Background: Stroke risk in atrial fibrillation is assessed by using the CHA ₂ DS ₂ -VASc score. Sex category (Sc, ie, female sex) confers 1 point on CHA ₂ DS ₂ -VASc. We hypothesized that female sex is a stroke risk modifier, rather than an overall risk factor, when added to a CHA ₂ DS ₂ -VA (sex-independent thromboembolism risk) score scale. Methods: Using 3 nationwide registries, we identified patients with incident nonvalvular atrial fibrillation from January 1, 1997, through December 31, 2015. Patients receiving oral anticoagulant treatment at baseline were excluded, and person-time was censored at the time of treatment initiation (if any). CHA ₂ DS ₂ -VA scores were calculated for men and women, and were followed for up to 1 year in the Danish National Patient Registry. The primary outcome was a primary hospital code for ischemic stroke or systemic embolism (thromboembolism). We calculated crude event rates for risk strata as events per 100 person-years. For quantifying absolute risk of stroke, we calculated risks based on the pseudovalue method. Female sex as a prognostic factor was investigated by inclusion as an interaction term on the CHA ₂ DS ₂ -VA score to calculate the thromboembolic risk ratio for different score points. Results: A total of 239 671 patients with atrial fibrillation (48.7% women) contributed to the analyses. The mean ages for women and men were 76.6 years and 70.3 years, respectively; the mean CHA ₂ DS ₂ -VA scores were 2.7 for women and 2.3 for men. The overall 1-year thromboembolic rate per 100 person-years for women was 7.3 and 5.7 for men. The 1-year absolute risk of thromboembolism was 0.5% among men and women with a CHA ₂ DS ₂ -VA score of 0 and increased up to >7% among very comorbid patients (score >5). The risk ratio (male as reference) across points >1 indicated that women exhibit a higher stroke risk. The interaction was statistically significant ( P <0.001). Conclusions: Female sex is a risk modifier for stroke in patients with atrial fibrillation. Initial decisions on oral anticoagulant treatment could be guided by a CHA ₂ DS ₂ -VA score (ie, excluding the sex category criterion), but the Sc risk component modifies and accentuates stroke risk in women who would have been eligible for oral anticoagulant treatment on the basis of ≥2 additional stroke risk factors.

Background: Atrial fibrillation (AF) increases the risk of stroke, but this risk is not homogenous. Many risk factors contribute to stroke risk however, the evidence for female sex as a risk factor is less well-established. Aim: To perform a systematic review and meta-analysis of the available evidence to establish if female sex is a risk factor for stroke/thromboembolism among patients with AF. Methods: A systematic literature search was conducted using Medline. The search term ‘atrial fibrillation’ was used in combination with ‘stroke risk’, ‘thromboembolism’, ‘female’ and ‘gender differences’ and returned 735 articles, of which 17 were appraised and included. Females with AF were compared with males with AF for the outcome of stroke/thromboembolism. Results: Seventeen studies, 5 randomized-controlled trials and 12 prospective observational studies were included; 10 demonstrated an increased risk of stroke in women. Meta-analysis of the 17 studies revealed a 1.31-fold (95% confidence intervals (CIs) 1.18–1.46) elevated risk of stroke in women with AF; the risk appearing greatest for women aged ≥75 years. Only three studies compared entirely anticoagulated populations; stroke rates among these patients varied from 1.2–1.44% per-patient year for men and 2.08–2.43% per-patient year for women. Risk of stroke in women appeared similar regardless of oral anticoagulation therapy [risk ratio (95% CI 1.29 (1.09–1.52) and 1.49 (1.17–1.90) in non-anticogulated vs. anticoagulated/mixed cohorts, respectively). Conclusions: Women with AF are at increased risk of stroke, particularly elderly women. Comprehensive stroke risk assessment, including sex as a risk factor, should be undertaken in all AF patients.

The comparative performance of existing models for prediction of type 2 diabetes across populations has not been investigated. We validated existing non-laboratory-based models and assessed variability in predictive performance in European populations. We selected non-invasive prediction models for incident diabetes developed in populations of European ancestry and validated them using data from the EPIC-InterAct case-cohort sample (27,779 individuals from eight European countries, of whom 12,403 had incident diabetes). We assessed model discrimination and calibration for the first 10 years of follow-up. The models were first adjusted to the country-specific diabetes incidence. We did the main analyses for each country and for subgroups defined by sex, age (0·05) except for three models. However, two models overestimated risk, DPoRT by 34% (95% CI 29-39%) and Cambridge by 40% (28-52%). Discrimination was always better in individuals younger than 60 years or with a low waist circumference than in those aged at least 60 years or with a large waist circumference. Patterns were inconsistent for BMI. All models overestimated risks for individuals with a BMI of <25 kg/m(2). Calibration patterns were inconsistent for age and waist-circumference subgroups. Existing diabetes prediction models can be used to identify individuals at high risk of type 2 diabetes in the general population. However, the performance of each model varies with country, age, sex, and adiposity. The European Union.

Introduction: Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. Methods: Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. Results: For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m² increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (P _het = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m²) than for more overweight women (BMI ≥25.9 kg/m²) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. Conclusions: An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

Background and Purpose—: Although oral anticoagulants (OACs) are highly effective in reducing stroke risk in atrial fibrillation, some patients still sustain stroke despite being on an OAC. Our aim was to identify the risk factors that contribute to stroke risk in atrial fibrillation, although patients were taking OACs in a clinical trial setting. Methods—: We identified contemporary clinical trials that investigated OACs in patients with atrial fibrillation. Event rates per year from each study and pooled event rates and relative risks, all with a 95% confidence interval, were calculated. Statistical heterogeneity was assessed using the I ² test. Results—: Six trials were included in the meta-analysis, with a total of 58 883 patients randomized. Characteristics associated with a higher relative risk of stroke while on an OAC included age ≥75 years (relative risk, 1.46 [95% confidence interval, 1.25–1.69]), female sex (1.30 [1.15–1.49]), previous stroke/transient ischemic attack (1.85 [1.32–2.60]), vitamin K-antagonist naive status (for vitamin K antagonist experienced, 0.85 [0.74–0.97]), moderate and severe renal impairment (1.54 [1.30–1.81] and 2.22 [1.85–2.66], respectively, compared with normal renal function), previous aspirin use (1.19 [1.04–1.37]), Asian race (1.70 [1.42–2.03]), and a CHADS ₂ score of ≥3 (1.64 [1.18–2.27]). Conclusions—: Stroke rates are higher on OACs with some patient clinical characteristics, that is, older age, female sex, previous stroke/transient ischemic attack, vitamin K-antagonist naive status, renal impairment, previous aspirin use, and higher CHADS ₂ score. The identified risk factors for stroke while on an OAC could potentially be used to consider a risk assessment tool to flag up high-risk patients while on an OAC (in this case, warfarin). Whether these risk factors apply to novel OACs is uncertain.