Is an EMA review on hormonal contraception and thrombosis needed?

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1464 (Published 07 March 2013) Cite this as: BMJ 2013;346:f1464

Re: Is an EMA review on hormonal contraception and thrombosis needed?

In a recent editorial by Professors Helmerhorst and Rosendaal, the authors state that the risk of thrombosis (venous and arterial) is related to both the amount of Ethinyl Estradiol (EE) and progestogen type (1). Based on this observation, they opine that women should be prescribed contraception containing levonorgestrel and 30mcg of Ethinyl Estradiol (LNG/EE), and that the need for EMA review is obviated. We are in agreement with the authors on two points: firstly, that the risk of thrombosis is related directly to the dose of EE, and that an EMA review is not required. However, we disagree with the assertion that the progestogen type plays a significant role in thrombosis risk.

In reviewing the literature on thrombosis risk and progestogen type, we must return to the principles of evidence-based medicine and first consider the quality of the evidence being presented. Owing to the low-cost and ability to rapidly amass many woman-years of observation, retrospective studies, particularly those which rely upon administrative databases, are both popular and frequently cited (2,3). This study design is well-known to be fraught with methodological flaws, including, but not limited to, lack of validation of diagnosis, lack of control of confounding variables, and violation of time order by not restricting data to first-time users (4,5,6). In the cited case-control MEGA study (7), the selection of controls (partners of those with VTE) make risk interpretation confusing for patients, and 95% confidence intervals of Odds Ratios for DVT/PE (i.e. excluding arm DVTs) overlap across progestogen types.

The continued use of retrospective database studies may threaten the introduction and uptake of new and potentially superior contraceptive options, limiting options for women. Owing to the significant adverse risks to patients of unintended pregnancies resulting from pill scares, conclusions regarding progestogen type and thrombosis risk, particularly VTE, must be made based on the best available studies: those which are prospective, use appropriate comparators (new users with similar age and risk characteristics), and utilise active surveillance. Of the available prospective cohort studies, no differences in VTE risk between levonorgestrel and other progestogens has been demonstrated (8, 9, 10, 11). The Society of Obstetricians and Gynaecologists of Canada has recently conducted a review of the existing literature and has released two position statements affirming the comparable safety of third-generation, fourth-generation, and CPA/EE to other contraceptives, reiterating that “for most women, the benefits of [oral] contraception will outweigh the risks” (12, 13).

As family planning practitioners, we clearly wish to reduce the risk to patients both from unintended pregnancy and from contraceptive use. While the strategy proposed by the authors is interesting, it is not adequately evidence-based. Furthermore, we discourage the application of a “one-pill-fits-all” approach to contraception. Women currently benefit from a range of products (medication, dose and schedule) that allow them to balance their own benefits (contraceptive and non-contraceptive) against risk. Such a restrictive practice may be viewed as paternalistic, creating dissatisfaction with providers, a known risk factor for non-adherence (14). We hope that the EMA will carefully weigh the existing data in its review, and, in doing so, reassure women that oral contraceptives are safe (not risk-free) across the progestogen classes. In the interim, we must continue to provide patients with a range of tools to prevent pregnancy, and knowledge to assist in safe contraceptive decision-making.

1. Helmerhorst FM, Rosendaal FR. Is an EMA review on hormonal contraception and thrombosis needed? BMJ 2013;346:f1464.
2. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011;343:d6423.
3. Sidney S, Cheetham TC, Connell FA, Ouellet-Hellstrom R, Graham DJ, Davis D, Sorel M, Quesenberry CP Jr, Cooper WO. Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception. 2013;87:93-100.
4. Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol. 2010;63:223-8.
5. Grimes D. Epidemiologic research using administrative databases: Garbage in, garbage out. Obstet Gynecol 2010;116:1018-9.
6. Shapiro S. Combined hormonal contraceptives and the risk of venous and arterial thromboembolism and cardiovascular death: misuse of automated databases. J Fam Plann Reprod Health Care. 2013;39:89-96.
7. van Hylckama Vlieg A, Helmerhorst, FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009;339:b2921
8. Dinger JC, Heinemann LA, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on Oral Contraceptives based on 142,475 women-years of observation. Contraception 2007; 75(5): 344–54.
9. Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007; 110(3): 587–93.
10. Dinger J, Assman A, Moehner S. Long-Term Active Surveillance Study for Oral Contraceptives (LASS): Impact of Oral Contraceptive Use on the Start of Antihypertensive Treatment. Pharmacoepidemiol Drug Saf 2010;19:S232.
11. Dinger J, Bardenheuer K, Moehner S. The risk of venous thromboembolism in users of a drospirenone-containing oral contraceptive with a 24-day regimen – results from the INAS-OC study. Fertil Steril 2009;94:S3.
12. Society of Obstetricians and Gynaecologists of Canada. Position Statement: Hormonal Contraception and Risk of Venous Thromboembolism (VTE). http://www.sogc.com/media/documents/medHormonalContraceptionVTE130219.pdf. Accessed March 26, 2013.
13. Society of Obstetricians and Gynaecologists of Canada. Position Statement: Diane-35 and risk of venous thromboembolism (VTE). http://www.sogc.com/media/documents/medDiane35VTE130219.pdf. Accessed March 26, 2013.
14. Rosenberg MJ, Waugh MS, Burnhill MS. Compliance, counseling, and satisfaction with oral contraceptives: A prospective evaluation. Fam Plann Perspect 1998;30:89-92.

Competing interests: Dr Costescu: Has previously received honoraria from Pfizer (Canada) and Bayer Healthcare (Canada). Dr Waddington: Has previously received honoraria from Bayer Healthcare (Canada), Merck (Canada), Pfizer (Canada), and Warner-Chilcott (Canada).

27 March 2013
Dustin J Costescu
Contraception Advice Research and Education Fellow
Ashley Waddington
Department of Obstetrics and Gynaecology, Queen's University
Victory 4, 76 Stuart St. Kingston ON K7L 2V7 Canada