Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study.

OBJECTIVE: To assess the relationships between female hormonal exposures and risk of RA in a prospective cohort of French women. METHODS: E3N (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is an on-going French prospective cohort that included 98 995 women aged 40-65 years in 1990. Every 2-3 years, women completed mailed questionnaires on their lifestyles, reproductive factors and health conditions. Cox proportional hazards regression models were used to determine factors associated with risk of incident RA, with age as the time scale, adjusted for known risk factors of RA, and considering endogenous and exogenous hormonal factors. Hazard ratios (HRs) and 95% CIs were estimated. Effect modification by smoking history was investigated. RESULTS: A total of 698 incident cases of RA were ascertained among 78 452 women. In multivariable-adjusted Cox regression models, risk of RA was increased with early age at first pregnancy (<22 vs ≥27 years; HR = 1.34; 95% CI 1.0, 1.7) and menopause (≤45 vs ≥53 years; HR = 1.40; 95% CI 1.0, 1.9). For early menopause, the association was of similar magnitude in ever and never smokers, although the association was statistically significant only in ever smokers (HR = 1.54; 95% CI 1.0, 2.3). We found a decreased risk in nulliparous women never exposed to smoking (HR = 0.44; 95% CI 0.2, 0.8). Risk of RA was inversely associated with exposure to progestogen only in perimenopause (>24 vs 0 months; multi-adjusted HR = 0.77; 95% CI 0.6, 0.9). CONCLUSIONS: These results suggest an effect of both endogenous and exogenous hormonal exposures on RA risk and phenotype that deserves further investigation.

Modifiable risk factors for advanced vs. early breast cancer in the French E3N cohort.

Advanced breast cancer (BC) is associated with heavier treatments and poorer prognosis than early BC. Despite mammographic screening, advanced BC incidence remains stable. Little is known about risk factors differentially associated with advanced BC. We analyzed factors predicting for postmenopausal advanced vs. early BC in the E3N cohort. E3N has been prospectively following 98,995 French women aged 50-65 years at baseline since 1990. Hazard ratios (HRs) and 95% confidence intervals (CIs) for advanced and early invasive BC were estimated with multivariate Cox competing risk hazard models. With a median follow-up of 15.7 years, 4,941 postmenopausal BC were diagnosed, including 1,878 (38%) advanced BC. Compared to early BC, advanced BC was differentially associated with excess weight (HR 1.39 [95% CI = 1.26-1.53] vs. 1.08 [95% CI = 1.00-1.17], phomogeneity < 0.0001) and living in a rural area (HR 1.14 [95% CI = 1.00-1.31] vs. 0.93 [95% CI = 0.82-1.04], phomogeneity 0.02). Excess weight was the only differential risk factor for advanced BC for hormone-dependent BC and for women compliant with screening recommendations. Previous mammography was associated with reduced advanced BC risk (HR 0.86 [95% CI = 0.73-1.00]) and increased early BC risk (HR 1.36 [95% CI = 1.18-1.56], phomogeneity < 0.0001), but only for hormone-dependent BC. Excess weight appears to be mostly associated with advanced BC, especially hormone-dependent BC. These results add to the evidence for maintaining weight within the recommended limits.

Chronic diarrhoea and risk of rheumatoid arthritis: findings from the French E3N-EPIC Cohort Study.

OBJECTIVES: To assess the relationship between gastrointestinal disorders and the risk of further development of RA. METHODS: The Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition Study is a French prospective cohort including 98 995 healthy women since 1990. Participants completed mailed questionnaires on their lifestyles and health-related information. Gastrointestinal disorders were assessed in the third questionnaire (sent in 1993). Hazard ratios and 95% CIs for incident RA were estimated using Cox proportional hazards regression models with age as the time scale. Models were age adjusted, and then additionally adjusted for known risk factors of RA such as smoking, and for potential cofounders. RESULTS: Among 65 424 women, 530 validated incident RA cases were diagnosed after a mean (s.d.) of 11.7 (5.9) years after study baseline. In comparison with no gastrointestinal disorder, chronic diarrhoea was associated with an increased risk of developing RA during follow-up (hazard ratio = 1.70, 95% CI 1.13, 2.58), independently of dysthyroidism or dietary habits. The association was stronger among ever-smokers (hazard ratio = 2.21, 95% CI 1.32, 3.70). There was no association between RA risk and constipation or alternating diarrhoea/constipation. CONCLUSION: Chronic diarrhoea was associated with an increased risk of subsequent RA development, particularly among ever-smokers. These data fit with the mucosal origin hypothesis of RA, where interaction between intestinal dysbiosis and smoking could occur at an early stage to promote emergence of autoimmunity, followed years later by clinical disease.

Patient characteristics, treatment patterns, and adherence to lipid-lowering therapies following an acute coronary syndrome.

Despite dyslipidaemia management guidelines, many patients do not reach low-density lipoprotein cholesterol targets due to insufficiently intensive regimens or lack of adherence to their medication. This was a retrospective cohort study on the Pharmacoepidemiologic General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Patients included were ≥ 18 years old who suffered an ACS between 2013 and 2016, and treated with lipid-lowering therapy (LLT) at hospital discharge or within 92 days. Patients were followed up to 12 months' post index ACS, a new cardiovascular event, loss to follow-up or death. Treatment intensity (high, moderate and low intensity statins ± ezetimibe) and adherence (proportion of days covered > 80%) are described. A total of 2,695 patients were included; mean age [SD] was 63.1 [12.8] years, and 77% were men. High, moderate and low intensity statins were started in 56% (1,520), 36% (971), and 3% (86) of patients, respectively. A further 2% (46) were on statin/ezetimibe combination, 2% (42) on other LLT and 1% (30) on ezetimibe alone. At follow-up, around 70% of patients were adherent to LLT, with those on moderate intensity treatments showing better adherence (76%) than those on low (63%) or high (67%) intensity treatments. Despite guideline recommendations, many patients following an ACS are not treated with high intensity statins, and adherence remains far from optimal. Effort should be made to increase the proportion of patients treated with high intensity statins following an ACS and to further improve treatment adherence.

Passive smoking in childhood increases the risk of developing rheumatoid arthritis.

OBJECTIVES: To investigate the link between smoking status, including childhood and adult passive exposure, and the risk of incident RA. METHODS: The French E3N cohort includes 98 995 female volunteers prospectively followed since 1990. Self-administered questionnaires sent every 2-3 years collected medical events, general, lifestyle and environmental characteristics. RA diagnoses were collected in three successive questionnaires and confirmed if women received reimbursement for an RA-specific medication. The risk of incident RA was estimated using an age-adjusted Cox model that considers smoking status as a time-dependent variable. RESULTS: Among 71 248 women, 371 incident RA cases were confirmed. Ever-smokers not exposed to passive smoking had an increased risk of RA [1.38 (95% CI 1.10, 1.74)]. In never-smokers, passive smoking exposure during childhood was associated with a borderline increased risk of RA in the same range as active smoking in adults, with an hazard ratio (HR) of 1.43 (95% CI 0.97, 2.11). Ever-smokers who also had childhood passive smoking exposure had a higher risk of RA than smokers not exposed during childhood [HR 1.67 (95% CI 1.17, 2.39)], but without a significant difference (P = 0.30). RA began earlier in smokers exposed to childhood passive smoking. CONCLUSION: This study confirms that active smoking is associated with an increased risk of RA. It suggests for the first time that passive exposure to tobacco during childhood might also increase the risk of RA in future light smokers and probably non-smokers. Our results highlight the importance of avoiding any tobacco environment in children, especially in those with a family history of RA.

Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years.

PURPOSE: To assess the association between use of benzodiazepines (including the Z-drugs zopiclone and zolpidem) and cardiovascular mortality in women aged over 50 years. METHODS: We used data from the E3N cohort. Data self-reported in biennial questionnaires was matched with drug reimbursement and vital status/causes of death data. In Cox models, exposure to benzodiazepines was fitted using time-varying variables, the reference category being women with no benzodiazepine delivery since January 2004. RESULTS: Among 85,353 women born 1925-1950 and followed between 2004 and 2011, 506 cardiovascular deaths occurred. Exposure to benzodiazepines was associated with increased cardiovascular mortality when hazard ratios (HRs) were adjusted only for age (HRever use 1.65; 95% CI 1.39, 1.97), but not when further adjusted for antidepressant use (HRever use 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HRever use 0.93; 95% CI 0.75, 1.16). Exposure to hypnotic benzodiazepines remained associated with increased cardiovascular mortality (HRever use 1.23; 95% CI 1.01, 1.51), but with no consistent trend across duration/dose or time since last use, while exposure to anxiolytic benzodiazepines was not (HRever use 0.83; 95% CI 0.67, 1.02). CONCLUSION: In our study, adjustment for antidepressant use strongly attenuated any benzodiazepine-cardiovascular mortality association. Whether the modest association observed with hypnotic benzodiazepines is due to residual confounding deserves further investigation.

Diet and Risk of Cholecystectomy: A Prospective Study Based on the French E3N Cohort.

OBJECTIVES: This study aimed to examine the relationship between diet and cholecystectomy risk, using three approaches, in a large French cohort. METHODS: In a prospective cohort study in French women who completed a food-frequency questionnaire at baseline, we analyzed diet with three approaches: food groups, dietary patterns obtained by factor analysis, and the Mediterranean diet score. The primary outcome was cholecystectomy. We used Cox proportional hazards regression to assess the relationship between diet and cholecystectomy risk, adjusting for the main potential confounders. RESULTS: During 1,033,955 person years of follow-up, we identified 2,778 incident cases of cholecystectomy. Higher intakes of legumes, fruit, vegetable oil, and wholemeal bread were associated with decreased cholecystectomy risk. Two dietary patterns were identified by factor analysis: "Western" (essentially processed meat, pizza, pies, high-alcohol beverages, French fries, sandwiches…) and "Mediterranean" (essentially fruits, vegetables, seafood, and olive oil). The "Mediterranean" pattern was inversely associated with cholecystectomy risk in the subgroup of postmenopausal women who ever used menopausal hormone therapy (hazard ratio for quartile 4 vs. 1=0.79, 95% confidence interval (CI): 0.65-0.95; P for linear trend=0.008). High adherence to the Mediterranean diet was associated with decreased risk of cholecystectomy (hazard ratio for a 6-9 score vs. 0-3=0.89, 95% CI: 0.80-0.99; P for linear trend=0.02). CONCLUSIONS: Adherence to a diet rich in fruit, vegetables, legumes, and olive oil was associated with a reduction in cholecystectomy risk in French women. Further studies in different settings are requested.

Growth Trajectories of Body Mass Index during Childhood: Associated Factors and Health Outcome at Adulthood.

OBJECTIVE: To identify body mass index (BMI) trajectories from birth to age 10 years and to assess their association with child and parental characteristics and with adult nutritional status and metabolic risk factors. STUDY DESIGN: Retrospective cohort study with 1188 subjects aged 20-60 years. Childhood growth was assessed using measured weight and height data collected retrospectively from health booklets, which also provided information on gestational age, birth weight, and early nutrition. Height, weight, waist circumference, fasting blood glucose, lipids profile, and blood pressure were measured at adulthood. Participants self-reported parental silhouette based on a 9-figural scale. Group-based modeling was applied to identify BMI trajectories. Associations were assessed using ANOVA and multiple logistic regression. RESULTS: Five growth trajectories following or crossing BMI percentiles emerged: stable-25th (15.3% of the sample), stable-50th (35.9%), stable-75th (28.0%), ascending-75th (19.2%), and ascending-obesity (1.6%). Overall, associated factors from early life were mother's corpulence (higher in the ascending-obesity group), gestational age (higher in the stable-50th, stable-75th, and in the ascending-obesity groups), and birth weight (higher in the ascending-obesity group) (all P < .05). Childhood trajectories were associated with adult BMI and waist circumference (higher in the stable-75th and in the ascending groups) (all P < .0001). CONCLUSIONS: This study shows heterogeneity in patterns of growth trajectories. Specific trajectories were associated with greater BMI and waist circumference during adulthood. Monitoring growth trajectories may improve chronic disease prevention.

Cross-sectional association of coffee and caffeine consumption with sex hormone-binding globulin in healthy nondiabetic women.

OBJECTIVE: Low sex hormone-binding globulin (SHBG) is a consistent risk factor for type 2 diabetes, particularly in women. Coffee consumption has been associated with a lower risk of type 2 diabetes, but its effects on SHBG are less known. DESIGN AND METHODS: This was a cross-sectional study of 2377 nondiabetic pre- and postmenopausal women from the E3N cohort study whose baseline SHBG was measured. Information on diet (including coffee and caffeine consumption), lifestyle and medical conditions was collected through questionnaires. The relationship between coffee and caffeine consumption and SHBG was modelled, with adjustment for covariates and stratification by body mass index (BMI) categories (< or ≥25 kg/m2 ) and menopausal status. RESULTS: The mean age was 57.2±6.4 years and 61% of the 2377 women were postmenopausal. High coffee (≥3 cups/day) and caffeine (≥265 mg/day) intakes were associated with a reduced risk of being in the 1st quartile of the SHBG level distribution (<46.3 nmol/L) in a multivariate adjusted model (OR: 0.72 [95% CI: 0.52-1.01] and OR: 0.71 [95% CI: 0.53-0.95], respectively). No association was found between tea consumption and SHBG levels. In multivariate models stratified on BMI categories and menopausal status, associations were restricted to women with a BMI ≥25 kg/m2 or being postmenopausal. The association with SHBG was consistently noted with consumption of both caffeinated coffee and caffeine, but not decaffeinated coffee. CONCLUSIONS: Consumption of high coffee and caffeine is associated with a reduced risk of low SHBG, an established risk marker for T2DM, which might contribute to the protective effects of coffee for type 2 diabetes.

Chronic Consumption of Artificial Sweetener in Packets or Tablets and Type 2 Diabetes Risk: Evidence from the E3N-European Prospective Investigation into Cancer and Nutrition Study.

BACKGROUND: The influence of artificial sweeteners on metabolic diseases is controversial. Artificially sweetened beverages have been associated with an increased risk of type 2 diabetes (T2D) but biases and reverse causation have been suspected to have influenced the observed association. In addition, it has been suggested that investigation into the relationship between the frequency and duration of the consumption of packet or tablet artificial sweeteners and T2D risk is necessary. METHODS: We used data from 61,440 women in the prospective E3N-European Prospective Investigation into Cancer and Nutrition study, conducted between 1993 and 2011. We estimated hazards ratios (HRs) and 95% CIs of T2D risk associated with both the frequency and the duration of use of artificial sweeteners consumed in packets or tablets. RESULTS: Compared to "never or rare" consumers of artificial sweeteners, those using them "always or almost always" had an increased risk of T2D (HR = 1.83 [95% CI 1.66-2.02] in the multivariate model [MM], HR = 1.33 [95% CI 1.20-1.47] when further adjusted for body mass index, BMI). Women consuming artificial sweeteners in packets or tablets for more than 10 years also had an increased risk of T2D compared to never or rare users (HR = 2.10 [95% CI 1.83-2.40] in the MM and HR = 1.15 [95% CI 1.00-1.33] when adjusted for BMI, respectively). CONCLUSIONS: Our data suggest that both a higher frequency and a longer consumption of artificial sweeteners in packets or tablets was associated with T2D risk, independently of major T2D risk factors, but partially mediated by adiposity. A precautionary principle should be applied to the promotion of these products that are still largely recommended as healthy sugar substitutes.

Assessment of the ecological bias of seven aggregate social deprivation indices.

BACKGROUND: In aggregate studies, ecological indices are used to study the influence of socioeconomic status on health. Their main limitation is ecological bias. This study assesses the misclassification of individual socioeconomic status in seven ecological indices. METHODS: Individual socioeconomic data for a random sample of 10,000 persons came from periodic health examinations conducted in 2006 in 11 French departments. Geographical data came from the 2007 census at the lowest geographical level available in France. The Receiver Operating Characteristics (ROC) curves, the areas under the curves (AUC) for each individual variable, and the distribution of deprived and non-deprived persons in quintiles of each aggregate score were analyzed. RESULTS: The aggregate indices studied are quite good "proxies" for individual deprivation (AUC close to 0.7), and they have similar performance. The indices are more efficient at measuring individual income than education or occupational category and are suitable for measuring of deprivation but not affluence. CONCLUSIONS: The study inventoried the aggregate indices available in France and evaluated their assessment of individual SES.

Let's move our health! The experience of 40 physical activity motivational workshops / Bougeons notre santé ! L'expérience de 40 ateliers de motivation à l'activité physique.

Aims: To set up physical activity promotion workshops in health centres to help people with a sedentary lifestyle achieve an adequate level of physical activity. Methods: This health programme, called 'Bougeons Notre Santé' (Let's move our health) has been implemented since 2006 by four health centres in the Pays de la Loire region, in France. This article describes implementation of the programme, its feasibility, how it can be integrated into a global preventive approach and its outcomes on promoting more physical activity. The "Let's move our health!" programme comprises four group meetings with participants over a period of several months. At these meetings, participants discuss, exchange and monitor their qualitative and quantitative level of physical activity. Realistic and achievable goals are set in consultation with each participant in relation to their personal circumstances and are monitored with a pedometer and a follow-up diary. Support on healthy eating is also provided. This programme is an opportunity to promote health and refer participants to existing local resources. Results: Forty groups, comprising a total of 275 people, have participated in the programme since 2006. After the four meetings, participants had increased their physical activity level by an average of 723 steps per day and 85% reported that they had changed their eating habits. Conclusion: This health promotion programme is feasible and effective: an increase in the physical activity of participants was observed, together with a favourable impact on perceived health, well-being and social links. These workshops are integrated into a network of associations and institutional partners and could be implemented by similar social or health organisations.

ABO and Rhesus blood groups and risk of type 2 diabetes: evidence from the large E3N cohort study.

AIMS/HYPOTHESIS: The objective of this study was to evaluate the relationship of ABO blood type (A, B, AB and O), Rhesus factor (positive or negative) and a combination of the two (ABO × Rhesus) with type 2 diabetes mellitus risk. METHODS: In total, 82,104 women from the large prospective E3N cohort were followed between 1990 and 2008. Multivariate Cox regression models were used to estimate HRs and 95% CIs. RESULTS: Those with either the A (HR 1.10 [95% CI 1.02, 1.18]) or B (HR 1.21 [95% CI 1.07, 1.36]) group were at increased risk of type 2 diabetes mellitus compared with those with the O group. The association with the AB group did not reach statistical significance (HR 1.17 [95% CI 0.99, 1.39]). There was no difference in type 2 diabetes mellitus risk between Rhesus positive and negative groups (HR 0.96 [95% CI 0.88, 1.05]). When the universal donors (O(-)) were taken as the reference category, we observed an increased risk for both A(+) (HR 1.17 [95% CI 1.02, 1.35]) and A(-) (HR 1.22 [95% CI 1.03, 1.45]) individuals. The greatest increase in risk was seen for those with the B(+) blood group (HR 1.35 [95% CI 1.13, 1.60]). We also observed a greater type 2 diabetes mellitus risk for those with the AB(+) group (HR 1.26 [95% CI 1.02, 1.57]). Adjustment for fasting plasma glucose and lipid concentrations in a case-control subsample did not alter the associations. CONCLUSIONS/INTERPRETATION: This study suggests that people with the O blood type have a lower risk of developing type 2 diabetes mellitus. Therefore, blood group should be investigated in future clinical and epidemiological studies on diabetes, and further pathophysiological research is needed to determine why individuals with blood type O have a lower risk of type 2 diabetes mellitus.

Deprivation and health risk indicators in full-time permanent workers.

BACKGROUND: Association between deprivation and health is well established, particularly among unemployed or fixed-term contract or temporary contract subjects. This study aimed to assess if this relationship existed as well in full-time permanent workers. METHODS: Biometrical, biological, behavioural and psychosocial health risk indicators and an individual deprivation score, the Evaluation of Precarity and Inequalities in Health Examination Centres score, were recorded from January 2007 to June 2008, in 34 905 full-time permanent workers aged 18-70 years, all volunteers for a free health examination. Comparisons of the behavioural, metabolic, cardiovascular and health risk indicators between quintiles of the deprivation score with adjustments on age and socioeconomic categories were made by covariance analysis or logistic regression. RESULTS: For both genders, degradation of nutritional behaviours, metabolic and cardiovascular indicators and health appeared gradually with deprivation, even for deprivation score usually considered as an insignificant value. The absence of only one social support or one social network was associated with a degradation of health. Full-time permanent workers with the poorest health risk indicators had more frequent social exclusion signs. These results were independent of socioeconomic categories and age. CONCLUSION: Understanding how deprivation influences health status may lead to more effective interventions to reduce social inequalities in health. The deprivation Evaluation of Precarity and Inequalities in Health Examination Centres score is a relevant tool to detect subjects who could benefit from preventive interventions. Our findings suggest that this deprivation score should be used as a health risk indicator even in full-time permanent workers. Assessing deprivation is useful to design and evaluate specific intervention programmes.

Survival of patients with chronic acid sphingomyelinase deficiency (ASMD) in the United States: A retrospective chart review study.

Background: Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease type A, A/B, and B, is a rare lysosomal storage pathology with multisystemic clinical manifestations. The aims of this study were to estimate the survival probability in patients in the United States with chronic ASMD (ASMD types B and A/B), and to describe the disease characteristics of these patients. Methods: This observational retrospective study included medical chart records of patients with chronic ASMD with retrievable data abstracted by 69 participating physicians from 25 medical centers in the United States. Included patients had a date of ASMD diagnosis or first presentation to a physician for ASMD symptoms (whichever occurred first) between January 01, 1990, and February 28, 2021. Medical chart records were excluded if patients were diagnosed with ASMD type A. Eligible medical chart records were abstracted to collect demographic, medical and developmental history, and mortality data. Survival outcomes were analyzed using Kaplan-Meier survival analyses from birth until death. Results: The overall study population (N = 110) included 69 patients with ASMD type B, nine with type A/B, and 32 with ASMD "non-type A" (ASMD subtype was unknown, but patients were confirmed as not having ASMD type A). The majority of patients were male with a median age at diagnosis of 3.8 years. Thirty-eight patients died during the study observation period, at a median age of 6.8 years. The median (95% confidence interval) survival age from birth was 21.3 (10.2; 60.4) years. At diagnosis or first presentation, 42.7% patients had ≥1 ASMD-related complication; splenic (30.0%) and hepatobiliary (20.9%) being the most common, and 40.9% required ≥1 medical visit due to complications. Conclusion: Patients with chronic ASMD in the United States have poor survival and significant burden of illness.

Low Molecular Weight Heparin Treatment Patterns and Outcomes in Cancer Patients with Acute Venous Thromboembolism: A Nationwide Cohort Study in France.

Patients with cancer have an increased risk of developing venous thromboembolism (VTE) and an increased risk of death from VTE. Until recently, the standard of care for treatment of VTE in cancer patients was low molecular weight heparins (LMWH). To determine treatment patterns and outcomes, we performed an observational study using a nationwide health database. Treatment patterns, rates of bleeding, and VTE recurrence at 6 and 12 months were assessed in cancer patients with VTE in France prescribed LMWH in 2013-2018. Of 31,771 patients administered LMWH (mean age 66.3 years), 51.0% were male, 58.7% had pulmonary embolism, and 70.9% had metastatic disease. At 6 months LMWH persistence was 81.6%, VTE recurrence had occurred in 1256 patients (4.0%) at a crude rate per 100 person-months (PM) of 0.90, and bleeding had occurred in 1124 patients (3.5%) at a crude rate per 100 PM of 0.81. At 12 months, VTE recurrence had occurred in 1546 patients (4.9%) at a crude rate per 100 PM of 0.71 and bleeding had occurred in 1438 patients (4.5%) at a crude rate per 100 PM of 0.66. Overall, VTE-related clinical event rates were high among patients administered LMWH, suggesting an unmet medical need.

Direct Oral Anticoagulant (DOAC) Dosing in Patients with Non-valvular Atrial Fibrillation (NVAF) in the United Kingdom: A Retrospective Cohort Study Using CPRD Gold Database.

INTRODUCTION: Per-label dosing of direct oral anticoagulants (DOACs) is important for the prevention of stroke and systemic embolism among patients with non-valvular atrial fibrillation (NVAF), especially those with poor renal function, advanced age, low body weight or concomitant P-glycoprotein inhibitors. The study described DOAC use and dosing patterns in patients with NVAF in the UK. METHODS: Using Clinical Practice Research Datalink (CPRD Gold), patients' profiles were described at DOAC initiation (1 January 2016-31 March 2021) and followed for a mean [standard deviation (SD)] 2 (1) years. Patients were categorised as under-dosing: received a lower dose with no indication for a reduced dose; over-dosing: received a standard dose with an indication for a reduced dose; per-label dosing, according to Summary Product Characteristics (SmPC). RESULTS: Forty thousand seven hundred forty-four adult patients with NVAF were identified (mean age: 75.3 (11.2) years; males: 55.4%); 22,827 (56.0%) initiated treatment with apixaban, 930 (2.3%) dabigatran, 5633 (13.8%) edoxaban and 11,354 (27.9%) rivaroxaban. Baseline Charlson comorbidity index ≥ 4 was 65.1%; CHA2DS2-VASc score ≥ 4 was 22.5%; HAS-BLED score ≥ 3 was 18.3%; ~ 2% had prior major bleed and 4.4% a stroke ≤ 2 years before DOAC initiation. Overall, 18.0% of patients received incorrect dosing (~ one in five). Under-dosing was highest for dabigatran (156, 16.8%) and over-dosing was highest for rivaroxaban (1084, 9.6%). Per-label dosing was highest for edoxaban (4773, 84.7%), followed by apixaban (18,756, 82.2%), rivaroxaban (9161, 80.7%) and dabigatran (732, 78.7%). Treatment persistence (no switching or discontinuation) was 79% among edoxaban users, followed by 75% for apixaban, 69% for rivaroxaban and 62% for dabigatran. About 15% of dabigatran users, 10% of rivaroxaban users, 5% of apixaban users and 4% of edoxaban users switched treatment to another DOAC during follow-up. CONCLUSION: Although most patients received per-label dosing, ~ one in five patients was incorrectly dosed with DOAC, which may lead to serious clinical consequences and increased healthcare burden.

Effectiveness and Safety of Oral Anticoagulants in the Treatment of Acute Venous Thromboembolism: A Nationwide Comparative Cohort Study in France.

INTRODUCTION: Data from clinical trials indicate that direct oral anticoagulants (DOACs) are noninferior and safer than conventional therapy (low-molecular-weight heparin followed by a vitamin K antagonist [VKA]) for treating venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism (PE). This study compared the effectiveness and safety of DOACs and conventional therapy in a real-world setting. METHODS: This observational study used French national claims data of adult, treatment-naïve patients diagnosed with VTE (majority PE) who were hospitalized and treated for VTE with a DOAC (apixaban or rivaroxaban) or VKAs during 2013 to 2018. Patients with active cancer were excluded. After propensity score matching for each DOAC-VKA comparison, risks of bleeding, recurrent VTE, and all-cause mortality were compared at 6 months. Cox proportional hazards regression was used to estimate adjusted hazard ratios of the endpoints. RESULTS: A total of 58,137 patients were included (10,775 VKAs, 10,440 apixaban, 36,922 rivaroxaban). Propensity score-matched cohort sizes were 7,503 for apixaban and 9,179 for rivaroxaban. The hazard ratio (95% confidence interval) was significantly lower for apixaban than VKAs for bleeding requiring hospitalization (0.43 [0.32-0.59]), all-cause death (0.61 [0.51-0.74]), and first recurrent VTE (0.67 [0.52-0.85]). The hazard ratio was also significantly lower for rivaroxaban than VKAs for all-cause death (0.63 [0.53-0.74]) but not for bleeding requiring hospitalization (0.86 [0.69-1.07]) or first recurrent VTE (0.91 [0.74-1.13]). CONCLUSION: Apixaban was associated with superior safety and effectiveness than VKAs. All-cause mortality was lower in both DOACs than VKAs. Our results support recommendations to use DOACs over VKAs for the treatment of VTE.

Comparative Analysis of All-Cause Health Care Resource Utilization and Costs Among Venous Thrombosis Patients Without Cancer Prescribed Apixaban or VKAs in France.

INTRODUCTION: The direct oral anticoagulant (DOAC) apixaban has shown to have non-inferior efficacy and better safety than vitamin K antagonists (VKAs) in patients with venous thromboembolism (VTE). We determined whether healthcare resource use (HCRU) and direct all-cause medical and non-medical costs in patients with VTE in France differed between VKAs and apixaban. METHODS: A retrospective cohort study was conducted using French national health data from January 2013-June 2018 for anticoagulant-naïve adults hospitalized with VTE. All-cause costs and HCRU per patient per month (PPPM) were compared between apixaban and VKA cohorts created by 1:1 propensity score matching. Two-part models with bootstrapping were used to calculate marginal effects for costs and HCRU. RESULTS: The matched VKA and apixaban cohorts each comprised 7503 patients. Compared to VKAs, patients prescribed apixaban had significantly lower (P < 0.0001) mean all-cause costs PPPM for outpatient visits (€438.54 vs. €455.58), overall laboratory tests (€21.26 vs. €83.73), and hospitalizations (€249.48 vs. €343.82), but significantly higher (P < 0.0001) mean all-cause costs PPPM for overall drugs (€97.06 vs. €69.56) and medical procedures (€42.12 vs. €35.50). Mean total all-cause direct medical costs (€687.93 vs. €798.70) and total all-cause direct medical and non-medical costs (€771.60 vs. €883.66) were significantly lower (P < 0.0001) for apixaban. Mean HCRU PPPM showed similar trends. Subgroup analyses showed that, among patients with recurrent VTE, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€17.26 vs. €18.12) and total all-cause direct medical and non-medical costs (€18.37 vs. €19.20) than patients prescribed VKAs. Similarly, among patients with bleeding, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€15.34 vs. €32.61) and total all-cause direct medical and non-medical costs (€16.23 vs. €34.63) than patients prescribed VKAs. CONCLUSION: Compared to VKAs, apixaban may be cost-saving in the treatment of patients hospitalized for acute VTE.

Exploring the treatment gap among patients with osteoporosis-related fractures in France.

The use of anti-osteoporosis treatment following a diagnosis of osteoporosis with fracture or a relevant fragility fracture remains low in France. Initiating an anti-resorptive may reduce the incidence of a subsequent fracture by 60%. PURPOSE: To describe real-world osteoporosis treatment patterns in individuals with a fragility fracture in France and to explore the impact of initiating treatment on the risk of subsequent fracture. METHODS: A retrospective cohort study, using the national French Health Insurance claims database. Males and females 50 years and over, with a hospital discharge diagnosis of osteoporosis with fracture or a relevant fragility fracture between 2011 and 2014, were included and followed until death or the end of 2016, whichever came first. The primary outcome was the proportion of patients receiving anti-osteoporosis treatments prior to and post-index fracture. Change in fracture rates before and after treatment initiation was assessed in an exploratory analysis. RESULTS: A total of 574,133 patients (138,567 males, 435,566 females) had a qualifying index fracture. The proportion of patients receiving any anti-osteoporosis treatment increased pre-index fracture to post-index fracture from 2.2 to 5.6% among males, and from 11.8 to 18.2% among females. Oral bisphosphonates were the most prescribed anti-osteoporosis treatment for both males and females among post-index fractures (60.6% and 68.8% of patients initiating treatment). Following initiation of anti-resorptives, the incidence of subsequent fracture was reduced by 60% (rate ratio (RR): 0.40, 95% confidence interval [CI]: 0.34-0.45). CONCLUSION: Anti-osteoporosis treatment following an index fracture in France remains low. Improved identification and pharmacologic management of patients at risk of fragility fractures are necessary to reduce the risk of subsequent fractures.