Comparing the Risk of Deep Vein Thrombosis of Two Combined Oral Contraceptives: Norethindrone/ethinyl Estradiol and Drospirenone/ethinyl Estradiol

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Mar 4

PMID 38434341

Authors

Jennifer Stalas

Robert Morris

Kun Bu

Kevin von Bargen

Rebekah Largmann

Kathryn Sanford

Jacob Vandeventer

Weiru Han

Feng Cheng

Affiliations

Soon will be listed here.

Abstract

Background: Deep vein thrombosis (DVT) has been reported as an adverse event for patients receiving combined oral contraceptives. Norethindrone/ethinyl estradiol (NET/EE) and drospirenone/ethinyl estradiol (DRSP/EE) are two commonly prescribed combined hormonal oral contraceptive agents used in the United States, differing in their progestin component.

Objective: The purpose of this study was to determine the association between the progestin component of a combined oral contraceptive and the risk of DVT in patients taking oral contraceptives for birth control using data derived from the FDA Adverse Event Reporting System (FAERS).

Methods: The risk of DVT was compared between patients that had taken NET/EE with those that had taken the DRSP/EE COC formulation for birth control. In addition, age was assessed as a possible confounder and the outcome severity for those diagnosed with DVT were compared between the two groups. Finally, association rule mining was utilized to identify possible drug-drug interactions that result in elevated DVT risk.

Results: DVT was the fourth most commonly adverse event reported for patients taking DRSP/EE accounting for 8558 cases and the seventeenth most commonly reported adverse event for NET/EE accounting for 298 cases. Age was found to be a significant confounder for users of DRSP/EE with regards to DVT risk across all age groups assessed: 20<Age ≤ 30 (ROR = 1.33, 95% CI 1.23-1.45), 30<Age ≤ 40 (ROR = 2.16, 95% CI 1.98-2.35), and Age>40 (ROR = 3.69, 95% CI 3.37-4.04) However, there was only a statistically significant elevated risk in patients over 40 years of age taking NET/EE (ROR = 1.98, 95% CI 1.36-2.88). Patients that had taken DRSP/EE and the corticosteroid prednisone simultaneously had an approximately 3-fold increase in DVT risk (ROR = 2.77, 95% CI 2.43-3.15) relative to individuals that had only taken DRSP/EE.

Conclusion: Based on this analysis, there is a higher risk of developing DVT when taking DRSP/EE than when taking NET/EE as hormonal contraception. In addition, a possibly significant drug-drug interaction between different COC formulations and prednisone were identified. This interaction may result in elevated DVT risk due to a synergistic impairment of fibrinolysis and a decrease in plasmin production.

References

Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G . Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis. Expert Rev Clin Pharmacol. 2017; 10(10):1129-1144. DOI: 10.1080/17512433.2017.1356718. View

Tchaikovski S, Rosing J . Mechanisms of estrogen-induced venous thromboembolism. Thromb Res. 2010; 126(1):5-11. DOI: 10.1016/j.thromres.2010.01.045. View

Quezada A, Jimenez D, Bikdeli B, Moores L, Porres-Aguilar M, Aramberri M . Systolic blood pressure and mortality in acute symptomatic pulmonary embolism. Int J Cardiol. 2019; 302:157-163. DOI: 10.1016/j.ijcard.2019.11.102. View

Christin-Maitre S . History of oral contraceptive drugs and their use worldwide. Best Pract Res Clin Endocrinol Metab. 2013; 27(1):3-12. DOI: 10.1016/j.beem.2012.11.004. View

Dragoman M . The combined oral contraceptive pill -- recent developments, risks and benefits. Best Pract Res Clin Obstet Gynaecol. 2014; 28(6):825-34. DOI: 10.1016/j.bpobgyn.2014.06.003. View

Oelkers W . Drospirenone, a progestogen with antimineralocorticoid properties: a short review. Mol Cell Endocrinol. 2004; 217(1-2):255-61. DOI: 10.1016/j.mce.2003.10.030. View

Keenan L, Kerr T, Duane M, Van Gundy K . Systematic Review of Hormonal Contraception and Risk of Venous Thrombosis. Linacre Q. 2020; 85(4):470-477. PMC: 6322116. DOI: 10.1177/0024363918816683. View

Cleuren A, Van der Linden I, De Visser Y, Wagenaar G, Reitsma P, van Vlijmen B . 17α-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor α. J Thromb Haemost. 2010; 8(8):1838-46. DOI: 10.1111/j.1538-7836.2010.03930.x. View

Elger W, Beier S, Pollow K, Garfield R, Shi S, Hillisch A . Conception and pharmacodynamic profile of drospirenone. Steroids. 2003; 68(10-13):891-905. DOI: 10.1016/j.steroids.2003.08.008. View

10.

van Zaane B, Nur E, Squizzato A, Gerdes V, Buller H, Dekkers O . Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors. J Thromb Haemost. 2010; 8(11):2483-93. DOI: 10.1111/j.1538-7836.2010.04034.x. View

11.

Zimmerman Y, Eijkemans M, Coelingh Bennink H, Blankenstein M, Fauser B . The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Hum Reprod Update. 2013; 20(1):76-105. PMC: 3845679. DOI: 10.1093/humupd/dmt038. View

12.

Britton L, Alspaugh A, Greene M, McLemore M . CE: An Evidence-Based Update on Contraception. Am J Nurs. 2020; 120(2):22-33. PMC: 7533104. DOI: 10.1097/01.NAJ.0000654304.29632.a7. View

13.

Morgante G, Cappelli V, Troia L, De Leo V . Evaluation of different antiandrogenic progestins on clinical and biochemical variables in polycystic ovary syndrome. Eur J Contracept Reprod Health Care. 2020; 25(3):176-181. DOI: 10.1080/13625187.2020.1736546. View

14.

Morris R, Luboff H, Jose R, Eckhoff K, Bu K, Pham M . Bradycardia Due to Donepezil in Adults: Systematic Analysis of FDA Adverse Event Reporting System. J Alzheimers Dis. 2021; 81(1):297-307. DOI: 10.3233/JAD-201551. View

15.

De Feo P, Horber F, Haymond M . Meal stimulation of albumin synthesis: a significant contributor to whole body protein synthesis in humans. Am J Physiol. 1992; 263(4 Pt 1):E794-9. DOI: 10.1152/ajpendo.1992.263.4.E794. View

16.

Lieber B, Han J, Appelboom G, Taylor B, Han B, Agarwal N . Association of Steroid Use with Deep Venous Thrombosis and Pulmonary Embolism in Neurosurgical Patients: A National Database Analysis. World Neurosurg. 2016; 89:126-32. DOI: 10.1016/j.wneu.2016.01.033. View

17.

Morris R, Umeukeje G, Bu K, Cheng F . The Association Between Use of Rivastigmine and Pneumonia: Systematic Analysis of FDA Adverse Event Reporting System. J Alzheimers Dis. 2021; 83(3):1061-1071. DOI: 10.3233/JAD-210662. View

18.

de Bastos M, Stegeman B, Rosendaal F, van Hylckama Vlieg A, Helmerhorst F, Stijnen T . Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014; (3):CD010813. PMC: 10637279. DOI: 10.1002/14651858.CD010813.pub2. View

19.

Regidor P, Schindler A . Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone. Oncotarget. 2017; 8(47):83334-83342. PMC: 5669973. DOI: 10.18632/oncotarget.19833. View

20.

Chapin J, Hajjar K . Fibrinolysis and the control of blood coagulation. Blood Rev. 2014; 29(1):17-24. PMC: 4314363. DOI: 10.1016/j.blre.2014.09.003. View