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Hormone Replacement Therapy Patches May NOT Increase the Risk of Venous Thromboembolism; However, Contraceptive Patches May Increase the Risk MORE Than Oral Contraceptives

Elisabeth Sharp, Pharm.D.
Pharm.D. Resident, Audie Murphy VA Hospital, San Antlonio, TX
Jennifer Roby
Pharm.D. Candidate, Philadelphia College of Pharmacy, Philadelphia, PA.
July, 2008

Recently, the U.S. FDA approved changes to the Ortho Evra contraceptive patch that warned of a possible increased risk of venous thrombosis (VTE) in users of the patch (see
). Interestingly, a new meta-analysis has examined the data of oral vs. patch administration of hormone replacement therapy (HRT) and concluded the opposite - that oral HRT increases the risk of VTE by approximately 2 fold but that HRT administered by patch does not increase VTE risk.

Randomized control trials have demonstrated an increased risk of venous thromboembolism (VTE) in post menopausal women who use hormone replacement therapy (HRT).1 A recent case-control study has suggested the importance of route of estrogen administration (oral versus transdermal) in determining risk of VTE.2 Biologic evidence supports this observed difference in risk of VTE among women using oral and transdermal HRT. Oral, but not transdermal, estrogen undergoes hepatic first pass effect and may affect the balance between prothrombotic and antithrombotic mechanisms, as well as may increase plasma concentration of prothrombin fragment 1+2 (a marker for in vivo thrombin production), lower antithrombin concentration, and result in acquired protein C resistance.3-9

A meta-analysis recently published in the British Medical Journal was designed to examine the risk of VTE among women on HRT, evaluating oral and transdermal routes. In this analysis, the risk of VTE was assessed using eight observational studies and nine randomized control trials. All but one of the observational studies reported an association between oral estrogen and an increased risk of VTE (odds ratio 2.5, CI 1.9-3.4). Based on the observational trials, it appeared that the risk of VTE was much less with transdermal estrogen (odds ratio 1.2, CI 0.9-1.7) versus oral estrogen. Results from randomized control trials confirmed the association between oral estrogen use and VTE (odds ratio 2.1, CI 1.4-3.1), as did the combined data from both observational and randomized control trials using oral estrogen (odds ratio 2.4, CI 1.9-3.0). It was also noted that women with hypercoagulable states, including factor V Leiden or the prothrombin G20210A mutation, were at three times greater risk of developing VTE than those without the mutation. The risk of VTE increased significantly when the hypercoagulable state was combined with oral estrogen (odds ratio 8.0, CI 5.4-11.9). However, when transdermal estrogen was added to the mutation, there was not significant difference in VTE risk (odds ratio 4.4, CI 2.0-9.9).10

Interestingly, the U.S. Food and Drug Administration has approved changes to the Ortho Evra transdermal contraceptive patch label to include a warning for the risk of VTE. The changes are based on the results of three epidemiologic studies that used information from electronic health care claims and compared Ortho Evra to oral contraceptive pills containing 30-35 micrograms of ethinyl estradiol in combination with either norgestimate or levonorgestrel. One study, by i3 Igentix, showed that some women using Ortho Evra were at a two-fold risk of developing VTE compared to those taking oral contraceptives (odds ratio 2.4, CI 1.1-5.5).12 The other studies, conducted by the Boston Collaborative Drug Surveillance Program, had conflicting results. The first found that the risk of VTE was similar with Ortho Evra versus oral contraceptive pills (odds ratio 0.9, CI 0.5-1.6).13 Further results of this study were published in February 2007, with similar conclusions (odds ratio 1.1, CI 0.6-2.1).14 The most recent study, which prompted the January 2008 label change, showed a two-fold increase in the risk of VTE with Ortho Evra versus oral contraceptive pills (odds ratio 2.0, CI 0.9-4.1).15 Of note, the concentration of estrogen in the blood stream is about 60% higher in the patch than the oral estrogen at steady state, though it is unknown if this significantly affects the risk of thromboembolism that may be associated with its use.15


  1. Beral V, Banks E, Reeves G. Evidence from randomized trials on the long-term effects of hormone replacement therapy. Lancet 2002;360:942-44.

  2. Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal osteogen-replacement therapy with venous thromboembolism therapy: a scientific review. Lancet 2003;362:428-32.

  3. Lowe GD, Upton MN, Rumley A, McConnachie A, O’Reilly DS, Watt GC. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein-a cross-sectional population survey. Thromb Haemost 2001;86:550-6.

  4. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17:3071-8.

  5. Oger E, Alhenc-Gelas M, Lacut K , Blouch MT, Roudaut N, Kerlan V, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol 2003;23:1671-6.

  6. Conard J, Samama M, Basdevant A, Guy-Grand B, de Lignieres B. Differential AT III-response to oral and parenteral administration of 17beta-estradiol. Thromb Haemost 1983;49:252.

  7. Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999;354:2036-40.

  8. Hoibraaten E, Mowinckel MC, de Ronde H, Bertina RM, Sandset PM. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001;115:415-20.

  9. Post MS, Christella M, Thomassen LG, van der Mooren MJ, van Baal WM, Rosing J, Kenemans P, Stehouwer CD. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol 2003;23:1116-21.

  10. Canonic M, Plu-Bureau G, Lowe G, and Scarabin PY. Hormone replacement therapy and risk of women: systematic review and meta-analysis venous thromboembolism in postmenopausal. BMJ 2008;336;1227-1231.

  11. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstetrics & Gynecology 2007;109(2):339-346.

  12. Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 mcg of ethinyl estradiol. Contraception 73 (2006): 223-228.

  13. Jick S, Kaye JA, Li L, Jick H. 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 mug of ethinyl estradiol. Contraception. 2007 Jul;76(1):4-7.

  14. 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.

  15. Ortho Evra package insert. Ortho-McNeil Pharmaceuticals. Raritan, NJ. 2001. Revised January 2008.
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