Progestogen Type in Contraceptive Dictates Thrombosis Risk

Jennifer Garcia

October 25, 2011

October 25, 2011 — Women who use oral contraceptives (OCs) containing desogestrel, gestodene, or drospirenone may double their risk for venous thromboembolism (VTE) compared with users of contraceptives containing levonorgestrel, according to a Danish study published online October 25 in BMJ.

According to study author Øjvind Lidegaard, MD, professor of obstetrics and gynecology, University of Copenhagen, Denmark, and colleagues: "The influence of specific types of combined [OCs] on the risk for thrombotic events remains the most important safety issue for these products."

Previous studies evaluating the association between VTE and OC use have shown differing results, the authors note. The goal of this study was to reevaluate the Danish registry data, specifically looking at the differences among patients receiving drospirenone- vs levonorgestrel-containing contraceptives.

A nationwide historical cohort study was conducted between 1995 through 2009 that included Danish women between the ages of 15 and 49 years. Women with a previous history of VTE, reproductive surgery, coagulopathy, cancer, use of ovarian stimulation drugs, or pregnancy were censored or excluded. The women were also classified based on the type, dose, and length of OC use; level of education; body mass index; and history of tobacco use.

A total of 1,296,120 women were included in the statistical analysis, with 4307 first-time VTE events recorded. Cerebral venous thrombosis accounted for 1.9% of these events, 26.2% were pulmonary embolism, deep venous thrombosis accounted for 63.6%, and 6.6% were unspecified deep vein thrombosis.

This study found that when compared with women who did not use hormonal contraception, current users of OCs with levonorgestrel were at a 3-fold increased risk for confirmed VTE. Users of OCs with desogestrel, gestodene, drospirenone, or cyproterone acetate were 6 to 7 times more likely to develop a VTE. This would give a rate ratio of at least 2 between the groups using OCs with desogestrel, gestodene, drospirenone, or cyproterone and those using OCs with levonorgestrel.

Analysis was restricted to only those VTE events that were confirmed (67% of all identified cases), which increased the strength of the data, according to Dr. Lidegaard and colleagues. This may have also led to an underestimation of the risk for VTE with combined OCs. The study authors do note, however, that variables such as family disposition and body mass index could not be controlled for, and may have affected the results.

According to independent commentator Susan Jick, DSc, Director of the Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Massachusetts, "[t]here is controversy over whether third-generation OCs and drospirenone OCs increase the risk of VTE more than second-generation OCs, such as the levonorgestrel-containing OC. This study supports the research that suggests that these OCs do carry a higher risk of VTE compared to the levo[norgestrel] OC."

"The levo[norgestrel] OCs are safer with respect to VTE than the third-generation OCs or the drospirenone OCs," she told Medscape Medical News. "All things being equal, I would not prescribe a third-generation OC or a drospirenone OC, given the higher VTE risk."

In accompanying editorial, Philip C. Hannaford, MD, Grampian Health Board chair of primary care at the University of Aberdeen, United Kingdom, notes that the progestogen content of oral contraceptives and the risk for VTE has been an area of intense medical research.

The current study, explains Dr. Hannaford, has attempted to eliminate previous censoring bias by including more comprehensive data on length of use and offers that "the similar proportion of confirmed cases [of VTE] in the different groups argues against differential referral or diagnostic bias as an explanation for the study's results."

He continues: "Although unpalatable to some, it is difficult not to conclude that combined [OCs] with desogestrel, gestodene, or drospirenone confer a higher risk of [VTE] than those with levonorgestrel. Many clinicians will choose to minimise the risk by prescribing a combined [OC] with levonorgestrel whenever possible," said Dr. Hannaford.

The authors acknowledge the following financial relationships: Bayer Schering Pharma covered the expenses of the analysis. All support was given to Rigshospitalet, and the primary investigator received no salary for his work with this study, the European Medicines Agency report, or the article. Dr. Lidegaard has, within the last 3 years, received honorariums for speeches on pharmacoepidemiologic issues, including fees from Bayer Pharma, Denmark, and Novo Nordisk, and will be an expert witness for plaintiffs in a legal US case in 2011 to 2012. A coauthor has received compensation for work in the steering committee of the European Medicines Agency report. Dr. Jick has disclosed no relevant financial relationships. Dr. Hannaford reports receiving no support from any organization for the submitted work; his academic department has received payments from Schering Plough and Wyeth Pharmaceutical for lectures and advisory board work provided by Dr. Hannaford.

BMJ. Published online October 25, 2011. Full text

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