Editor’s note: In each issue of OB/GYN Clinical Alert, our physician experts choose a study of interest and importance to write about. Occasionally, the same study is chosen by more than one physician. In the May 2024 issue, Dr. Allen reviewed the study by Bauerfeind et al. In this issue, Dr. Shin and Dr. Bayer offer their perspectives on this valuable research. We hope you will find these additional viewpoints to be helpful in your practice.
By Rachel Shin, MD, MPH, and Lisa Bayer, MD, MPH
Dr. Shin is a Clinical Fellow, Complex Family Planning Division, Department of Obstetrics and Gynecology, Oregon Health & Science University. Dr. Bayer is Associate Professor, Complex Family Planning Division, Department of Obstetrics and Gynecology, Oregon Health & Science University.
SYNOPSIS: A pooled analysis comparing the risk of venous thromboembolism associated with combined oral contraceptives (COC) found significantly decreased venous thromboembolism risk in estradiol valerate-dienogest COCs compared with ethinyl estradiol-levonorgestrel COCs (propensity score-stratified hazard ratio, 0.46; 95% confidence interval, 0.22-0.98).
SOURCE: Bauerfeind A, Von Stockum S, Boehnke T, Heinemann K. Venous thromboembolic risk of estradiol valerate-dienogest compared with ethinyl estradiol-levonorgestrel combined oral contraceptives. Obstet Gynecol 2024;143:431-434.
Since the development of combined oral contraceptives (COCs), the ethinyl estradiol (EE) content has been reduced in an effort to lower the incidence of venous thromboembolism (VTE).1 Although reduced ethinyl estradiol doses in currently available COCs have improved COC safety significantly, efforts continue to further reduce COC-related risk and maintain tolerable bleeding profiles. Newer COC preparations include the use of estradiol (E2) or E2 valerate, which exert a lower effect on the hepatic system, reduced effect on hemostatic parameters, and negligible effects on carbohydrate and lipid metabolism compared to ethinyl estradiol.2
In 2009 and 2010, an E2-based COC containing E2 valerate and dienogest — a progestin with highly selective binding to the progesterone receptor and high progestational and antiandrogenic activity — was introduced in Europe and the United States.3 The International Active Surveillance study “Safety of Contraceptives: Role of Estrogens” (INAS-SCORE) conducted a prospective, observational cohort study following the launch of this new COC, revealing that formulations containing E2 valerate and dienogest exhibited trends toward lower cardiovascular risk than those containing levonorgestrel or other progestogens.4 This current study sought to further characterize VTE risk in a larger population.
The data for this study came from a pooled analysis of two large, prospective observational cohort studies, the INAS-SCORE and the International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC). This pooled analysis focused on self-reported, medically confirmed VTE events associated with use of COCs.
All new COC users (including first-ever users or those switching from another COC) were eligible. Every six to 12 months, participants received questionnaires with patient-reported clinical outcomes, adverse events, and hormonal treatment history. Reported VTE events were validated via medical records. Subjects from both studies were from the United States and Europe. The two cohorts analyzed in this study were those who received 3 mg E2 valerate/3 mg dienogest compared with 30 mcg or less ethinyl estradiol/90 mcg to 150 mcg levonorgestrel.
The primary outcome was VTE, including rates of deep venous thrombosis (DVT) and pulmonary embolism (PE). The VTE incidence rate was based on the occurrence of new cases per 10,000 woman-years. For statistical analysis, a Cox regression analysis was used with adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Propensity score subclassification was used to balance baseline covariates between cohorts. Age and body mass index were included as quadratic terms, and baseline population characteristics were included as linear terms.
The dataset from these two large, international surveillance studies included 11,616 E2 valerate-dienogest users and 18,681 ethinyl estradiol-levonorgestrel users. VTE events were categorized as DVT, PE, or both. There was an incidence rate of 6.1 VTE events per 10,000 women-years (95% CI, 3.1-11.0) in E2 valerate-dienogest users and an incidence rate of 10.3 VTE events per 10,000 women-years in ethinyl estradiol-levonorgestrel users (95% CI, 7.0-14.7). When the ethinyl estradiol-levonorgestrel cohort was divided into subgroups with different ethinyl estradiol doses (< 30 mcg and 30 mcg), there was no substantial difference in VTE rates compared with the overall ethinyl estradiol-levonorgestrel cohort.
The crude HR for E2 valerate-dienogest compared with ethinyl estradiol-levonorgestrel was 0.58, with a 95% CI (0.29-1.17). The propensity score-adjusted HR was 0.46 (95% CI, 0.22-0.98) for E2 valerate-dienogest compared with ethinyl estradiol-levonorgestrel, showing a significantly decreased VTE risk in E2 valerate-dienogest users. E2 valerate-dienogest users also showed lower risk when considering DVT events only (crude HR, 0.46; 95% CI, 0.20-1.08; propensity score-stratified HR, 0.39; 95% CI, 0.16-0.96). There was no significant difference between cohorts for PE events. Sensitivity analyses considering the subgroup of European COC users confirmed these results for VTE events, with a propensity score-stratified HR of 0.40 (85% CI, 0.18-0.89).
COMMENTARY
E2 valerate is structurally different from E2 by the presence of a valerate group on carbon 17 and can be converted readily to E2.5 Although the dose-dependent effects of ethinyl estradiol on VTE risk are well established, replacement of ethinyl estradiol with less potent preparations such as E2 have been problematic because of reduced cycle control and, therefore, decreased tolerability. The combination of E2 valerate with dienogest in a multiphasic dosing regimen was formulated to achieve ovulation inhibition and acceptable cycle control.6,7 A North American Phase III study demonstrated that E2 valerate-dienogest had reliable contraceptive efficacy and a tolerable bleeding profile.8 The European Phase III study additionally showed reliable contraceptive efficacy, high tolerability, and low discontinuation over 20 treatment cycles.8 The authors contribute to existing knowledge about E2 valerate-dienogest by demonstrating reduced VTE risk in E2 valerate-dienogest users compared with ethinyl estradiol-based COC formulations using data from large, prospective, observational cohort studies.
This study used a statistical modeling methodology called propensity score matching to balance the distribution of covariates and reduce confounding biases in the observational studies. Confounding variables not included in the propensity score model — such as differences in risk factors associated with VTE not considered in this observational study —could lead to hidden bias.9 However, strengths of this study include the prospective cohort study design, validation of self-reported VTE events by electronic medical records, and rigorous statistical analysis with the use of sensitivity analyses to confirm the results.
These findings expand on data from a prior surveillance study that showed reduced VTE risk for E2 valerate-dienogest users compared with ethinyl estradiol-levonorgestrel COC users, although the overall VTE incidence in both groups remains low. This is consistent with prior studies suggesting that these products may have reduced effect on thrombotic markers.2 At the very least, this suggests E2 valerate-dienogest formulations are as safe as ethinyl estradiol-levonorgestrel-based formulations of COCs.
At this time, the E2 valerate-dienogest COC formulation represents an effective option for contraception with tolerable bleeding profiles and it also carries the Food and Drug Administration approval for use to decrease heavy menstrual bleeding. The E2 valerate-dienogest COC is a novel quadriphasic formulation with 24 active pills and two placebo pills. Although we see a decrease in VTE over other ethinyl estradiol COC forumulations, E2 valerate-dienogest still should not be used in individuals with high risk factors for thrombotic events.
Other important considerations before starting this formulation include cost and adherence. Since there currently is not a generic formulation available, out-of-pocket cost for E2 valerate-dienogest COC can be cost-prohibitive. In addition, the quadriphasic pill poses some challenges with the complexity of dealing with missed doses, which can be confusing to patients or affect adherence. Contraceptive method selection is a preference-sensitive decision, and not everyone will prioritize the potential for reduced adverse effects. With more than 70 COCs to choose from in the United States, having a deeper understanding of the different estrogen and progestogen components of COCs can help tailor pill selection for patients. It is crucial to use a shared decision-making approach to identify a contraceptive method that aligns with the patient’s preferences and health considerations.
REFERENCES
- Liao PV, Dollin J. Half a century of the oral contraceptive pill: Historical review and view to the future. Can Fam Physician 2012;58:e757-760.
- Wiegratz I, Lee JH, Kutschera E, et al. Effect of four oral contraceptives on hemostatic parameters. Contraception 2004;70:97-106.
- Foster RH, Wilde MI. Dienogest. Drugs 1998;56:825-833.
- Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 2016;94:328-339.
- Stanczyk FZ, Winer SA, Foidart JM, Archer DF. Comparison of estrogenic components used for hormonal contraception. Contraception 2024;130:110310.
- Fruzzetti F, Bitzer J. Review of clinical experience with estradiol in combined oral contraceptives. Contraception 2010;81:8-15.
- Barnett C, Dinger J, Do Minh T, Heinemann K. Unintended pregnancy rates differ according to combined oral contraceptive – results from the INAS-SCORE study. Eur J Contracept Reprod Health Care 2019;24:247-250.
- Nelson A, Parke S, Mellinger U, et al. Efficacy and safety of a combined oral contraceptive containing estradiol valerate/dienogest: Results from a clinical study conducted in North America. J Womens Health (Larchmt) 2014;23:204-210.
- Reiffel JA. Propensity score matching: The ‘devil is in the details’ where more may be hidden than you know. Am J Med 2020;133:178-181.
A pooled analysis comparing the risk of venous thromboembolism associated with combined oral contraceptives (COC) found significantly decreased venous thromboembolism risk in estradiol valerate-dienogest COCs compared with ethinyl estradiol-levonorgestrel COCs (propensity score-stratified hazard ratio, 0.46; 95% confidence interval, 0.22-0.98).
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