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 χ 2 and I 2 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

We thank Drs Micheletti and Chevallier for their interest in our report. 1 First, we believe that odds ratios (ORs) and 95% confidence intervals (CIs) estimated from logistic regressions provide adequate information about significance and the size and direction of the effect of norpregnane derivatives. Because elevation in venous thromboembolism (VTE) risk is substantial (OR: 4) and significantly different from 1 (with the 95% CI not crossing 1), our results suggest a thrombogenic effect of norpregnanes, and the probability value (PϽ0.006) indicates that the probability of the result being due to chance is very small. Second, only the main effects of the route of estrogen administration and type of progestogens were estimated with a joint model ( Table 2 of the original article 1 ). Stratified analyses by route of estrogen administration and type of progestogens have also been performed. Among transdermal estrogen users, women received estrogen alone (10 cases and 35 controls; OR: 0.8, 95% CI: 0.4 to 1.8 after adjustment for obesity, family history of VTE, and varicose veins) or combined with either micronized progesterone (13 cases and 63 controls; OR: 0.6, 95% CI: 0.3 to 1.2), pregnane derivatives (16 cases and 51 controls; OR: 0.8, 95% CI: 0.4 to 1.6), or norpregnane derivatives (28 cases and 31 controls; OR: 3.1, 95% CI: 1.7 to 5.9). Among oral estrogen users, women received estrogen alone (4 cases and 5 controls) or combined with either micronized progesterone (6 cases and no controls), pregnane derivatives (23 cases and 28 controls), norpregnane derivatives (12 cases and 6 controls), or nortestosterone derivatives (12 cases and 7 controls). There was no significant difference in VTE risk between any of the progestogen subgroups among current users of oral estrogen (overall OR: 4.5, 95% CI: 2.6 to 7.5).Third, to allow for adequate numbers of subjects within subgroups, stratified analysis by time of exposure used the median of the distribution (5 years) as a cutoff point. Unlike oral estrogens, there was no significant interaction between the time of exposure to either transdermal estrogens or norpregnane derivatives and VTE risk. Therefore, differences in exposure time to hormone therapy cannot explain our results.Finally, although our results may be clinically relevant, we acknowledge that interpretation of data may have been biased by the inclusion of women with hyperestrogenic symptoms who were prescribed norpregnane derivatives. This prescription bias was emphasized in the Discussion section. Regarding the absence of thrombogenic mechanism underlying our results, Micheletti and Chevallier quote an inconclusive small trial 2 that failed to also show the well-known activation of blood coagulation among women using oral estrogens. In addition, relevant hemostatic tests such as plasmaactivated protein C sensitivity were not included as end points in this trial. Because relevant data are lacking, we are presently investigating the impact of norpregnanes on hemostasis among users of hormone therapy in the Stu...

The risk of deep vein thrombosis and pulmonary embolism after surgery is substantially increased in the first 12 postoperative weeks, and varies considerably by type of surgery. An estimated 1 in 140 middle aged women undergoing inpatient surgery in the UK will be admitted with venous thromboembolism during the 12 weeks after surgery (1 in 45 after hip or knee replacement and 1 in 85 after surgery for cancer), compared with 1 in 815 after day case surgery and only 1 in 6200 women during a 12 week period without surgery.

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. (Circulation.

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 80 308 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 (HRϭ1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HRϭ1.7; 95% CI: 1.1 to 2.8 and HRϭ1.1; 95% CI: 0.8 to 1.8; homogeneity: Pϭ0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: PϽ0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HRϭ0.9; 95% CI: 0.6 to 1.5, HRϭ1.3; 95% CI: 0.9 to 2.0 and HRϭ1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HRϭ1.8; 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.

Summary. Background: Current use of menopausal hormone therapy (HT) increases the risk of venous thromboembolism (VTE) and the formulations used may affect risk. Methods: A total of 1 058 259 postmenopausal UK women were followed by record linkage to routinely collected National Health Service hospital admission and death records. HT use and risk of VTE was examined using Cox regression to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: During 3.3 million years of follow-up, 2200 women had an incident VTE, diagnosed, on average, 1.5 years after last reporting HT use. RRs in current vs. never users at last reporting varied by HT formulation: the risk was significantly greater for oral estrogen-progestin than oral estrogen-only therapy (RR = 2. P heterogeneity = 0.0007). Current users of oral HT at last reporting had twice the risk of VTE in the first 2 years after starting HT than later (P heterogeneity = 0.0006). Associations were similar for deep vein thrombosis with and without pulmonary embolism. Over 5 years, 1 in 660 who had never used HT were admitted to hospital for (or died from) pulmonary embolism, compared with 1 in 475 current users of oral estrogen-only HT,1 in 390 users of estrogen-progestin HT containing norethisterone/norgestrel, and 1 in 250 users of estrogen-progestin HT containing medroxyprogesterone acetate. Conclusions: The risk of VTE varied considerably by HT formulation, being greatest in users of oral estrogen-progestin HT, especially formulations containing medroxyprogesterone acetate.

BackgroundParkinson’s disease (PD) is 1.5 times more frequent in men than women. Whether age modifies this ratio is unclear. We examined whether male-to-female (M–F) ratios change with age through a French nationwide prevalence/incidence study (2010) and a meta-analysis of incidence studies.MethodsWe used French national drug claims databases to identify PD cases using a validated algorithm. We computed M–F prevalence/incidence ratios overall and by age using Poisson regression. Ratios were regressed on age to estimate their annual change. We identified all PD incidence studies with age/sex-specific data, and performed a meta-analysis of M–F ratios.ResultsOn the basis of 149 672 prevalent (50% women) and 25 438 incident (49% women) cases, age-standardised rates were higher in men (prevalence=2.865/1000; incidence=0.490/1000 person-years) than women (prevalence=1.934/1000; incidence=0.328/1000 person-years). The overall M–F ratio was 1.48 for prevalence and 1.49 for incidence. Prevalence and incidence M–F ratios increased by 0.05 and 0.14, respectively, per 10 years of age. Incidence was similar in men and women under 50 years (M–F ratio <1.2, p>0.20), and over 1.6 (p<0.001) times higher in men than women above 80 years (p trend <0.001). A meta-analysis of 22 incidence studies (14 126 cases, 46% women) confirmed that M– F ratios increased with age (0.26 per 10 years, p trend=0.005).ConclusionsAge-increasing M–F ratios suggest that PD aetiology changes with age. Sex-related risk/protective factors may play a different role across the continuum of age at onset. This finding may inform aetiological PD research.

AimsTo assess whether AF is a risk factor for cognitive dysfunction we used prospective data on AF, repeat cognitive scores, and dementia incidence in adults followed over 45 to 85 years.Methods and resultsData are drawn from the Whitehall II study, N = 10 308 at study recruitment in 1985. A battery of cognitive tests was administered four times (1997–2013) to 7428 participants (414 cases of AF), aged 45–69 years in 1997. Compared with AF-free participants, those with longer exposure to AF (5, 10, or 15 years) experienced faster cognitive decline after adjustment for sociodemographic, behavioural, and chronic diseases (P for trend = 0.01). Incident stroke or coronary heart disease individually did not explain the excess cognitive decline; however, this relationship was impacted when considering them together (P for trend 0.09). Analysis of incident dementia (N = 274/9302 without AF; N = 50/912 with AF) showed AF was associated with higher risk of dementia in Cox regression adjusted for sociodemographic factors, health behaviours and chronic diseases [hazard ratio (HR): 1.87; 95% confidence interval (CI): 1.37, 2.55]. Multistate models showed AF to increase risk of dementia in those free of stroke (HR: 1.67; 95% CI: 1.17, 2.38) but not those free of stroke and coronary heart disease (HR: 1.29; 95% CI: 0.74, 2.24) over the follow-up.ConclusionIn adults aged 45–85 years AF is associated with accelerated cognitive decline and higher risk of dementia even at ages when AF incidence is low. At least in part, this was explained by incident cardiovascular disease in patients with AF.