Review data on Pill use and thrombosis risk
Despite the findings of two new studies,1,2 providers should focus on the fact that two earlier, large studies have compared safety data from women using Yasmin (Bayer HealthCare Pharmaceuticals; Wayne, NJ) to that of other oral contraceptive (OC) users,3,4 family planning experts emphasize. Both studies confirm the risk for adverse cardiovascular outcomes for Yasmin does not differ from those associated with the use of oral contraceptives.5
Data from the two earlier large, prospective, comparative cohort post-marketing surveillance studies give clinicians extensive safety data about drospirenone OCs, says Anita Nelson, MD, professor in the Obstetrics and Gynecology Department at the David Geffen School of Medicine at the University of California in Los Angeles. Such research should be kept in mind in evaluating findings from two new observational studies, which suggest the risk of venous thrombosis in women who use oral contraceptives differs by type of progestin, estrogen dose, and length of use.1,2
"I think we need to remind people about these before we get excited by smaller studies showing different answers," Nelson states.
Remind patients that even though there is a relative risk of thrombosis with use of any combined oral contraceptive, Pill users face a low absolute risk of thrombosis because venous thromboembolism is a rare event.6 The absolute risk of having venous thromboembolism is low. The baseline risk is five per 100,000 person years, and it increases to about 15-25 per 100,000 person-years when taking the Pill.7
In the post-marketing study conducted in the United States, 22,429 ethinyl estradiol/drospire-none initiators and 44,858 other oral contraceptive initiators were followed for an average of 7.6 months. There were 18 cases of thromboembolism in ethinyl estradiol/drospirenone initiators and 39 in the comparators (rate ratio 0.9, 95% confidence interval 0.5-1.6).3 In the European post-marketing study, 58,674 women were followed for 142,475 women-years of observation.4 Cox regression analysis of cardiovascular outcomes yielded hazard ratios for drospirenone-containing OCs vs. levonorgestrel-containing OCs and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively.
In the two new studies — one designed as a control study in six Dutch anticoagulation clinics, and the other designed as a cohort study in Danish women — both arrived at relatively similar results.1,2 The findings for both studies suggest that risk for venous thrombosis is lowest for pills containing levonorgestrel and norethisterone, and relative risk is 1.5-2 for pills containing gestodene, desogestrel, and norgestimate, compared with levonorgestrel OCs.
Both drospirenone and cyproterone acetate (which is not contained in any OC used in the United States) were found to have similar risks to desogestrel and gestodene: about 1.6-1.8 greater than with levonorgestrel, notes an accompanying editorial.8 The risk with norgestimate was similar to that with levonorgestrel in the Danish study (relative risk 1.19, 95% confidence interval 0.96 to 1.47), the editorial notes.
The findings regarding drospirenone have caught the eye of the popular press, because it is the progestin found in Yaz and Yasmin and the generic form of Yasmin, Ocella, from Teva Pharmaceuticals USA, North Wales, PA. Yaz was the leading OC dispensed in the United States in 2008, and Yasmin was the fourth most-dispensed OC, according to data from IMS Health.9 "Whenever, this kind of information hits the press, it is critical for health care providers to get all the evidence," Susan Wysocki, RNC, NP, president and CEO of the Washington, DC-based National Association of Nurse Practitioners in Women's Health. "Clinicians should consider the design of the study, possible confounding factors, biases, and whether or not there are other studies that have determined different results."
To perform the Dutch study, scientists enrolled pre-menopausal women under age 50 who were not pregnant, not within four weeks postpartum, and not using a hormonal intrauterine device or injectable contraceptive. The analysis included 1,524 patients and 1,760 controls.1
The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to nonusers, whereas the risk of venous thrombosis compared with nonuse was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7).1
The second study was designed as a 10-year national cohort follow-up study of Danish women ages 15-49. Scientists looked at the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, estrogen dose, type of progestogen, and route of administration.
Compared with oral contraceptives containing levonorgestrel and with the same dose of estrogen and length of use, the rate ratio of venous thromboembolism for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42).(2)
References
- Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: Results of the MEGA case-control study. Br Med J 2009. DOI: 10.1136/bmj. b2921.
- Lidegaard Ø, Løkkegaard E, Svendsen AL, et al. Hormonal contraception and risk of venous thromboembolism: National follow-up study. Br Med J 2009. DOI: 10.1136/bmj.b2890.
- Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism in women taking ethinyl estradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007; 110:587-593.
- Dinger JC, Heinemann LA, Kühl-Habich D. The 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. Contraception 2007; 75:344-354.
- Cronin M, Korner P. The safety profile of Yasmin is similar to other combined oral contraceptives. Clin Appl Thromb Hemost 2008; 14:245-246.
- Nelson AL. "Combined Oral Contraceptives." In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 19th revised edition. New York City: Ardent Media; 2007.
- World Health Organization (WHO). 1 Cardiovascular disease and steroid hormone contraception. Technical Report Series 877. Geneva: WHO; 1998.
- Dunn N. Oral contraceptives and venous thromboembolism. Br Med J 2009; DOI: 10.1136/bmj.b3164.
- IMS Health. The Contraceptive Market and Top 5 Products by Dispensed Total Scripts. Year to Date December 2008 (January 2008 to December 2008). Norwalk, CT; 2009.
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