Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel

Christine Klipping, Ingrid Duijkers, Susanne Parke, Uwe Mellinger, Marco Serrani, Wolfgang Junge, Christine Klipping, Ingrid Duijkers, Susanne Parke, Uwe Mellinger, Marco Serrani, Wolfgang Junge

Abstract

Background: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance.

Objective: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel.

Study design: Healthy women aged 18-50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2 mg/dienogest 2 mg, 17 days estradiol valerate 2 mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three.

Results: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/levonorgestrel.

Conclusion: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/levonorgestrel.

Figures

Fig. 1
Fig. 1
Design of the crossover study. E2V/DNG = estradiol valerate/dienogest; = ethinylestradiol/levonorgestrel; EOT = end of treatment; SOT = start of treatment (first day of bleeding); V1 = screening visit; V2 = baseline (days 15–21 of the cycle); V3 = end of treatment period 1 (end of treatment cycle 3).[E2V/DNG = treatment days 74–80; EE/LNG = treatment days 71–77]; V4 = end of washout cycle 1 (days 15–21 of the cycle); V5 = end of washout cycle 2 (days 15–21 of the cycle)/baseline for treatment period 2; V6 = end of treatment period 2 (end of treatment cycle 6).[E2V/DNG = treatment days 158–164; EE/LNG = treatment days 155–161]; V7 = up to 2 weeks after the end of treatment, but at least 2 days after the end of the withdrawal bleeding that followed treatment cycle 6.
Table I
Table I
Hemostatic markers assessed [product name; manufacturer]
Fig. 2
Fig. 2
Study flow chart showing the number of women screened, randomized, and completing treatment. For sequence A, full analysis set (FAS) was n = 14, per-protocol set (PPS) was n = 13 (one volunteer from FAS with major protocol deviation[s]). For sequence B, FAS was n = 15, PPS was n = 11 (four volunteers from FAS with major protocol deviation[s]). AEs = adverse events; E2V/DNG = estradiol valerate/dienogest; EE/LNG = ethinylestradiol/levonorgestrel; GI = gastrointestinal.
Table II
Table II
Absolute level at cycle three and intra-individual absolute change from baseline to cycle three in activation markers in women (n = 29) during treatment with estradiol valerate/dienogest (E2V/DNG) or ethinylestradiol/levonorgestrel (EE/LNG).[n = 28]
Table III
Table III
Absolute level at cycle three, intra-individual absolute change and intra-individual change from baseline to cycle three in pro- and anti-coagulatory markers in women (n = 29) during treatment with estradiol valerate/dienogest (E2V/DNG) or ethinylestradiol/levonorgestrel (EE/LNG).[n = 28]
Table IV
Table IV
Most commonly reported adverse events (occurring in >10% of women; full analysis set)

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