Background: The European Medicines Agency requested a meta-analysis of four large, multi-national cohort studies on hormonal contraceptives to clarify whether dienogest/ethinylestradiol-containing combined oral contraceptives (DNG/EE) carry a different risk of venous thromboembolic events (VTE) compared to levonorgestrel/ethinylestradiol-containing preparations (LNG/EE). The primary objective of the meta-analysis was to assess VTE risk in a study population that is representative for the actual users of the individual preparations.

Methods: All four studies were prospective, observational cohort studies. Cohorts consisted of new users of hormonal contraceptives: starters, switchers and restarters. Study participants were followed up for up to 10 years. The analysis was restricted to preparations containing 30 µg of ethinylestradiol. Primary risk measure: VTE hazard ratio (HR) in the European study population for DNG/EE versus LNG/EE adjusted for age, BMI, duration of current use, family history of VTE and data source.

Results: The analysis set included data from 228,122 users of hormonal contraceptives. The European study participants had used DNG/EE and LNG/EE (WY) for 38,708 and 45,359 woman years, respectively. The meta-analysis includes 102 VTEs: DNG/EE, 56 cases and 14.5 VTE/10,000 WY; LNG/EE, 46 cases and 10.1 VTE/10,000 WY. The primary analysis showed an adjusted HR for DNG/EE versus LNG/EE of 1.6 (95% confidence interval 1.1-2.3). Four alternative analyses showed similar results although only one of these analyses reached statistical significance.

Conclusion: DNG/EE is probably associated with a slightly higher risk of VTE compared to LNG/EE. However, some uncertainty regarding the validity of this result remains.