Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial

Abstract

Introduction: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin.

Material and methods: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover).

Clinical trial registration: NCT02352090.

Results: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers.

Conclusions: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Keywords: coagulation; combined oral contraception; dienogest; estradiol valerate; thrombin generation.

Conflict of interest statement

TP has received honoraria for lectures and consultation and research grants from Exeltis, Gedeon Richter, MDS, Merck, Pfizer, Roche, and Mithra Pharmaceuticals. OH occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have no relevant conflicts of interest to disclose.

© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).

Figures

FIGURE 1

Flowchart of our 9‐week randomized study comparing the effects of estradiol valerate + dienogest (EV + DNG), ethinylestradiol + dienogest (EE + DNG), and dienogest alone (DNG) on coagulation biomarkers.

FIGURE 2

Thrombin Generation. (A) The mean results of the calibrated automated thrombogram (CAT) at baseline and after 9 weeks of the study shown as thrombin generation curves. (a) estradiol valerate+diengoest (EV + DNG); (b) ethinylestradiol+dienogest (EE + DNG); (c) dienogest alone (DNG). The thrombin generation curves depict the formation and subsequent inactivation of thrombin (nm) over time (min) after initiation of coagulation with 1 pm tissue factor in the study groups. The variables include lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential (ETP), which refers to the area under the curve. The change from baseline was analyzed by paired samples t tests. Eleven healthy individuals (not age‐ or sex‐matched) were included in the plot as control. (B) The change from baseline in thrombin generation variables in the three study groups EV + DNG, EE + DNG, and DNG alone and comparisons between the groups. (a) Lag time; (b) time to thrombin peak; (c) thrombin peak; (d) ETP. The data are shown as boxplots (median and mean [+], interquartile range, min–max) and analyzed by Kruskal‐Wallis test with post hoc paired comparisons (Dunn test). The EV + DNG vs DNG‐alone comparison did not differ for any variable.

FIGURE 3

Schematic overview of the coagulation system and changes induced by hormonal contraceptives. In the present study, coagulation activation in vivo was assessed by prothrombin fragment 1 + 2 (F1 + 2), a degradation product of prothrombin arising during its conversion to thrombin, and D‐dimer, a marker of fibrin turnover. Thrombin generation was measured in vitro using calibrated automated thrombogram (CAT) in response to tissue factor (TF). Plus and minus signs denote the direction of the changes in individual pro‐ and anticoagulant factors or their activity observed during hormonal contraceptive use., ATIII, antithrombin; F1 + 2, prothrombin fragment 1 + 2; PC, protein C; PS, protein S; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin. Figure adapted from reference and created with Biorender.com.