Article

Venous Thromboembolism, Myocardial Infarction, and Stroke Among Transdermal Contraceptive System Users

i3 Drug Safety, Auburndale, Massachusetts, USA.
Obstetrics and Gynecology (Impact Factor: 5.18). 03/2007; 109(2 Pt 1):339-46. DOI: 10.1097/01.AOG.0000250968.82370.04
Source: PubMed

ABSTRACT

To estimate the incidence of venous thromboembolism, acute myocardial infarction, and ischemic stroke among transdermal contraceptive system users compared with users of norgestimate-containing oral contraceptives with 35 mcg ethinyl estradiol.
We began with insurance claims data from UnitedHealthcare. We identified women exposed to the transdermal contraceptive system or norgestimate-containing oral contraceptives from April 2002 through December 2004. Outcomes were confirmed from medical records. We calculated incidence rates and age-adjusted incidence rate ratios. In a nested case-control analysis, we investigated and controlled for confounding.
There were 49,048 woman-years of transdermal contraceptive system exposure and 202,344 woman-years of norgestimate-containing oral contraceptives exposure. There was a more than two-fold increase in the venous thromboembolism rate (incidence rate ratio 2.2, 95% confidence interval [CI] 1.3-3.8) among transdermal contraceptive system users (20 cases, 40.8 per 100,000 woman-years) compared with norgestimate-containing oral contraceptives users (37 cases, 18.3 per 100,000 woman-years). Acute myocardial infarction occurred in three transdermal contraceptive system users compared with seven among norgestimate-containing oral contraceptives users (incidence rate ratio 1.8, 95% CI 0.5-6.8). No strokes occurred among transdermal contraceptive system users, whereas 10 occurred among norgestimate-containing oral contraceptives users. In the nested case-control analysis, after exclusions for high-risk factors, the odds ratio for venous thromboembolism was 2.4 (95% CI 1.1-5.5).
There was a more than two-fold increase in the risk of venous thromboembolism associated with use of the transdermal contraceptive system. Acute myocardial infarction and stroke occurred too rarely to ascertain precise risk estimates.
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    • "These progestins are considered to be less androgenic than levonorgestrel. In combination with EE, these nonoral CHCs have also been associated with an increased risk of VTE compared with oral CHCs [21,293031 and demonstrate biological changes similar to oral CHCs32333435. Nestorone® (NES) is a new, potent 19-nor-progesterone that is not active orally but is effective when administered via nonoral routes such as implants, vaginal rings and transdermal systems. "
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    ABSTRACT: Objectives: Estrogen-sensitive hepatic proteins were assessed in women using a contraceptive vaginal ring (CVR) delivering 150 μg Nestorone® (NES) and 15 μg ethinyl estradiol (EE). Study design: A sub-study of the Contraceptive Clinical Trials Network of the National Institute of Child Health (NICHD) enrolled 129 participants, with assessments of factor VIII, fibrinogen, Protein S (PS) and Sex Hormone Binding Globulin (SHBG). Thirty-six participants had used combined hormonal contraceptives (CHCs) in the cycle preceding first CVR use (recent users) and 70 had no history of recent use (non-users). Results: Mean values at baseline were within the normal range for all four proteins, but were higher for factor VIII, fibrinogen and SHBG and significantly lower for PS in recent compared to non-users. During NES/EE CVR use, Factor VIII, fibrinogen, and Protein S were within the normal range, however SHBG levels were increased by nearly 100% at cycle 13. The change from baseline to final evaluation was statistically significant for all proteins in non-users. The change in recent users was significant for factor VIII at cycle 6 and SHBG at 6 and 13, but not for PS or fibrinogen. Conclusion: NES/EE CVR for up to 13 cycles was associated with changes from baseline in plasma levels of factor VIII, fibrinogen, and Protein S that were within the normal range, with SHBG levels above the normal range by Cycle 6. Non-users of CHC before CVR showed wider changes in values versus recent users whose baseline values were increased by previous EE exposure. Implications: Recent use of CHCs demonstrated significant changes in all 4 measured hepatic proteins at baseline compared to non-users. Use of the NES/EE CVR further changed these hepatic protein markers, but values remained within the normal range. Pre-baseline exposure to estrogen can obscure interpretation of hepatic proteins changes associated with a second CHC.
    No preview · Article · Sep 2015 · Contraception
    • "The first TCDS approved by the US Food and Drug Administration (FDA), Ortho Evra [norelgestromin and ethinyl estradiol (EE); Ortho-McNeil- Janssen Pharmaceuticals, Inc., Raritan, NJ, USA), was reported to have an EE area under the curve (AUC) about 60% higher than those found with COCs containing 35 mcg/d EE [4] [5] [6]. Increased estrogen exposure is a safety concern due to the elevated risk for venous thromboembolism and other hormone-related cardiovascular adverse events (AEs) [7]. The EE dose in COCs has decreased over the years; now, 20–35 mcg EE daily COCs are routinely prescribed in the United States. "
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    ABSTRACT: The new transdermal contraceptive delivery system (TCDS) developed by Agile Therapeutics containing ethinyl estradiol and levonorgestrel (EE/LNG) is a reversible contraceptive method that maintains stable serum levels of both estrogen and progestin, and has efficacy similar to that of combination oral contraceptives (COC). We provided information of this new TCDS compared with the only TCDS available on the market that contains EE and norelgestromin, and has a higher EE exposure than a COC with 35 µg of EE potentially increasing the risk of venous thromboembolism. The article will summarize finding from clinical studies Phase I, II and III of EE/LNG TCDS. The development of the lower dose EE/LNG TCDS has demonstrated less EE exposure. The serum levels of EE and LNG were stable and comparable between various application sites and daily life conditions. Moreover, the EE/LNG TCDS showed comparable efficacy among obese and non-obese users. However, the Pearl index of this EE/LNG TCDS is questionable and the problem of compliance is a potential confounder of the results. The current Phase III efficacy study will contribute to a further evaluation of compliance and efficacy and will be completed in 2016.
    No preview · Article · Aug 2015 · Expert Opinion on Pharmacotherapy
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    • "Furthermore, for both third- and second-generation formulations, COC-induced increases in the activity of (pro)coagulatory factors are not always balanced by increased biological levels of coagulation inhibitors [21]. There is some indication that transdermal delivery of hormones may reduce the risk of VTE associated with COC use [22], although the supporting data are limited, and results from clinical trials are conflicting [16, 23–25]. "
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    ABSTRACT: Transdermal delivery of contraceptives offers several advantages over combined oral contraceptives (COCs), including effective absorption and the provision of relatively constant serum concentrations. Ethinyl estradiol (EE) and the progestin gestodene are well-absorbed through the skin and, therefore, well-suited for use in a transdermal contraceptive patch. The objective of this study was to investigate the impact of a once-weekly transparent, transdermal patch delivering low doses of EE and gestodene equivalent to a COC containing 0.02 mg EE and 0.06 mg gestodene on hemostasis parameters compared with a monophasic COC containing 0.03 mg EE and 0.15 mg levonorgestrel. In this single-center, open-label, randomized, crossover study, 30 women (aged 18-35 years) received three cycles of each treatment, separated by a two-cycle washout period. The primary outcome measure was the absolute change from baseline in prothrombin fragments 1 + 2 and D-dimer. For both treatments, prothrombin fragments 1 + 2 remained stable during the first treatment period, and increased only slightly in the second period (mean absolute change 0.025 and 0.028 nmol/L in the novel Bayer patch and COC groups, respectively). Increases in D-dimer were observed in both periods (mean absolute change 107.0 ± 147.2 ng/L for the novel Bayer patch and 113.7 ± 159.0 ng/L for the COC). There were no statistically significant treatment differences in prothrombin 1 + 2 or D-dimer (p = 0.667 and p = 0.884, respectively) and no statistically significant treatment sequence or period effects. A COC containing 0.03 mg EE and 0.15 mg levonorgestrel and the novel Bayer patch have comparable influence on hemostatic endpoints. Both treatments were well-tolerated by subjects.
    Full-text · Article · Sep 2013
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