Marianne Canonico

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women Impact of the Route of Estrogen Administration and Progestogens: The ESTHER Study

Background— Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen. Methods and Results— We performed a multicenter case–control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0). Conclusions— Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.

Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis

Objective To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background. Design Systematic review and meta-analysis. Data sources Medline. Studies reviewed Eight observational studies and nine randomised controlled trials. Inclusion criteria Studies on hormone replacement therapy that reported venous thromboembolism. Review measures Homogeneity between studies was analysed using χ2 and I2 statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model. Results Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism. Conclusion Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.

Postmenopausal Hormone Therapy and Risk of Idiopathic Venous Thromboembolism. Results From the E3N Cohort Study

Objective—Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established. Methods and Results—We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7). Conclusions—In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.

Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.

Summary.  Background: Oral estrogen use and elevated body mass index (BMI) increase the risk of venous thromboembolism (VTE). Recent data suggest that transdermal estrogen might be safe with respect to thrombotic risk. However, the impact of transdermal estrogen on the association between overweight (25 kg m−2 < BMI ≤ 30 kg m−2) or obesity (BMI >30 kg m−2) and VTE risk has not been investigated. Methods: We carried a multicenter case–control study of VTE among postmenopausal women aged 45–70 years, between 1999 and 2005, in France. Case population consisted of women with a first documented idiopathic VTE. We recruited 191 hospital cases matched with 416 hospital controls and 62 outpatient cases matched with 181 community controls. Results: The odds ratio (OR) for VTE was 2.5 [95% confidence interval (CI):1.7–3.7] for overweight and 3.9 (95% CI: 2.2–6.9) for obesity. Oral, not transdermal, estrogen was associated with an increased VTE risk (OR = 4.5; 95% CI: 2.6–7.7 and OR = 1.1; 95% CI: 0.7–1.7, respectively). Compared with non‐users with normal weight, the combination of oral estrogen use and overweight or obesity further enhanced VTE risk (OR = 10.2; 95% CI: 3.5–30.2 and OR = 20.6; 95% CI: 4.8–88.1, respectively). However, transdermal users with increased BMI had similar risk as non‐users with increased BMI (OR = 2.9; 95% CI: 1.5–5.8 and OR = 2.7; 95% CI: 1.7–4.5 respectively for overweight; OR = 5.4; 95% CI: 2.1–14.1 and OR = 4.0; 95% CI: 2.1–7.8 respectively for obesity). Conclusions: In contrast to oral estrogen, transdermal estrogen does not confer an additional risk of idiopathic VTE in women with increased BMI. The safety of transdermal estrogen on thrombotic risk has to be confirmed.

Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women.

Purpose of reviewVenous thromboembolism (VTE) is a main harmful effect of oral estrogen therapy among postmenopausal women. Transdermal estrogens may be safer but early results need to be confirmed. This review provides a summary of the most recent findings regarding the VTE risk among oral versus transdermal estrogens users. Recent findingsSince 2008, we identified five relevant observational studies. Among them, two large cohort studies confirmed that oral but not transdermal estrogens were associated with VTE risk among postmenopausal women. In an updated meta-analysis of current data, pooled risk ratios for VTE were 1.9 [95% confidence interval (CI) 1.3–2.3] and 1.0 (95% CI 0.9–1.1) among oral and transdermal estrogens users, respectively. In addition, one recent cohort study showed that transdermal estrogens did not confer an excess risk of recurrent VTE among postmenopausal women with a history of VTE. The difference in VTE risk between oral and transdermal estrogen users is supported by biological data. Whereas oral estrogens can increase thrombin generation and induce a resistance to activated protein C, transdermal estrogens have minimal effects on hemostatic variables. SummaryTransdermal estrogens may improve substantially the benefit/risk ratio of postmenopausal hormone therapy and should be considered as a safer option, especially for women at high risk for VTE.

Progestogen-Only Contraceptives and the Risk of Stroke A Meta-Analysis

Background and Purpose— The association between combined oral contraceptives (OC) use and increased risk of stroke has been reported. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular disease remains unclear. Methods— A meta-analysis based on EMBASE and MEDLINE referenced literature corresponding to OCs marketed since 1960 was carried out. Eligible articles assessing the risk of stroke in relation to OC or POC were reviewed, and relevant studies were extracted. All types of POC and routes of administration were taken into account in the meta-analysis. Results— Six case–control studies were identified. The combined odd ratio (OR) showed no increase in the risk of stroke among POC users (OR=0.96; 95% confidence interval: 0.70 to 1.31). This result was similar according to the route of administration (either implant or injectable or oral POC). Conclusion— Data from observational studies show that POC use is not associated with an increased risk of stroke. However, these results are based on limited data. Further investigations are needed in women with risk factors of stroke.

Hormone therapy and recurrence of venous thromboembolism among postmenopausal women.

Objectives: The route of estrogen administration is an important determinant of the risk of the first venous thromboembolism (VTE) event in postmenopausal women using hormone therapy (HT). However, the impact of transdermal estrogens on VTE recurrence risk has not been investigated. The aim of our study was to assess the impact of HT by route of estrogen administration on the risk of recurrent VTE. Methods: A total of 1,023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE were recruited from an outpatient clinic of a hemostasis hospital unit between January 2000 and December 2008 and were followed for an average of 79 months after discontinuation of anticoagulation therapy. Results: Recurrent VTE occurred in 77 women (1.1% per year). During the follow-up, 130 women used HT (12.7%), including 103 transdermal estrogen users (10.0%) and 10 oral estrogen users (1.0%). After adjustment for potential confounders, there was no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), with the nonusers as a reference group. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio, 6.4; 95% CI, 1.5-27.3). Consistently, no subgroup of women had evidence of a risk of recurrent VTE with transdermal HT that significantly differed from that observed for all women. Conclusions: Oral but not transdermal estrogens are associated with a higher risk of recurrent VTE among postmenopausal women. This result provides further epidemiological evidence that transdermal estrogens may be safe with respect to VTE risk.

Hormonal contraceptives and venous thromboembolism: An epidemiological update

Since the early 1960s, it has been well documented that combined hormonal contraceptives increase the risk of cardiovascular disease. Newer generation of oral formulations, as well as non-oral contraceptives (transdermal and vaginal), have been recently studied for thrombotic risk. This review provides a summary of the association between hormonal contraceptives and venous thromboembolism with emphasis on new formulations of hormonal contraceptives as well as route of administration. A systematic search of Medline database was done for all relevant articles which included women having used third generation pills, and the development of new progestins. Eligible articles published in English and reporting the risk of venous thromboembolism (VTE) (pulmonary embolism or deep venous thrombosis) among users of hormonal contraceptives were reviewed. A quantitative assessment was made from included studies. Current use of drospirenone or cyproterone oral combined contraceptives increased the risk of VTE compared with second generation pills (pooled OR: 1.7; 95% confidence interval [95% CI]: 1.4-2.2 and OR: 1.8; 95% CI: 1.4-2.3, respectively). In the context of contraceptive use, non-oral route of ethinyl-estradiol administration seems to be more thrombogenic than oral route. In contrast, low doses of both oral progestin contraceptives and intrauterine levonorgestrel could be safe with respect to VTE risk. In conclusion, newer generation formulations of hormonal contraceptives, as well as the non-oral hormonal contraceptive, seem to be more thrombogenic than second generation hormonal contraceptives.

Progestogen-only contraceptives and the risk of acute myocardial infarction: a meta-analysis.

CONTEXT The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear. OBJECTIVE We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960. METHODS Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered. RESULTS Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62-1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC. CONCLUSION Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk.

Hormonal contraceptives and arterial disease: An epidemiological update

The cardiovascular safety of widely used combined hormonal contraceptives is still debated. Newer generations of oral formulations as well as non-oral contraceptives (transdermal and vaginal) have been recently evaluated in the context of cardiovascular disease. This review provides a summary of the association between combined oral contraceptives (COCs) and arterial diseases, with an emphasis on new formulations of hormonal contraceptives, as well as routes of administration. A systematic search of the Medline database was performed to find all relevant articles which included women who had widely use third generation pills, and the development of new progestins. Eligible articles published in English and reporting risk of arterial events (myocardial infarction [MI] and stroke) among users of hormonal contraceptives were reviewed. A quantitative assessment was made from included studies. Overall, current use of oral combined contraceptives increased the risk of MI and ischemic stroke (pooled OR: 1.7; 95% confidence interval [95% CI]: 1.2-2.3 and OR: 1.8; 95% CI: 1.2-2.8, respectively), but this was not associated with the risk of hemorrhagic stroke (OR: 1.1; 95% CI: 0.7-1.9). The increase in ischemic arterial disease was higher among first generation pill users compared with second or third generation pill users. In contrast, risk of ischemic arterial disease among current users of second or third generation pill was similar (p = 0.23 for MI risk and 0.99 for ischemic stroke). In conclusion, newer generation formulations of COCs, as well as the non-oral hormonal contraceptive, do not seem to be safer than second generation hormonal contraceptives.