Original research articleThe 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
Introduction
Oral contraceptives (OCs) are a very popular and efficacious form of reversible birth control. The pill's efficacy plus its convenience gives women both autonomy and flexibility in family planning. This played no small role in the major social movements of the 1960s and 1970s.
The first OCs introduced in the early 1960s contained high doses of both estrogen and progestin. The estrogen doses [150 μg mestranol and 50 μg ethinylestradiol (EE), respectively] were found to be associated with an elevated incidence of cardiovascular side effects, especially venous thromboembolism (VTE).
During the following decades, the estrogen as well as progestin doses were considerably reduced. The scientific discussion on VTE shifted to the type of progestin in the mid-1990s. Epidemiological studies [1], [2], [3], [4] appeared to indicate that OCs containing gestodene and desogestrel had a higher risk of VTE than OCs with levonorgestrel (LNG) and the same amount of EE. In subsequent years, a number of studies have been published with conflicting results. Whether the VTE risk associated with gestodene and desogestrel is real or the result of bias and confounding has been the subject of heated scientific debate. This debate, which has yet to be conclusively resolved [5], [6], is due to the fact that robust safety data that could either substantiate or refute a higher risk of VTE were not available at the time of the “pill scare.”
In order to avoid a comparable situation for the market introduction of an OC with a novel progestin [30 μg EE and 3 mg drospirenone (DRSP)] [7], [8], [9], [10], [11], the manufacturer of this OC commissioned the Center for Epidemiology and Health Research in Berlin to perform a large, prospective, controlled cohort study as part of a phase IV commitment. The safety of this DRSP-containing preparation was assessed using active surveillance of the study participants under the supervision of an independent Advisory Council, which was formed in late 1999.
The methodology and logistics of the study were designed to ensure that within a few years, the risks of short- and long-term use of DRSP-containing OCs and established OCs could be characterized and compared in a study population that was representative of the users of the individual preparations. The main clinical outcomes of interest were cardiovascular events, i.e., incidence rates of arrhythmias, myocardial infarction, stroke, VTE and sudden death.
This publication presents the main safety outcomes of this European Active Surveillance (EURAS) study. Other results of the EURAS study (e.g., return to fertility and pearl index data) will be reported separately.
Section snippets
Materials and methods
A large cohort of women starting OC treatment (first-ever users or switchers to a new product) was actively monitored for the occurrence of rare or unexpected adverse outcomes possibly related to exposure to OCs. The primary focus of the active study monitoring was to assess the occurrence of new cardiovascular events. These events were monitored continuously for the duration of the study. In addition, all other serious adverse events (SAEs; i.e., adverse events that result in death, a
Results
The study was initiated in November 2000 and recruitment was completed in June 2004. The follow-up of study outcomes was terminated in December 2005. The study was conducted in seven European countries where DRSP-containing OCs are marketed: Austria, Belgium, Denmark, France, Germany, the Netherlands and the United Kingdom. A total of 59,510 women (see Table 1) were enrolled by 1113 study centers. Overall, 836 (1.4%) of these 59,510 women had to be excluded because (1) they refused to sign the
Discussion
As a class, estrogen/progestin combinations — OCs as well as hormone replacement preparations — increase the risk of VTE [13]. This heightened risk has been associated with both estrogens and progestins [1], [2], [3], [4]. Given the serious clinical impacts that VTEs can have, the question of whether a newly introduced progestin is associated with a higher risk of VTE is by no means academic. But the heated scientific debate over whether OCs containing gestodene and desogestrel are associated
Conclusions
The independent Advisory Council came to the following conclusions: (1) no major differences among the cohorts were found in the rates for overall SAEs, organ-system specific SAEs, overall mortality and outcome-specific mortality, overall cancer and organ system-specific cancer. (2) Overall, for all outcomes studied, an increased risk for users of a DRSP-containing OC compared to users of other OCs (including LNG-containing OCs) was not identified. These results suggest that the risks of
Acknowledgments
The study was funded by an unrestricted grant from Schering AG. The authors would like express their appreciation to the members of the independent Advisory Council for their constructive criticism and unfailingly fair scientific discussion. The Advisory Council had the following members: Prof. Walter Spitzer (chairman), Canada; Ms. Midori Ashida, Japan (till 2002); Dr. Siham Benchekroun, Morocco (since 2002); Prof. Serge Carriere, Canada; Dr. Jean Cohen, France; Prof. Joe Goldzieher, USA (till
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