Postmenopausal Hormone Therapy and Risk of Stroke: Impact of the Route of Estrogen Administration and Type of Progestogen.

BACKGROUND AND PURPOSE: The benefit/risk analysis of hormone therapy in postmenopausal women is not straightforward and depends on cardiovascular disease. Evidence supports the safety of transdermal estrogens and the importance of progestogens for thrombotic risk. However, the differential association of oral and transdermal estrogens with stroke remains poorly investigated. Furthermore, there are no data regarding the impact of progestogens. METHODS: We set up a nested case-control study of ischemic stroke (IS) within all French women aged 51 to 62 years between 2009 and 2011 without personal history of cardiovascular disease or contraindication to hormone therapy. Participants were identified using the French National Health Insurance database, which includes complete drug claims for the past 3 years and French National hospital data. We identified 3144 hospitalized IS cases who were matched for age and zip code to 12 158 controls. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Compared with nonusers, the adjusted ORs of IS were1.58 (95% CI, 1.01-2.49) in oral estrogen users and 0.83 (0.56-1.24) in transdermal estrogens users (P<0.01). There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67), and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81). CONCLUSIONS: Both route of estrogen administration and progestogens were important determinants of IS. Our findings suggest that transdermal estrogens might be the safest option for short-term hormone therapy use.

Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis.

BACKGROUND: Parkinson'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. METHODS: We 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. RESULTS: On 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). CONCLUSIONS: Age-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.

Carotid plaque as a predictor of dementia in older adults: the Three-City Study.

BACKGROUND: The contribution of carotid atherosclerosis to incident dementia remains unclear. We examined the association between carotid plaques (CP) and common carotid intima media thickness (CCA-IMT) with incident dementia and its subtypes, and their added value for dementia risk prediction. METHODS: At baseline, 6025 dementia-free subjects aged 65-86 years underwent bilateral carotid ultrasonography measures of CP and plaque-free CCA-IMT. Subjects were followed-up over 7 years for the detection of dementia. RESULTS: After a mean 5.4 years of follow-up, 421 subjects developed dementia including 272 Alzheimer's disease and 83 vascular/mixed dementia (VaD). Only CP were independently related to VaD (HR(≥2 sites with plaques) = 1.92; 95% confidence interval or CI = 1.13-3.22) and improved VaD risk prediction (continuous Net Reclassification Index = 30.1%; 95% CI = 8.4-51.7) beyond known dementia risk factors. Accounting for stroke or competing risk by death marginally modified the results. CONCLUSION: In older adults, CP are independent predictors of incident VaD and may improve VaD risk prediction.

A new operational definition of frailty: the Frailty Trait Scale.

OBJECTIVES: To provide a new instrument to diagnose frailty, the Frailty Trait Scale (FTS), that allows a more precise assessment and monitoring of individuals. DESIGN: Prospective population-based cohort study. SETTING: The Toledo Study for Healthy Aging, Spain. PARTICIPANTS: A total of 1972 men and women aged 65 years or older. MEASUREMENTS: We identified 7 frailty dimensions (energy balance-nutrition, physical activity, nervous system, vascular system, strength, endurance, and gait speed) represented by 12 items. Each item was pondered based on the quintiles of its distribution in the study population. Validity was evaluated by testing its association with factors related to frailty and its predictive value for adverse events. This predictive capacity was further compared with the capacity of 2 well-established frailty models (the frailty phenotype and the Frailty Index). RESULTS: FTS score was associated with several comorbidities and biomarkers classically associated with frailty. The FTS was associated with the incidence of hospitalization and mortality (hazard ratio associated with a score in the highest quartile [versus the first quartile] = 2.3, 95% confidence interval [CI] 1.6-3.4, and 2.5, 95% CI 1.8-3.6, respectively). Compared with Fried et al's definition, the FTS showed a better predictor for hospitalization in persons younger than 80 (area under the curve [AUC] = 0.65 vs 0.62, P = .01), and for mortality in the oldest group (AUC = 0.77 vs 0.72, P = .02). FTS showed similar predictive value to the Frailty Index. CONCLUSION: FTS associates with many of the factors linked to frailty and has a similar predictive capacity to that provided by the classical instruments. Its characteristics offer some advantages over them, with potential utility in research and clinical practice.

High plasma estradiol interacts with diabetes on risk of dementia in older postmenopausal women.

OBJECTIVE: We aimed to investigate the impact of endogenous estradiol (E2) on dementia and to evaluate the contribution of vascular risk factors and inflammatory and blood coagulation markers to this association. METHODS: Using data from a French population-based prospective study (the Three-City Study) including 5,644 postmenopausal women aged 65 years or older, we investigated the association of endogenous total-E2 and bioavailable-E2 and total-testosterone with the 4-year incidence of all-cause dementia. We further focused on the role of dementia and cardiovascular risk factors as well as inflammation (C-reactive protein, fibrinogen) and hypercoagulability (fibrin d-dimers, thrombin generation) in these associations. We used a case-cohort design consisting of a random subcohort of 562 women not using hormone therapy and 132 incident dementia cases. RESULTS: Adjusted Cox proportional hazards models showed a J-shaped relationship between total-E2 and risk of dementia (p = 0.001). Total-E2 values in the lower and upper quartiles were associated with an increased dementia risk (adjusted hazard ratio [HR] [95% confidence interval] = 2.2 [1.1-4.5] and HR = 2.4 [1.2-5.2], respectively). Importantly, the risk associated with higher E2 levels was dramatically increased in women with diabetes compared with nondiabetic women (adjusted HR associated with the upper E2 quartile = 14.2 [1.60-123] and HR = 3.4 [0.1-147], respectively, p interaction <0.05). Similar results were found for bioavailable-E2. Adjustment for inflammatory and blood coagulation markers did not modify our results. No significant association was found for total-testosterone. CONCLUSION: High E2 level is an independent predictor of incident dementia, particularly in postmenopausal women with diabetes.

Association between endothelial dysfunction and frailty: the Toledo Study for Healthy Aging.

Cardiovascular disease (CVD), both clinical and subclinical, has been proposed as one of the mechanisms underlying frailty. However, there is no evidence addressing the relationship between the earliest stage of CVD (endothelial dysfunction) and frailty. The goal of the study was to analyze the association between endothelial dysfunction, evaluated by asymmetric dimethylarginine (ADMA) levels, and frailty. We used data from the Toledo Study for Healthy Aging, a prospective Spanish cohort study. Biological samples were obtained and ADMA levels were determined using an enzyme immunoassay method. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals of frailty associated with ADMA. Adjustments were made for age, gender, cardiovascular risk factors, and presence of atherosclerotic disease (assessed by ankle­brachial index; ABI). One thousand two hundred eighty-seven community-dwelling elderly were included. One hundred seven (8.3 %) were identified as frail, 542 (42.1 %) as pre-frail, and 638 (49.6 %) as non-frail. ADMAvalues were higher in frail subjects than in non-frail ones. In addition, an interaction between the presence of atherosclerotic disease and ADMA on the odds of frailty (p=0.045) was detected. After adjustments for age, classical cardiovascular risk factors, and ABI, the risk of frailty was associated with increasing levels of ADMA in subjects without atherosclerotic disease [OR for 1 standard deviation increase in ADMA=1.14 (1.01­1.28), p=0.032] but not in those with atherosclerotic disease. In our study, endothelial dysfunction, assessed by ADMA levels, is associated with frailty. These findings provide additional support for a relevant role of vascular system since its earliest stage in frailty.

Low testosterone and the risk of dementia in elderly men: Impact of age and education.

OBJECTIVE: The objective of this study was to examine the association of plasma estradiol and testosterone with risk for dementia in elderly men. METHODS: Within the population based Three-City study, including 3650 men age 65 years and older, a case-cohort design was set up after 4-years of follow-up. Baseline plasma levels of total 17-ß estradiol (Total-E2), total testosterone (total-T) and bioavailable testosterone (bio-T) were measured for all cases of incident dementia (n=105) and for a random sample of the cohort (n=413). Cox regression models were used to estimate multivariate steroid sex hormone-associated hazard ratios (HR) and 95% confidence intervals of dementia. RESULTS: There was a reverse J-shaped relationship between total-T and risk for dementia (P=.007). Compared with the median tertile, the HRs associated with total-T in the lower and upper tertile were increased (HR, 2.33; P=.026; HR, 1.9, P=.126; respectively). Low bio-T was associated with a greater risk for dementia (HR for one standard deviation of decreasing log(bio-T), 1.29; 95% confidence interval, 1.03-1.62). An interaction was found between bio-T and age (P<.0001), and bio-T and education (P=.044). Risk for dementia associated with low bio-T was greater in older men (80 years or older) than in younger men (younger than 80 years; HR, 3.11; P=.011 vs. HR, 1.07, P=.715, respectively) and in men with high level of education compared with those with low level of education (HR, 2.32; P=.0002 vs. HR, 0.95; P=.790, respectively). No significant association was found between Total-E2 and dementia. CONCLUSIONS: Low levels of testosterone are associated with a risk for dementia in elderly men. The association between low bio-T and dementia may be more relevant to men 80 years or older and men with a high level of education.

Estrogen receptor polymorphisms and incident dementia: the prospective 3C study.

BACKGROUND: Genetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors. METHODS: The association between five ESR α (ESR1) and ß (ESR2) polymorphisms with 7-year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate-adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association. RESULTS: Among women, the CC genotype of ESR1rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03-2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE ε4 allele (adjusted HR: 3.24, 95% CI: 1.81-5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37-2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men. CONCLUSIONS: Although there was only weak support for a gender-specific association between the common ESR1rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE ε4 allele.

A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project.

BACKGROUND: There is no consensus regarding the definition of frailty for clinical uses. METHODS: A modified Delphi process was used to attempt to achieve consensus definition. Experts were selected from different fields and organized into five Focus Groups. A questionnaire was developed and sent to experts in the area of frailty. Responses and comments were analyzed using a pre-established strategy. Statements with an agreement more than or equal to 80% were accepted. RESULTS: Overall, 44% of the statements regarding the concept of frailty and 18% of the statements regarding diagnostic criteria were accepted. There was consensus on the value of screening for frailty and about the identification of six domains of frailty for inclusion in a clinical definition, but no agreement was reached concerning a specific set of clinical/laboratory biomarkers useful for diagnosis. CONCLUSIONS: There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established.

Is frailty a prodromal stage of vascular dementia? Results from the Three-City Study.

OBJECTIVES: To investigate the relationship between frailty and incident vascular dementia (VaD). DESIGN: Seven-year longitudinal study. SETTING: Three-City Study, a French prospective study designed to evaluate the risk of dementia and cognitive decline attributable to vascular risk factors. PARTICIPANTS: Five thousand four hundred eighty community-dwelling persons aged 65 to 95. MEASUREMENTS: An expert committee established a clinical diagnosis of VaD. Frailty was defined as having at least three of the following criteria: weight loss, weakness, exhaustion, slowness, and low physical activity. Participants with prior stroke or prevalent dementia at baseline were excluded from analyses. Multivariate models were used to evaluate the relationship between frailty and incident VaD. RESULTS: At baseline, 6.5% of participants were classified as frail. After 7 years of follow-up, 54 persons were diagnosed with VaD, seven of whom where frail. In the proportional hazards models, frailty was marginally associated with greater risk of all types of dementia and was not associated with incident Alzheimer's disease, but frailty status was independently associated with incident VaD. CONCLUSION: Frailty is a major risk factor for incident VaD, so its identification could contribute to better estimates of the risk of VaD in elderly adults.

Endogenous oestradiol as a positive correlate of plasma fibrinogen among older postmenopausal women: a population-based study (the Three-City cohort study).

BACKGROUND: Plasma fibrinogen is a strong predictor of ischaemic arterial disease in women. Sex steroid hormones including hormone therapy may play an important role in the development of cardiovascular disease. However, whether endogenous sex steroid hormones influence the plasma fibrinogen concentrations among postmenopausal women remains unclear. OBJECTIVES: To investigate the association of plasma fibrinogen levels with endogenous sex steroid hormones and sex hormone binding globulin (SHBG) among postmenopausal women. METHODS: We used data from the French prospective Three-City cohort study that included 9294 noninstitutionalized men and women over 65 years of age. Total 17ß-oestradiol (E2, pg/ml), total testosterone (T, ng/ml), SHBG (nm) and fibrinogen (g/l) were measured in stored plasmas in a subcohort of 602 randomly selected postmenopausal women who used neither hormone medication nor anticoagulation therapy. Multivariate linear regression models were used to estimate the regression coefficients assessed in fibrinogen unit by 1 SD increase in log-distribution of sex steroid hormones and SHBG. RESULTS: E2 but neither T nor SHBG was positively associated with plasma fibrinogen levels (ß = 0·148, P < 0·001). Adjustment for cardiovascular risk factors including diabetes made no substantial change to the results (ß = 0·145, P < 0·001). The association of fibrinogen with E2 was stronger among women with body mass index over 25 kg/m(2) compared with those with normal weight (ß = 0·156, P < 0·001 and ß = 0·092, P = 0·02, respectively, P for interaction = 0·04). CONCLUSION: E2 emerges as a positive and independent correlate of plasma fibrinogen among postmenopausal women, especially in subjects who are overweight. These findings suggest a deleterious effect of endogenous oestrogens on cardiovascular risk profile among postmenopausal women.

Sex differences in the association between serum levels of testosterone and frailty in an elderly population: the Toledo Study for Healthy Aging.

BACKGROUND: Age-associated decline in testosterone levels represent one of the potential mechanisms involved in the development of frailty. Although this association has been widely reported in older men, very few data are available in women. We studied the association between testosterone and frailty in women and assessed sex differences in this relationship. METHODS: We used cross-sectional data from the Toledo Study for Healthy Aging, a population-based cohort study of Spanish elderly. Frailty was defined according to Fried's approach. Multivariate odds-ratios (OR) and 95% confidence intervals (CI) associated with total (TT) and free testosterone (FT) levels were estimated using polytomous logistic regression. RESULTS: In women, there was a U-shaped relationship between FT levels and frailty (p for FT(2) = 0.03). In addition, very low levels of FT were observed in women with ≥ 4 frailty criteria (age-adjusted geometric means = 0.13 versus 0.37 in subjects with <4 components, p = 0.010). The association of FT with frailty appeared confined to obese women (p-value for interaction = 0.05).In men, the risk of frailty levels linearly decreased with testosterone (adjusted OR for frailty = 2.9 (95%CI, 1.6-5.1) and 1.6 (95%CI, 1.0-2.5), for 1 SD decrease in TT and FT, respectively). TT and FT showed association with most of frailty criteria. No interaction was found with BMI. CONCLUSION: There is a relationship between circulating levels of FT and frailty in older women. This relation seems to be modulated by BMI. The relevance and the nature of the association of FT levels and frailty are sex-specific, suggesting that different biological mechanisms may be involved.

Multiple imputation for estimating hazard ratios and predictive abilities in case-cohort surveys.

BACKGROUND: The weighted estimators generally used for analyzing case-cohort studies are not fully efficient and naive estimates of the predictive ability of a model from case-cohort data depend on the subcohort size. However, case-cohort studies represent a special type of incomplete data, and methods for analyzing incomplete data should be appropriate, in particular multiple imputation (MI). METHODS: We performed simulations to validate the MI approach for estimating hazard ratios and the predictive ability of a model or of an additional variable in case-cohort surveys. As an illustration, we analyzed a case-cohort survey from the Three-City study to estimate the predictive ability of D-dimer plasma concentration on coronary heart disease (CHD) and on vascular dementia (VaD) risks. RESULTS: When the imputation model of the phase-2 variable was correctly specified, MI estimates of hazard ratios and predictive abilities were similar to those obtained with full data. When the imputation model was misspecified, MI could provide biased estimates of hazard ratios and predictive abilities. In the Three-City case-cohort study, elevated D-dimer levels increased the risk of VaD (hazard ratio for two consecutive tertiles = 1.69, 95%CI: 1.63-1.74). However, D-dimer levels did not improve the predictive ability of the model. CONCLUSIONS: MI is a simple approach for analyzing case-cohort data and provides an easy evaluation of the predictive ability of a model or of an additional variable.

Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study.

BACKGROUND: The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. CONCLUSIONS/SIGNIFICANCE: The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT.

Gender differences in the prodromal signs of dementia: memory complaint and IADL-restriction. a prospective population-based cohort.

Subjective memory complaint (SMC) and restriction in cognitively-complex activities of daily living (such as instrumental ADL) are two early symptoms observed in the prodromal phase of dementia and may represent useful alarm signals for general practitioners for an increased risk of subsequent dementia. We here studied in a large population-based epidemiological cohort on aging, the risk of dementia associated with SMC and restriction in IADL, with a specific interest in a potential interaction by gender. The sample included 2,901 subjects, aged 65 years and over, initially free of dementia and followed over 15 years. After controlling for education, marital status, depressive symptomatology, and global cognition (MMSE), IADL-restriction was associated with an increased risk of dementia only in men (HR = 2.04, 1.27 to 3.29), whereas SMC was not (p = 0.95). The reverse was observed in females, in whom SMC almost doubled the risk of dementia (1.48 to 2.41), with no association with IADL-restriction (p = 0.74). Finally, we distinguished the risk of dementia at short-term (in the first 5 years), mid-term (between 5 and 10 years), and long-term (between 10 and 15 years). In women, SMC was significantly associated with greater risk of dementia whatever the risk period considered, even at longer term (HR = 1.61, p = 0.0216), whereas in men the increased risk was also observed with IADL-restriction and only in the first 5 years. To conclude, women would report the first symptoms very early in the process by SMC, whereas men would tend to later report their difficulties and only in terms of IADL-restriction.

Increased thrombin generation is associated with acute ischemic stroke but not with coronary heart disease in the elderly: the Three-City cohort study.

OBJECTIVE: A high thrombin generation level has been associated with the risk of venous thrombosis. Whether changes in this biomarker are relevant to arterial disease remains unknown. We investigated the association of thrombin generation with coronary heart disease (CHD) and acute ischemic stroke (AIS) in the elderly. METHODS AND RESULTS: We used data from the Three-City study, a prospective cohort including 9294 subjects aged >65 years. After 4 years of follow-up, a case-cohort study was established. Using the calibrated automated thrombography method, endogenous thrombin potential and peak height were measured in plasma samples of all CHD and AIS cases and a random sample of 1177 controls. We did not find any significant association between thrombin generation and CHD. In multivariate analyses, high levels of endogenous thrombin potential and peak height were associated with an increased risk of AIS (hazard ratio=1.16 [95% CI, 0.90 to 1.50] and 1.31 [95% CI, 1.01 to 1.69] for a 1 SD increase, respectively). Data also suggested that these associations might be more important in women (hazard ratio=1.55 [95% CI, 1.05 to 2.33] and 1.71 [95% CI, 1.11 to 2.63], respectively) than in men (P for interaction=0.04 and 0.08, respectively). CONCLUSION: Thrombin generation emerges as an independent predictor of AIS, particularly in women. Hypercoagulability may have an important role in the pathogenesis of AIS.

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 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 (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.

Higher level of systemic C-reactive protein is independently predictive of coronary heart disease in older community-dwelling adults: the three-city study.

OBJECTIVES: To assess the association between systemic C-reactive protein (CRP) and incident coronary heart disease (CHD) in community-dwelling elderly people. DESIGN: A French population-based multicenter prospective cohort study. SETTING: Three cities in France: Bordeaux in the southwest, Dijon in the northeast, and Montpellier in the southeast. PARTICIPANTS: After 4 years of follow-up, a case-cohort study was designed including 1,004 subjects randomly selected from the initial cohort of 9,294 subjects free of CHD at baseline and 174 subjects who developed first CHD events during follow-up. MEASUREMENTS: Hazard ratios (HRs) were estimated using a Cox proportional hazard model adapted for the case-cohort design using a CRP level less than 1 mg/L as the reference category. RESULTS: Of the random sample, 24.3% had a CRP level less than 1.0 mg/L, 45.8% had a CRP level of 1.0 to 2.9 mg/L, and 29.9% had a CRP level of 3.0 to 10.0 mg/L. The HRs for CHD, adjusted for age, sex, and study center, were 1.69 (95% confidence interval (CI)=1.04-2.75) for CRP from 1.0 to 2.9 mg/L and 2.32 (95% CI=1.41-3.82) for CRP from 3.0 to 10.0 mg/L (P for trend <.001). After additional adjustment for smoking, body mass index, diabetes mellitus, systolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, statin use, and antihypertensive treatment, a baseline CRP of 3.0 to 10.0 mg/L remained associated with risk of CHD (HR=1.87, 95% CI=1.09-3.25), although CRP did not improve the discriminative ability of a predicting model based on traditional risk factors (receiver operating characteristic curves from 0.740 to 0.749). CONCLUSION: CRP is an independent CHD risk marker but does not improve CHD risk prediction in community-dwelling elderly people.

Association of influenza vaccination with reduced risk of venous thromboembolism.

Influenza vaccination can reduce the risk of cardiovascular events in patients with coronary heart disease, but its impact on the risk of venous thromboembolism (VTE) has not been studied. It was the aim of this study to investigate whether influenza vaccination reduces the risk of VTE. We conducted a case-control study involving 1,454 adults enrolled in 11 French centers between 2003 and 2007, comprising 727 consecutive cases with a first documented episode of VTE and 727 age- and sex-matched controls. In the case and control groups 202 (28.2%) and 233 (32.1%) subjects, respectively, had been vaccinated against influenza during the previous 12 months. After multivariate regression analysis, the odds ratios (OR) for VTE associated with vaccination were 0.74 (95% confidence interval [CI], 0.57-0.97) and 0.52 (95% CI, 0.32-0.85), respectively, for the whole population and for subjects aged 52 years or less. The protective effect of vaccination was similar for deep venous thrombosis (OR 0.9, 95% CI, 0.60-1.35) and pulmonary embolism (OR 0.71, 95% CI, 0.53-0.94) and for both provoked (OR 0.71, 95% CI, 0.53-0.97) and unprovoked VTE (OR 0.85, 95% CI, 0.59-1.23). This case-control study suggests that influenza vaccination is associated with a reduced risk of VTE.