Impact of estrogen type on cardiovascular safety of combined oral contraceptives

Contraception. 2016 Oct;94(4):328-39. doi: 10.1016/j.contraception.2016.06.010. Epub 2016 Jun 22.


Objectives: The International Active Surveillance study "Safety of Contraceptives: Role of Estrogens" (INAS-SCORE) investigated the cardiovascular risks associated with the use of a combined oral contraceptive (COC) containing dienogest and estradiol valerate (DNG/EV) compared to established COCs in a routine clinical setting.

Study design: Transatlantic, prospective, noninterventional cohort study conducted in the United States and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models.

Results: A total of 50,203 new COC users were followed up for up to 5.5years (mean value, 2.1years). Overall 20.3% and 79.7% of these women used DNG/EV and oCOC (including 11.5% LNG users), respectively. A low loss to follow-up of 3.1% was achieved. Based on 47 (VTE) and 233 (SCE) events, the primary analysis (European data set) yielded adjusted hazard ratios for DNG/EV vs. oCOC of 0.4 and 0.5, respectively. The upper bounds of the 95% confidence intervals were 0.98 (VTE) and 0.96 (SCE). The corresponding hazard ratios for DNG/EV vs. LNG showed similar point estimates but the confidence intervals included unity.

Conclusion: DNG/EV is associated with similar or even lower cardiovascular risk compared to oCOC and LNG.

Implication statement: A COC containing DNG and EV is associated with similar or even lower cardiovascular risk compared to COCs containing levonorgestrel or other progestogens.

Trial registration: NCT01009684.

Keywords: ATE; Combined oral contraceptives; Dienogest; Estradiol valerate; Routine clinical practice; VTE.

Publication types

  • Comparative Study
  • Multicenter Study

MeSH terms

  • Adult
  • Cardiovascular Diseases / chemically induced*
  • Cardiovascular Diseases / epidemiology
  • Contraceptives, Oral, Combined / adverse effects*
  • Contraceptives, Oral, Combined / chemistry
  • Estradiol / adverse effects
  • Estradiol / analogs & derivatives*
  • Europe / epidemiology
  • Female
  • Follow-Up Studies
  • Humans
  • Incidence
  • Levonorgestrel / adverse effects*
  • Longitudinal Studies
  • Nandrolone / adverse effects
  • Nandrolone / analogs & derivatives*
  • Patient Reported Outcome Measures
  • Proportional Hazards Models
  • Prospective Studies
  • Surveys and Questionnaires
  • United States / epidemiology
  • Venous Thromboembolism / chemically induced*
  • Venous Thromboembolism / epidemiology
  • Young Adult


  • Contraceptives, Oral, Combined
  • dienogest
  • Estradiol
  • Levonorgestrel
  • Nandrolone

Associated data