International Active Surveillance Study - Safety of Contraceptives: Role of Estrogens

Contraception

Contraception, Estradiol valerate

The primary objective of the study is to assess the risks of short and long-term use of estradiol valerate/dienogest (EV/DNG) and of established oral contraceptives (OCs) in a study population that is representative for the actual users of the individual preparations. This includes an estimate of the absolute risk of rare serious adverse outcomes.

During the development of oral contraceptives (OCs) over the last decades, ethinyl-estradiol (EE) has been reduced under the hypothesis that lower EE doses lead to a better safety profile and specifically to a lower venous thromboembolism (VTE) incidence. However, the reduction of the EE dose led to a less favorable bleeding control. Though EE has been utilized within numerous OCs, efforts have been made to utilize estradiol (E2) and estradiol valerate (EV) which have lower impact on the hepatic system and subsequently on hemostatic parameters. Bayer Schering Pharma has developed a new EV based OC in a dosing regimen that combines both reliable contraception and acceptable bleeding profile. The INAS-SCORE study was designed as an international, prospective, controlled, non-interventional cohort study. The study was started in Europe and was extended to the US after the launch of the new regimen. New users of an OC (starters or switchers) are accrued by a network of prescribing physicians. Even in the event of high drop-out rates, a 3 to 5-year follow-up of 50,000 women should be sufficient to document about 150,000 women-years. Baseline and follow-up information are collected via a self-administered questionnaire. All self-reported clinical outcomes of interest will be validated via health care professionals. Classification of reported outcomes as confirmed or unconfirmed will be checked via blinded, independent adjudication. A multifaceted 4-level follow-up procedure proved to ensure low loss to follow-up rates. The main clinical outcomes of interest for the short and long-term follow-up are cardiovascular events, primarily deep venous thrombosis, pulmonary embolism, acute myocardial infarction, and cerebrovascular accidents. Data analysis will be based on life-table methods. All analyses will make allowance for confounding, using multivariate techniques such as Cox regression. Study amendment: Follow-up was initially expected to last until 2014 for the United States and Europe. However, the European regulatory authorities were concerned about the low proportion of Qlaira users in the United States and requested that the primary analysis should be based on the European study arm only. However, this reduction in sample size results in a reduction of the statistical power. Therefore it was agreed upon with the European regulatory authorities to extend the follow-up period in Europe till 2016. This will ensure that the statistical power in the European study arm will be as high as the originally planned power for the complete study population (European and US study population combined). The total exposure in Europe will be sufficient to exclude a twofold risk of VTE and a threefold risk of ATE for Qlaira compared to 'Other COCs'.

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