., Svensson, P.J., Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 90 (1993), 1004–1008.
Wu, O., Robertson, L., Langhorne, P., et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 94 (2005), 17–25.
Rosing, J., Tans, G., Nicolaes, G.A., et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 97 (1997), 233–238.
Tchaikovski, S.N., Rosing, J., Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 126 (2010), 5–11.
Lidegaard, O., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E., Lokkegaard, E., Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ, 343, 2011, d6423.
Westhoff, C.L., Pike, M.C., Cremers, S., Eisenberger, A., Thomassen, S., Rosing, J., Endogenous thrombin potential changes during the first cycle of oral contraceptive use. Contraception 95 (2017), 456–463.
Farris, M., Bastianelli, C., Rosato, E., Brosens, I., Benagiano, G., Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis. Expert Rev Clin Pharmacol 10 (2017), 1129–1144.
Dragoman, M.V., Tepper, N.K., Fu, R., Curtis, K.M., Chou, R., Gaffield, M.E., A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int J Gynaecol Obstet 141 (2018), 287–294.
Wiegratz, I., Kuhl, H., Metabolic and clinical effects of progestogens. Eur J Contracept Reprod Health Care 11 (2006), 153–161.
Agren, U.M., Anttila, M., Maenpaa-Liukko, K., et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17beta-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care 16 (2011), 444–457.
Gaussem, P., Alhenc-Gelas, M., Thomas, J.L., et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17beta-estradiol, compared with those of levonorgestrel/ethinyl estradiol. A double-blind, randomised study. Thromb Haemost 105 (2011), 560–567.
Fruzzetti, F., Cagnacci, A., Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?. Open Access J Contracept 9 (2018), 75–79.
Heinemann, K., Franke, C., Moehner, S., Do Minh, T., Dinger, J., Cardiovascular safety in users of different combined oral contraceptives – Final results from the INAS-SCORE study. Abstract FC-03. Eur J Contracept Reprod Health Care, 23, 2018, 40.
Holinka, C.F., Diczfalusy, E., Coelingh Bennink, H.J., Estetrol: a unique steroid in human pregnancy. J Steroid Biochem Mol Biol 110 (2008), 138–143.
Coelingh Bennink, H.J., Holinka, C.F., Diczfalusy, E., Estetrol review: profile and potential clinical applications. Climacteric 11:Suppl 1 (2008), 47–58.
Kluft, C., Zimmerman, Y., Mawet, M., et al. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception 95 (2017), 140–147.
Apter, D., Zimmerman, Y., Beekman, L., et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception 94 (2016), 366–373.
Apter, D., Zimmerman, Y., Beekman, L., et al. Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur J Contracept Reprod Health Care 22 (2017), 260–267.
Zia, A., Callaghan, M.U., Callaghan, J.H., et al. Hypercoagulability in adolescent girls on oral contraceptives-global coagulation profile and estrogen receptor polymorphisms. Am J Hematol 90 (2015), 725–731.
Folsom, A.R., Cushman, M., Heckbert, S.R., Ohira, T., Rasmussen-Torvik, L., Tsai, M.Y., Factor VII coagulant activity, factor VII -670A/C and -402G/A polymorphisms, and risk of venous thromboembolism. J Thromb Haemost: JTH 5 (2007), 1674–1678.
Marlar, R.A., Gausman, J.N., Protein S abnormalities: a diagnostic nightmare. Am J Hematol 86 (2011), 418–421.
Raps, M., Helmerhorst, F.M., Fleischer, K., et al. The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI. Thromb Haemost 109 (2013), 606–613.
Dahm, A., Van Hylckama Vlieg, A., Bendz, B., Rosendaal, F., Bertina, R.M., Sandset, P.M., Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 101 (2003), 4387–4392.
Curvers, J., Thomassen, M.C., Rimmer, J., et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb and Haemost 88 (2002), 5–11.
Kluft, C., Meijer, P., LaGuardia, K.D., Fisher, A.C., Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables. Contraception 77 (2008), 77–83.
Morimont, L., Dogńe, J.-M., Douxfils, J., Letter to the Editors-in-Chief in response to the article of Abou-Ismail, et al. entitled “Estrogen and thrombosis: A bench to bedside review” (Thrombosis Research 192 (2020) 40-51). Thromb Res. 193 (2020), 221–223.
Abot, A., Fontaine, C., Buscato, M., et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med 6 (2014), 1328–1346.
Mawet, M., Maillard, C., Klipping, C., Zimmerman, Y., Foidart, J.M., Coelingh Bennink, H.J., Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care 20 (2015), 463–475.
Douxfils, J., Morimont, L., Delvigne, A.S., et al. Validation and standardization of the ETP-based activated protein C resistance test for the clinical investigation of steroid contraceptives in women: an unmet clinical and regulatory need. Clin Chem Lab Med: CCLM / FESCC 58 (2020), 294–305.
