Blood clots and "The Patch"
Abstract & Commentary
By Alison Edelman, MD, MPH, Assistant Professor, Assistant Director of the Family Planning Fellowship Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, is Associate Editor for OB/GYN Clinical Alert.
Dr. Edelman reports no financial relationship to this field of study
Synopsis: The risk of venous thromboembolism was double in users of a transdermal contraceptive as compared to users of an oral contraceptive with a 35 mcg ethinyl estradiol component. Warning: no abstract skimming—it's worth your while to keep reading!
Source: Cole JA, et al. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstetrics & Gynecology. 2007;109:339-346.
JA Cole, et al used two years of insurance claims data from a large national health insurer (confirmed with medical records) to determine incidence of venous thromboembolism in women exposed to a transdermal contraception (Ortho Evra®) vs a norgestimate-containing oral contraceptive with a 35 mcg ethinyl estradiol component.1 This case-controlled study found 57 cases of venous thromboembolism (VTE; 20 cases in patch-users and 37 in pill-users) out of 340,377 women who were dispensed at least one cycle of medication (OR 2.2, 95% CI 1.3-3.8). After excluding high-risk factors (recent trauma, pregnancy, recent surgery, postoperative complications, anticoagulant or antithrombolytic therapy), the odds ratio increased slightly to 2.4 (95% CI 1.1-5.5).
Commentary
Many of you recently received a mailing regarding an update in prescribing information for Ortho Evra®.2 This letter contained a summary of the current literature regarding venous thromboembolism (VTE) and transdermal patch use. I assume these types of mailings provide some liability safeguard for the company? However, I found the letter to be clinically unhelpful and downright scary. If I didn't know any better, my first inclination after reading the letter would be to stop prescribing the patch.
So let's review the literature. To date there have been three published studies specifically focusing on VTE risk and patch use. As mentioned above, Cole, et al found a statistically significant increased risk of VTE in patch users with an odds ratio of 2.4 (95% CI 1.1-5.5).1 Jick, et al performed a case-control study using a database from PharMetrics, a company that collects information on claims paid by managed care plans. They also compared patch users to users of a norgestimate-containing oral contraceptive with a 35 mcg ethinyl estradiol component and found no increased risk of VTE in patch users (OR 0.9, 95% CI 0.5-1.6).3 A follow-up study to this one was recently published which included 17 months of additional data using the same database and again, no significant increase in VTE risk for patch users was demonstrated (OR 1.1. 95% 0.6-2.1).4 Just to muddy the waters further, a post-marketing surveillance program using the same database as Jick, et al released information on the patch compared to a levonorgestrel-containing oral contraceptive with a 30 mcg ethinyl estradiol component and found an increased risk of VTE in patch users (OR 2.0, 95% CI 0.9-4.1).5
Is it plausible that the patch has a slightly increased VTE risk compared to other estrogen containing hormonal contraception? Possibly. A small pharmacokinetic study comparing the patch, the contraceptive vaginal ring and a combination OC with a 35 mcg ethinyl estradiol component, the patch was found to have a greater area under the curve but a lower ethinyl estradiol peak level than the OC.6 It is unknown how these pharmacokinetic differences affect VTE risk. The patch also contains a third-generation progestin. Although controversial, third-generation progestins have been linked to a slightly higher risk of VTE as compared to first- or second-generation progestins.7-9 This would explain the difference in risk found by the post-marketing surveillance program5 mentioned earlier but not the findings reported in Cole's study.1 Finally, thrombosis biomarkers are affected by estrogen-containing hormonal contraception but differences exist between OCs versus the patch as to which markers change and by how much.10 It is unclear how this affects VTE risk.
So what does all this mean? The increased risk of VTE with the use of an estrogen-containing contraceptive is not a surprise. We already knew that OC users have a slightly increased risk of VTE as compared to non-users (4-5 cases versus 12-20 cases per 100,000 women per year).11 However, VTE risk in OC users is still significantly lower than compared to pregnancy (48-60 cases per 100,000 women per year). Using the most conservative estimate that the patch "doubles the risk" of VTE, the risk is still lower in patch users than in pregnancy. Thus even with this conflicting data, the patch remains a safe and effective method of contraception—one that I will continue to prescribe until further evidence to the contrary emerges.
Finally, avoid the trap of using language that can inflate a patient's perception of risk. Although "double the risk" is easy to remember and statistically correct when comparing an odds ratio that increases from 1 to 2, it does not accurately reflect what the VTE risk is for an individual patient. "Double the risk" of a rare event is still a rare event when looking at actual case numbers.
Clinical tips:
- Estrogen-contraception (patch, ring, OCs) should be avoided in women with VTE risk.
- VTE risk should always be discussed and documented with any woman starting an estrogen-containing hormonal contraceptive.
- VTE risk is slightly increased with any use of an estrogen-containing hormonal contraceptive but this is significantly less then the risk of VTE in pregnancy.
- The VTE risk with the contraceptive patch vs OCs may be similar or slightly increased but overall is still low.
- VTE risk in nonusers 4-5 cases per 100,000 women per year
- VTE risk in OC users 12-20 cases per 100,000 women per year
- VTE risk in patch users 12-20 vs 24-40 cases per 100,000 women per year
- VTE risk in pregnancy 48-60 cases per 100,000 women per year.
References
- Cole JA, et al. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstetrics & Gynecology. 2007;109:339-346.
- Ortho Women's Health & Urology. Letter: Ortho Evra Important Prescribing Information. Feb 2008.
- Jick SS, et al. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 µg of ethinyl estradiol. Contraception. 2006;73:223-228.
- Jick S, et al. Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 µg of ethinyl estradiol. Contraception. 2007;76:4-7.
- Boston Collaborative Drug Surveillance Program. Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 µg of EE in relation to non-fatal venous thromboembolism, ischemic stroke, and myocardial infarction. Accessed March 27, 2008 http://www.clinicaltrials.gov.
- van den Heuval MW, et al. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72:168-174.
- Spitzer WO. The aftermath of a pill scare: regression to reassurance. Hum Reprod Update. 1999;5:736-745.
- Lidegaard O. Thrombotic diseases in young women and the influence of oral contraceptives. Am J Obstet Gynecol. 1998;179:S62-67.
- Lidegaard O, et al. Oral contraceptives and venous thromboembolism: a case-control study. Contraception. 1998;57:291-301.
- Kluft C, et al. Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables. Contraception. 2007;77:77-83.
- Speroff and Darney. A clinical guide for contraception. 4th Edition. Lippincott, Williams & Wilkins 2005. Philadelphia, PA.
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