Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol

Summary

Use of oral contraceptives (OC) that combine a progestogen with synthetic ethinyl estradiol (EE) is associated with increased risk of venous thromboembolism. NOMAC/E2 is a new monophasic OC that combines nomegestrol acetate (NOMAC), a highly selective progestogen, with 17β-estradiol (E2). The study objective was to compare the effects on markers of haemostasis of NOMAC/E2 (2.5 mg/1.5 mg) versus the second-generation OC, levonorgestrel (LNG)/EE (100 μg/20 μg). Healthy women (age 18–38 years) received once-daily treatment for three consecutive 28-day cycles in a double-blind, randomised study: either NOMAC/E2 for 24 days with a four-day placebo interval (n=45) or LNG/ EE for 21 days with a seven-day placebo interval (n=45) per cycle. Mean changes from baseline to end-of-treatment in coagulation markers, including prothrombin fragment 1+2 (primary endpoint), fibrinolysis markers and platelet functions were assessed. Mean prothrombin fragment 1+2 levels (primary endpoint) did not increase with NOMAC/E2 compared with LNG/EE ( –0.02 vs. +0.08 nM, p<0.01). Other significant differences between NOMAC/E2 and LNG/EE were mean changes in antithrombin (+0.3% vs. –4.4%, p<0.001), activated protein C resistance – normalised ratio (+0.20 vs. +0.46, p<0.01), D-dimer ( –53 vs. +43 ng/ml, p<0.001), plasminogen (+6% vs. +30%, p<0.0001) and plasminogen activator inhibitor-1 ( –3.1 vs. –8.0 ng/ml, p<0.001). There was no effect of either treatment on platelet aggregation. The NOMAC/E2 pill regimen has fewer adverse effects on blood biological coagulation and fibrinolysis markers than LNG/EE. This suggests that NOMAC/E2 could have a more favourable venous thromboembolism risk profile than LNG/EE; further epidemiological data are required to confirm this.

Keywords

Coagulation factors - estradiol - ethinylestradiol - fibrinolysis - progestogen

• References

• 1 Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study.. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 346: 1575-1582.
• 2 Blanco-Molina A, Rota LL, Di Micco P. et al. Venous thromboembolism during pregnancy, postpartum or during contraceptive use. Thromb Haemost 2010; 103: 306-311.
• 3 van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP. et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. Br Med J 2009; 339: b2921.
• 4 Lidegaard Ø, Løkkegaard E, Svendsen AL. et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. Br Med J 2009; 339: b2890.
• 5 Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update 2006; 12: 169-178.
• 6 Toy JL, Davies JA, Hancock KW. et al. The comparative effects of a synthetic and a ‘natural’ oestrogen on the haemostatic mechanism in patients with primary amenorrhoea. Br J Obstet Gynaecol 1978; 85: 359-362.
• 7 Sandset PM, Høibraaten E, Eilertsen AL. et al. Mechanisms of thrombosis related to hormone therapy. Thromb Res 2009; 123 (Suppl. 02) S70-73.
• 8 Norris LA, Devitt M, Bonnar J. The role of thromboxane A2 in increased whole blood platelet aggregation in oral contraceptive users. Thromb Res 1996; 81: 407-417.
• 9 Roell A, Schueller P, Schultz A. et al. Effect of oral contraceptives and ovarian cycle on platelet function. Platelets 2007; 18: 165-170.
• 10 Saleh AA, Ginsburg KA, Duchon TA. et al. Hormonal contraception and platelet function. Thromb Res 1995; 78: 363-367.
• 11 Guideline on clinical investigation of steroid contraceptives in women. London: European Medicines Agency; Committee for Medicinal Products for Human Use (CHMP) 2005. Available at http://www.ema.europa.eu./docs/en-GB/document-library/Scientific-guideline/2009/09/WC500003349.pdf
• 12 Tans G, van Hylckama Vlieg A, Thomassen MC. et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-470.
• 13 van Rooijen M, Silveira A, Hamsten A. et al. Sex hormone--binding globulin--a surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 2004; 190: 332-337.
• 14 Odlind V, Milsom I, Persson I. et al. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?. Acta Obstet Gynecol Scand 2002; 81: 482-490.
• 15 van Vliet HA, Rosendaal FR, Rosing J. et al. Sex hormone-binding globulin: an adequate surrogate marker for venous thromboembolism in women using new hormonal contraceptives. Contraception 2009; 79: 328-329 Author reply 329–330.
• 16 Endrikat J, Parke S, Trummer D. et al. Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive: results of two prospective, randomized, open-label studies. Contraception 2008; 78: 218-225.
• 17 Bazin B, Thevenot R, Bursaux C. et al. Effect of nomegestrol acetate, a new 19-norprogesterone derivative, on pituitary-ovarian function in women. Br J Obstet Gynaecol 1987; 94: 1199-1204.
• 18 Couzinet B, Young J, Brailly S. et al. The antigonadotropic activity of progestins (19-nortestosterone and 19-norprogesterone derivatives) is not mediated through the androgen receptor. J Clin Endocrinol Metab 1996; 81: 4218-4223.
• 19 Couzinet B, Young J, Kujas M. et al. The antigonadotropic activity of a 19-norprogesterone derivative is exerted both at the hypothalamic and pituitary levels in women. J Clin Endocrinol Metab 1999; 84: 4191-4196.
• 20 Basdevant A, Pelissier C, Conard J. et al. Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women. Contraception 1991; 44: 599-605.
• 21 Conard J, Basdevant A, Thomas JL. et al. Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol. Fertil Steril 1995; 64: 957-962.
• 22 The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study.. Oral Contraceptive and Hemostasis Study Group. Contraception 2003; 67: 173-185.
• 23 Basdevant A, Conard J, Pelissier C. et al. Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel. Contraception 1993; 48: 193-204.
• 24 Wiegratz I, Lee JH, Kutschera E. et al. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004; 70: 97-106.
• 25 Winkler UH, Holscher T, Schulte H. et al. Ethinylestradiol 20 versus 30 micrograms combined with 150 micrograms desogestrel: a large comparative study of the effects of two low-dose oral contraceptives on the hemostatic system. Gynecol Endocrinol 1996; 10: 265-271.
• 26 Ay C, Vormittag R, Dunkler D. et al. D-dimer and prothrombin fragment 1+2 predict venous thromboembolism in patients with cancer: result from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27: 4124-4129.
• 27 Alhenc-Gelas M, Plu-Bureau G, Guillonneau S. et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost 2004; 2: 1594-1600.
• 28 Rosing J, Middeldorp S, Curvers J. et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-2040.
• 29 Tchaikovski SN, van Vliet HA, Thomassen MC. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007; 98: 1350-1356.
• 30 Ozaki Y, Satoh K, Yatomi Y. et al. Detection of platelet aggregates with a particle counting method using light scattering. Anal Biochem 1994; 218: 284-294.
• 31 Dupont A, Fontana P, Bachelot-Loza C. et al. An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN. Blood 2003; 101: 1833-1840.
• 32 Archer DF, Mammen EF, Grubb GS. The effects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors. Am J Obstet Gynecol 1999; 181: 63-66.
• 33 Endrikat J, Klipping C, Cronin M. et al. An open label, comparative study of the effects of a dose-reduced oral contraceptive containing 20 microg ethinyl estradiol and 100 microg levonorgestrel on hemostatic, lipids, and carbohydrate metabolism variables. Contraception 2002; 65: 215-221.
• 34 Jespersen J, Endrikat J, Dusterberg B. et al. A 1-year study to compare the hemostatic effects of oral contraceptive containing 20 microg of ethinylestradiol and 100 microg of levonorgestrel with 30 microg of ethinylestradiol and 100 microg of levonorgestrel. Contraception 2005; 72: 98-104.
• 35 Post MS, Christella M, Thomassen LG. et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol 2003; 23: 1116-1121.
• 36 Høibraaten E, Mowinckel MC, de Ronde H. et al. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001; 115: 415-420.
• 37 van Vliet HA, Bertina RM, Dahm AE. et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost 2008; 6: 346-351.
• 38 Dahm A, Van Hylckama Vlieg A, Bendz B. et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101: 4387-4392.
• 39 Høibraaten E, Qvigstad E, Andersen TO. et al. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial. Thromb Haemost 2001; 85: 775-781.
• 40 Mashchak CA, Lobo RA, Dozono-Takano R. et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol 1982; 144: 511-518.
• 41 Klipping C, Junge W, Mellinger U. et al. Haemostatic effects of a novel four-phasic combined oral contraceptive containing estradiol valerate and dienogest. Eur J Contracept Reprod Health Care 2008; 13: 96-97.
• 42 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-650.