Impact of Estetrol Combined with Drospirenone on Blood Coagulation and Fibrinolysis in Patients with Endometriosis: A Multicenter, Randomized, Open-Label, Active-Controlled, Parallel-Group Study

• Published in: Clinical and applied thrombosis/hemostasis 2024-01, Vol.30, p.10760296241286514
• Main Authors: Kobayashi, Takao, Hirayama, Masashi, Nogami, Masayoshi, Meguro, Kanna, Iiduka, Masato, Foidart, Jean-Michel, Douxfils, Jonathan, Harada, Tasuku
• Format: Article
• Language: English
• Subjects: Adult; Androstenes - pharmacology; Androstenes - therapeutic use; Blood Coagulation - drug effects; Contraceptives, Oral, Combined - pharmacology; Contraceptives, Oral, Combined - therapeutic use; Endometriosis; Endometriosis - blood; Endometriosis - drug therapy; Estetrol - pharmacology; Estetrol - therapeutic use; Estrogens; Ethinyl Estradiol - pharmacology; Ethinyl Estradiol - therapeutic use; Female; Fibrinolysis - drug effects; Humans; Original
• ISSN: 1076-0296; 1938-2723; 1938-2723
• DOI: 10.1177/10760296241286514

Venous thromboembolism is a serious safety concern in women using combined oral contraceptives; ethinyl estradiol (EE) is widely used as an estrogen. Estetrol (E4) is a native estrogen with selective tissue activity and exclusively produced by the fetal liver. This study used a multicenter, randomized, open-label, active-controlled, parallel-group design to evaluate the effects of E4 combined with drospirenone (DRSP) on coagulation and fibrinolysis in Japanese patients with endometriosis. Participants were randomized to receive either E4 15 mg/DRSP 3 mg or EE 20 µg/DRSP 3 mg for 12 weeks. E4/DRSP and EE/DRSP were administered orally once a day in a cyclic regimen, ie, 24-day active use followed by a 4-day hormone-free period, and a flexible extended regimen, respectively, and blood coagulation and fibrinolysis markers were measured. The effect on coagulation and fibrinolysis was considerably less in the E4/DRSP group than in the EE/DRSP group. Major anticoagulant proteins, protein S (free, total) and tissue factor pathway inhibitor (free), were reduced following EE/DRSP treatment. Consequently, thrombin generation determined by the activated protein C sensitivity ratio was increased by approximately 4-fold in the EE/DRSP group than in the E4/DRSP group. Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090).