NOMAC-E2 compares to LNG combined oral contraceptives in women over forty: real-world PRO-E2 study

Abstract

Objective

To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COC_LNG) in users over 40.

Methods

In this large, observational study, new users¹ of NOMAC-E2 and COC_LNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/10⁴ women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight.

Results

Overall, 7,762 NOMAC-E2 and 6,059 COC_LNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COC_LNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9–13.7) vs 4 COC_LNG (IR 5.9; 95% CI, 1.6–15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01–0.13) vs 5 COC_LNG (PI 0.08; 95% CI, 0.03–0.18). No differential effect on mood and weight was observed between cohorts.

Conclusions

NOMAC-E2 can be considered a valid alternative to COC_LNG in perimenopausal women.

Keywords:

• NOMAC-E2
• nomegestrol acetate
• estradiol
• levonorgestrel
• unintended pregnancy
• venous thromboembolism
• perimenopause

Acknowledgements

The authors would like to acknowledge the valuable scientific contribution of the SMAC. Their critical review of the data and challenging discussions substantially enhanced the overall quality of the study and the interpretation of the results. SMAC members included David Grimes, Michael Lewis, Robert Reid, Samuel Shapiro⁸, Carolyn Westhoff, Ulrich Winkler and Stephanie Teal. Advisors to the SMAC included Jochen Albrecht and Fritz von Weizsäcker⁹. The authors would also like to thank the colleagues in the local field organizations who conducted the day-to-day field work. Their remarkable dedication and flexibility despite the challenging circumstances caused by the pandemic ensured the success of the study. The authors would also like to thank the ZEG Berlin staff members (statisticians, data managers, event validation staff, and medical advisers) whose contribution to the study was invaluable.

Disclosure statement

SVS, KB, AB, CF, and KH are full-time employees at ZEG Berlin. FF has received honoraria from Bayer, Gedeon Richter, EffiK, MSD, Pfizer and Theramex for educational or advisory activities. JC has received honoraria from Bayer, Gedeon Richter, Lilly, MSD, and Theramex for educational or advisory activities. CK has received honoraria for educational or advisory activities from Theramex, Theva, Exeltis, Besins, Merck, Organon, Henry Schein, Gedeon Richter, Jenapharm, Bayer, Serono.

Notes

1 First-ever users of an eligible COC or restarting with an eligible COC (same COC as before or a new COC) after a break of at least 2 months.

2 First-ever users of an eligible COC

3 Restarting with an eligible COC (same COC as before or a new COC) after a break of at least 2 months

4 This definition of the primary outcome and the exclusion of women with pre-defined risk factors conformed with requirements of the Pharmacovigilance Risk Assessment Committee of the EMA for this study.

5 1) NOMAC-E2, 2) COC_LNG monophasic preparation containing 20-30mcg of ethinylestradiol, 3) COC_LNG multiphasic preparation containing up to 40mcg of ethinylestradiol. LNG concentrations ranged from 90 to 150 mcg depending on COC formulation.

6 If there was ambiguity concerning the date of conception or COC use, the woman and/or her HCP were contacted for clarification. The consent form included permission to contact any treating physician to follow up on specific outcomes.

7 Study participants reported their reason(s) for COC use only at study entry; their reason(s) for use may have changed during follow-up (e.g. a woman who began using a COC for contraceptive only reasons may have experienced a relationship change and continued using the COC for non-contraceptive reasons).

8 Died 19 April 2016.

9 Died 19 November 2019.

Additional information

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Theramex Ireland Limited, Dublin, Ireland provided funding for this research.