By Rebecca H. Allen, MD, MPH, Editor
Recently, novel combined oral contraceptives containing estradiol valerate-dienogest, estetrol-drospirenone, and 17-beta estradiol with nomegestrol acetate have been released. Whether these types of estrogen are safer than ethinyl estradiol formulations in terms of venous thromboembolism risk is unknown.
Bauerfeind A, von Stockum S, Boehnke T, Heinemann K. Venous thromboembolism risk of estradiol-valerate-dienogest compared with ethinyl estradiol-levonorgestrel combined oral contraceptives. Obstet Gynecol 2024;143:431-434.
This was a secondary analysis using data from two prospective European observational cohort studies: the INAS-SCORE (International Active Surveillance Safety of Contraceptives: Role of Estrogens) and the INAS-OC (International Active Surveillance Study of Women Taking Oral Contraceptives). These studies enrolled individuals in the United States and Europe after a combined oral contraceptive pill was prescribed. Every six to 12 months, participants answered a questionnaire regarding clinical events. The authors compared those women taking the estradiol valerate-dienogest pill to women taking 30 mcg or less of ethinyl estradiol plus 90 mcg to 150 mcg of levonorgestrel formulations. The primary outcome was the venous thromboembolism (VTE) incidence rate based on new cases per 10,000 women-years of use. VTE events were medically confirmed. Both crude hazard ratios (HRs) were calculated as well as adjusted HRs using propensity score matching of baseline characteristics including age and body mass index.
The pooled data set consisted of 11,616 estradiol valerate-dienogest users and 18,681 ethinyl estradiol-levonorgestrel users. A total of 41 individuals were diagnosed with VTE events, with 31 deep vein thromboses (DVTs) and 14 pulmonary embolisms (PEs). Patients could have both DVT and PE. There were 11 VTEs among the estradiol valerate group for an incidence rate of 6.1 per 10,000 women-years (95% confidence interval [CI], 3.1, 11.0). There were 30 VTEs among the ethinyl estradiol group for an incidence rate of 10.3 per 10,000 women-years (95% CI, 7.0,14.7).
The crude HR comparing estradiol valerate to ethinyl estradiol was 0.58 (95% CI, 0.29, 1.17). The propensity score adjusted HR was 0.46 (95% CI, 0.22, 0.98). DVT-only events also were lower (crude HR 0.46; 95% CI, 0.20, 1.08 and adjusted HR 0.39; 95% CI, 0.16, 0.96). There was no significant difference between the two groups in PE events. There also was no difference when analyzing ethinyl estradiol formulations containing less than 30 mcg.
COMMENTARY
Most combined oral contraceptives (COCs) on the market contain ethinyl estradiol as the estrogen component. Ethinyl estradiol is a potent synthetic estrogen that has effects on the liver to stimulate protein production, including coagulation proteins.1 Because of this, COCs are associated with a three to four times increased risk of VTE, although the absolute risk is low. Furthermore, this is much less than the risk of VTE during pregnancy, which is the condition that COCs are preventing. Therefore, the benefits of COCs generally outweigh the risks for most people.2
Recently, novel COCs containing estradiol valerate-dienogest, estetrol-drospirenone, and 17-beta estradiol with nomegestrol acetate have been released. The first two are available in the United States with brand names Natazia and Nextstellis, respectively. Whether these newer COCs are safer in terms of VTE risk currently is being explored. There were some previous studies showing less of an effect on cardiovascular parameters.3,4 This current study is reassuring, demonstrating that the estradiol valerate-dienogest pill is as safe as the older ethinyl estradiol-levonorgestrel pills — and probably safer. The study showed a significantly decreased risk of DVT but no difference in PE risk. That is a little confusing, and the authors did not have an explanation for it. Nevertheless, other studies have had similar findings of decreased VTE risk.4 In general, with the multiple types and brands of COCs on the market, which pill to prescribe often comes down to cost, insurance coverage, and the patient’s previous experience. There is no evidence that one pill is superior to another, and COCs containing 35 mcg or less of ethinyl estradiol are treated as modern low-dose formulations that are equally safe. These novel COCs still are brand name and not as well covered by insurance compared to generic COC formulations. Therefore, for COCs in my practice, I typically prescribe a generic 20 mcg ethinyl estradiol pill as first-line for most patients who do not have a particular preference.
REFERENCES
- American College of Obstetricians and Gynecologists. Use of hormonal contraception in women with coexisting medical conditions. Practice Bulletin Number 206. Published February 2019. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2019/02/use-of-hormonal-contraception-in-women-with-coexisting-medical-conditions
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-103.
- Wiegratz I, Lee JH, Kutschera E, et al. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004;70:97-106.
- Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 2016;94:328-339.
