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Data emerges on drospirenone pills: How to counsel on their use
Review similar VTE studies, weigh risks and benefits
Results of two case-control studies indicate that women without risk factors for venous thromboembolism (VTE) who use oral contraceptives (OCs) containing drospirenone have an increased risk for nonfatal VTE compared with those who use levonorgestrel OCs.1,2
Drospirenone is the progestin contained in the Yaz/Yasmin line of oral contraceptives from Bayer HealthCare Pharmaceuticals of Wayne, NJ. The line is the best-selling combination birth control pill in the United States. According to IMS Health, sales of Yaz in 2009 reached $782 million, accounting for 23% of the top five products in the combined oral contraceptive category.3 The progestin also is found in the North Wales, PA-based Teva Pharmaceuticals pills Ocella and Gianvi, the generic equivalents of Yasmin and Yaz, as well as in the Parsippany, NJ-based Watson Laboratories' Zarah, the generic equivalent of Yasmin. In 2010, Bayer received Food and Drug Administration approval for two new drospirenone pills with added folate, Beyaz and Safyral. Beyaz contains 20 mcg of ethinyl estradiol, while Safyral contains 30 mcg of ethinyl estradiol; both pills contain 3 mg of drospirenone.
The current observational database studies looked at women ages 15-44 years who received an oral contraceptive containing drospirenone or levonorgestrel. Cases were women with current use of a study oral contraceptive and a diagnosis of venous thromboembolism in the absence of identifiable clinical risk factors. Up to four controls were matched to each case by age and calendar time.
Prescription data on 55 million
For the first study, researchers looked at the U.S.-based PharMetrics database, which contains prescription data on 55 million people reaching back to 1995.1 Data for the second study came from the United Kingdom (UK)-based General Practice Research Database, which contains data from more than 3 million people.2
In the U.S. study, there were 186 case patients and 681 control patients. In the case-control analysis, the conditional odds ratio for VTE comparing use of drospirenone pills compared with use of levonorgestrel pills was 2.3 (95% confidence interval [CI] 1.6 to 3.2). The incidence rates for VTE in the study population were 30.8 (95% CI 25.6 to 36.8) per 100,000 woman years among drospirenone pill users and 12.5 (9.61 to 15.9) per 100,000 woman years among levonorgestrel pill users. The age-adjusted incidence rate ratio for VTE for current use of drospirenone OCs compared with those containing levonorgestrel was 2.8 (2.1 to 3.8).
The risk of non-fatal VTE among users of drospirenone pills seems to be about twice that of users of levonorgestrel pills, after the effects of potential confounders and prescribing biases have been taken into account, researchers conclude. Researchers note limitations of the study include a lack of primary record review, inability to determine the effect of smoking, lack of data on height and weight, and lack of data on a family history of VTE.1
In looking at the UK database, 61 case patients were identified, along with 215 control patients. In the case-control analysis, current use of the drospirenone pill was associated with a threefold higher risk of non-fatal idiopathic VTE compared with levonorgestrel use. The odds ratio adjusted for body mass index was 3.3 (95% CI 1.4 to 7.6). Subanalyses indicate that referral, diagnostic, first time user, duration of use, and switching biases were unlikely explanations for this finding, researchers note. The crude incidence rate was 23.0 (95% CI 13.4 to 36.9) per 100,000 woman years in current users of drospirenone pills and 9.1 (6.6 to 12.2) per 100,000 woman years in current users of levonorgestrel OCs. The age-adjusted incidence rate ratio was 2.7 (1.5 to 4.7). Limitations of this study include a relatively small number of case patients and lack of information regarding a family history of VTE.2
Weigh risks, benefits
The two new studies follow two similar analyses published in 2009. All four studies suggest that drospirenone increases the risk of venous thromboembolism compared with levonorgestrel.4,5 However, results from two earlier prospective, comparative cohort postmarketing surveillance studies do not indicate such risk.6,7
Bayer has affirmed the benefit/risk profile of its oral contraceptives. The company has sponsored and is sponsoring several independently conducted, large-scale, post-marketing studies examining the cardiovascular risks associated with the use of not only its own combination oral contraceptives, but also other prescribed pills, says company spokesperson Rose Talarico.
Three of the studies that are ongoing include the Long-Term Active Surveillance Study for Oral Contraceptives, the International Active Surveillance Study of Women Taking Oral Contraceptives, and the International Active Surveillance Study Folate in Oral Contraceptives Utilization Study, says Talarico.
The clear answer
Is there going to be more information coming out over the next several years that might change providers' stance on use of drospirenone pills? Susan Jick, DSc, MPH, director of the Boston Collaborative Drug Surveillance Program at Boston University School of Medicine and professor of epidemiology at the Boston University School of Public Health, says, "I don't know the answer, but to me, it is pretty clear that these drospirenone pills increase the risk relative to the levonorgestrel pills." Jick served as a co-author of the two current papers.
As with any oral contraceptive, providers and their patients need to weigh the risks and benefits of drospirenone pills. Even though the relative risk of thrombosis with OCs is increased, pill users face a low absolute risk because VTE is a rare event.8 The absolute risk of VTE for women on low-dose oral contraceptives is about 12-20 per 100,000 women years of use.9
In an editorial accompanying the two new studies, Nicholas Dunn, MD, senior lecturer in medical education in the Faculty of Medicine at the UK-based University of Southampton, comments that "in light of the new data, it appears sensible to prescribe an oral contraceptive with a well-known favorable safety profile (one that contains levonorgestrel) unless there is a persistent reason to use another type."10