Antidepressants and Hepatotoxicity: A Cohort Study among 5 Million Individuals Registered in the French National Health Insurance Database.

BACKGROUND: Hepatotoxicity may be a concern when prescribing antidepressants. Nevertheless, this risk remains poorly understood for serotonin and noradrenaline reuptake inhibitors (SNRIs: venlafaxine, milnacipran, duloxetine) and 'other antidepressants' (mianserin, mirtazapine, tianeptine and agomelatine), particularly in comparison with selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram), which are by far the most commonly prescribed antidepressants. OBJECTIVE: We quantified the risk of serious liver injury associated with new use of SNRIs and 'other antidepressants' compared with SSRIs in real-life practice. METHODS: Based on the French national health insurance database, this cohort study included 4,966,825 individuals aged 25 years and older with a first reimbursement of SSRIs, SNRIs or 'other antidepressants' between January 2010 and June 2015. We compared the risk of serious liver injury within the 6 months following antidepressant initiation according to antidepressant class, with SSRIs as the reference, using an inverse probability-of-treatment-weighted Cox proportional hazard model adjusted for demographic characteristics and risk factors of liver injury. RESULTS: We identified 382 serious liver injuries overall (none for milnacipran initiators). Age and gender standardized incidence rates per 100,000 person-years were 19.2 for SSRIs, 22.2 for venlafaxine, 12.6 for duloxetine, 21.5 for mianserin, 32.8 for mirtazapine, 31.6 for tianeptine and 24.6 for agomelatine initiators. Initiation of antidepressants of interest versus SSRIs was not associated with an increased risk of serious liver injury [adjusted hazard ratios (95% confidence interval): venlafaxine 1.17 (0.83-1.64), duloxetine 0.54 (0.28-1.02), mianserin 0.90 (0.58-1.41), mirtazapine 1.17 (0.67-2.02), tianeptine 1.35 (0.82-2.23) and agomelatine 1.07 (0.51-2.23)]. This finding was confirmed by the results of an additional study using a case-time-control design. CONCLUSION: These results do not provide evidence of an increased risk of serious liver injury following initiation of SNRIs or 'other antidepressants' compared with SSRIs in real-life practice. This could reflect an inherent lack of difference in risk between the drug classes, or the fact that individuals with higher susceptibility to drug-induced liver injury are not prescribed drugs considered to be more hepatotoxic.

Is There a Cardiotoxicity Associated With Metallic Head Hip Prostheses? A Cohort Study in the French National Health Insurance Databases.

BACKGROUND: There are four distinguishable types of THA devices in wide use, as defined by the femoral and acetabular bearing surfaces: metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), metal-on-metal (MoM), and ceramic-on-ceramic (CoC). Metallic head THAs (MoP and MoM) can potentially induce cardiac toxicity because cobalt species, generated at the head-neck trunnion, and in the case of MoM devices, at the articular surface as well, can be absorbed systemically. However, studies have provided inconsistent results. QUESTIONS/PURPOSES: The purpose of this study was to assess the risk of dilated cardiomyopathy (DCM) or heart failure (HF) associated with metallic head THAs using data from the French national health insurance databases. METHODS: Between 2008 and 2011 in France, 399,968 patients ≥ 55 years had a first THA. A total of 127,481 were excluded after we applied the exclusion criteria regarding arthroplasty and 17,137 as a result of a history of DCM/HF, recorded in the French national health insurance reimbursement databases, between January 1, 2006, and the date of inclusion. The final cohort included 255,350 individuals (43% men; mean age 72 ± 9 years). Of them, 93,581 (37%) had been implanted with MoP, 58,095 (23%) with CoP, 11,298 (4%) with MoM, and 92,376 (36%) with CoC THAs. Patients were followed until December 2015. Patients with incident DCM/HF were identified by a new entitlement to the long-term disease scheme or a first hospitalization with a diagnosis of DCM or HF. MoP and CoP THAs are generally implanted in old patients, whereas MoM and CoC are mostly indicated in young, active male patients. Thus, to consider the specific indications of the bearing couples, analyses were separately performed in two distinct subcohorts, one comprising patients with MoP or CoP and one comprising patients with MoM or CoC THA. In each subcohort, the DCM/HF risk was compared between patients with metallic head versus nonmetallic head THAs (MoP versus CoP, MoM versus CoC). Hazard ratios (adjusted HRs) of incident DCM/HF were estimated using Cox models adjusted for baseline sex, age, THA characteristics (fixation technique with cement, use of a modular femoral neck), and comorbidities at baseline. Cox models were stratified by sex and age. RESULTS: The crude incidence of DCM/HF per 100 person-years was 2.4 in patients with MoP, 1.8 with CoP, 1.2 with MoM, and 1.1 with CoC THAs. Overall, metallic head THAs were associated with a slight increase in DCM/HF risk (MoP versus CoP: adjusted HR, 1.08; 95% confidence interval [CI], 1.05-1.12; p < 0.001; MoM versus CoC: adjusted HR, 1.11; 95% CI, 1.03-1.19; p = 0.007). In the MoM-CoC subcohort, the risk tended to be more pronounced with MoM versus CoC THAs in women (MoM versus CoC: adjusted HR, 1.20; 95% CI, 1.07-1.35; p = 0.002) and patients aged ≥ 75 years (MoM versus CoC: adjusted HR, 1.16; 95% CI, 1.04-1.29; p = 0.009). CONCLUSIONS: Metallic head THAs were associated with a slightly increased DCM/HF risk, especially with MoM in women and older patients. Some caveats should be mentioned: severity of DCM or HF was not available and residual confounding cannot be ruled out despite considering many covariates. Our findings suggest that cardiac function should be regularly monitored in patients with metallic head THAs. Further investigations should be planned on large international cohorts. LEVEL OF EVIDENCE: Level III, therapeutic study.

Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study.

BACKGROUND: The safety and effectiveness of non-vitamin K antagonist (VKA) oral anticoagulants, dabigatran or rivaroxaban, were compared with VKA in anticoagulant-naive patients with nonvalvular atrial fibrillation during the early phase of anticoagulant therapy. METHODS AND RESULTS: With the use of the French medico-administrative databases (SNIIRAM and PMSI), this nationwide cohort study included patients with nonvalvular atrial fibrillation who initiated dabigatran or rivaroxaban between July and November 2012 or VKA between July and November 2011. Patients presenting a contraindication to oral anticoagulants were excluded. Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, or December 31 of the inclusion year. Hazard ratios of hospitalizations for bleeding and arterial thromboembolic events were estimated in an intent-to-treat analysis using Cox regression models. The population was composed of 19 713 VKA, 8443 dabigatran, and 4651 rivaroxaban new users. All dabigatran- and rivaroxaban-treated patients were matched to 16 014 and 9301 VKA-treated patients, respectively. Among dabigatran-, rivaroxaban-, and their VKA-matched-treated patients, 55 and 122 and 31 and 68 bleeding events and 33 and 58 and 12 and 28 arterial thromboembolic events were observed during follow-up, respectively. After matching, no statistically significant difference in bleeding (hazard ratio, 0.88; 95% confidence interval, 0.64-1.21) or thromboembolic (hazard ratio, 1.10; 95% confidence interval, 0.72-1.69) risk was observed between dabigatran and VKA new users. Bleeding (hazard ratio, 0.98; 95% confidence interval, 0.64-1.51) and ischemic (hazard ratio, 0.93; 95% confidence interval, 0.47-1.85) risks were comparable between rivaroxaban and VKA new users. CONCLUSIONS: In this propensity-matched cohort study, our findings suggest that physicians should exercise caution when initiating either non-VKA oral anticoagulants or VKA in patients with nonvalvular atrial fibrillation.

Associations between dietary patterns and arterial stiffness, carotid artery intima-media thickness and atherosclerosis.

BACKGROUND: Few studies have examined the association between global diet, assessed through dietary patterns, and arterial structure and function. The aim of this study was to investigate the relationship between carotid-femoral pulse-wave velocity (PWV), common carotid-arteries intima-media thickness (CCA-IMT) and plaques with dietary patterns measured 7.5 years earlier. DESIGN: A prospective cohort study between diet and markers of structure and function of large arteries. METHODS: Dietary patterns (linear combination of food consumption) were identified using principal component analysis among 1026 middle-aged participants in the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) vascular substudy. Dietary data were based on repeated 24-h dietary records (at least three records during 2 years) obtained at inclusion. Carotid-femoral PWV was used to assess aortic stiffness. Carotid ultrasound examination included measurements of CCA-IMT and carotid plaques. RESULTS: Four dietary patterns were identified. In multivariate models, a significant positive association was observed between PWV and a dietary pattern positively correlated with meat and alcohol consumption and negatively correlated with fibers, vitamins B9 and C, ß-carotene and calcium consumption. Adjusted PWV mean across tertiles of this pattern score was 11.15, 11.26 and 11.58 m/s in the first, second and third tertiles, respectively (P for trend=0.03). Others dietary patterns were not associated with PWV and we detected no association between dietary patterns and IMT or plaques. CONCLUSION: This study suggests that a nutritionally poor dietary pattern, characterized by a high meat and alcohol consumption and low micronutrients intake, is related to an increased stiffening of large arteries.

Tea consumption is inversely associated with carotid plaques in women.

OBJECTIVE: The aim of this study was to assess the relationship of tea consumption with common carotid artery intima-media thickness (CCA-IMT) and carotid plaques. METHODS AND RESULTS: The study was performed on 6597 subjects aged > or = 65 years, recruited in the French population for the Three-City Study. Atherosclerotic plaques in the extracranial carotid arteries and CCA-IMT were measured using a standardized protocol. Results were tested for replication in another, younger, French population sample (EVA-Study, 1123 subjects). In the Three-City Study, increasing daily tea consumption was associated with a lower prevalence of carotid plaques in women: 44.0%, 42.5%, and 33.7% in women drinking no tea, 1 to 2 cups/d, and > or = 3 cups/d (P=0.0001). This association was independent of age, center, major vascular risk factors, educational level, and dietary habits (adjOR=0.68[95%CI:0.54 to 0.86] for women drinking > or = 3 cups/d compared with none). There was no association of tea consumption with carotid plaques in men, or CCA-IMT in both genders. In the EVA-Study, carotid plaque frequency was 18.8%, 18.5%, and 8.9% in women drinking no tea, 1 to 2 cups/d, and > or = 3 cups/d (P=0.08). CONCLUSIONS: In a large sample of elderly community subjects we showed for the first time that carotid plaques were less frequent with increasing tea consumption in women.

Allergic rhinitis and onset of bronchial hyperresponsiveness: a population-based study.

RATIONALE: Patients with allergic rhinitis have more frequent bronchial hyperresponsiveness (BHR) in cross-sectional studies. OBJECTIVES: To estimate the changes in BHR in nonasthmatic subjects with and without allergic rhinitis during a 9-year period. METHODS: BHR onset was studied in 3,719 subjects without BHR at baseline, who participated in the follow-up of the European Community Respiratory Health Survey. MEASUREMENTS AND MAIN RESULTS: BHR was defined as a >or=20% decrease in FEV(1) for a maximum dose of 1 mg of methacholine. Allergic rhinitis was defined as having a history of nasal allergy and positive specific IgE (>or=0.35 IU/ml) to pollen, cat, mites, or Cladosporium. The cumulative incidence of BHR was 9.7% in subjects with allergic rhinitis and 7.0% in subjects with atopy but no rhinitis, compared with 5.5% in subjects without allergic rhinitis and atopy (respective odds ratios [OR] and their 95% confidence intervals [95% CI] for BHR onset, 2.44 [1.73-3.45]; and 1.35 [0.86-2.11], after adjustment for potential confounders including sex, smoking, body mass index and FEV(1)). Subjects with rhinitis sensitized exclusively to cat or to mites were particularly at increased risk of developing BHR (ORs [95% CI], 7.90 [3.48-17.93] and 2.84 [1.36-5.93], respectively). Conversely, in subjects with BHR at baseline (n = 372), 35.3% of those with allergic rhinitis, compared with 51.8% of those without rhinitis had no more BHR at follow-up (OR [95% CI], 0.51 [0.33-0.78]). BHR "remission" was more frequent in patients with rhinitis treated by nasal steroids than in those not treated (OR [95% CI], 0.33 [0.14-0.75]). CONCLUSIONS: Allergic rhinitis was associated with increased onset of BHR, and less chance for remission except in those treated for rhinitis.

Metabolic syndrome in relation to structure and function of large arteries: a predominant effect of blood pressure. A report from the SU.VI.MAX. Vascular Study.

BACKGROUND: Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease. However, the contribution of MetS to intermediate cardiovascular endpoints such as structure and function alterations of large arteries is still unclear. METHODS: A total of 917 middle-aged French men and women participating to the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) Vascular study were included. Carotid-femoral pulse wave velocity was used to assess aortic stiffness. Carotid ultrasound examination included measurements (at sites free of plaques) of intima-media thickness (IMT) at the common carotid arteries (CCA) and assessment of atherosclerotic plaques in the extracranial carotid arteries. RESULTS: Prevalence of the MetS defined by the National Cholesterol Education Program was 8.7%. Compared with subjects without MetS, subjects with MetS had significant higher mean values of CCA-IMT (P = .02) and pulse wave velocity (P = .0001). We found that MetS was not significantly related to the presence of carotid plaques. Blood pressure was the only MetS component associated with all vascular parameters. Addition of other MetS components in the multivariate models contributed poorly to the explained variance of these parameters. CONCLUSIONS: The MetS is adversely associated with markers of early arterial dysfunction, such as CCA-IMT and arterial stiffness. Although the associations between MetS and these arterial parameters are related to insulin resistance, blood pressure was shown to be the most important MetS component in relation to structure and function of large arteries.

Parental longevity and 7-year changes in blood pressures in adult offspring.

In this report, we examined the cross-sectional and the 7-year longitudinal changes in blood pressures in adult offspring according to parental longevity. A population of volunteers free of symptomatic cardiovascular diseases who participated to the Supplementation en Vitamines et en Minéraux Antioxydants (SUVIMAX) Vascular Study (mean age 52.3 years; 48.3% women) were examined at baseline and 7 years later. Paternal (n=994) and maternal (n=896) longevity were analyzed separately. The prevalence of hypertension at baseline in subjects whose father died at <65 years of age, in those whose fathers were alive by age 65 but died by 80 years of age, and in those whose fathers were alive by age 80 was respectively 34.9%, 28.5%, and 20.2% (P<0.001). The means of systolic blood pressure in the 3 groups of paternal longevity were respectively 128.4 (+/-16.0), 125.3 (+/-14.2), and 123.6 (+/-14.4) mm Hg (P<0.001). During the follow-up, the mean systolic blood pressure increases in the 3 groups of paternal longevity were respectively 5.3 (+/-17.0), 4.2 (+/-14.0), and 1.6 (+/-13.2) mm Hg (P<0.001). In subjects without hypertension at baseline, hypertension occurred during the follow-up in 26.6%, 17.7%, and 15.3% (P<0.009), respectively. Multivariate analyses adjusted for baseline or changes in cardiovascular risk factors did not modify these results. In contrast, there was no relationship between maternal longevity and blood pressure measurements in either cross-sectional or longitudinal analyses. This study suggests that paternal premature death was associated with accelerated progression of systolic blood pressure and higher occurrence of hypertension in offspring. These results indicate that there are dynamic and continuous processes linking paternal longevity to blood pressure in adults.

Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries.

OBJECTIVE: Limited data exist from randomized trials evaluating, noninvasively, the impact of antioxidant supplementation on vascular structure and function. METHODS AND RESULTS: This is a substudy of the SU.VI.MAX Study, which is a randomized, double-blind, placebo-controlled, cardiovascular and cancer primary prevention trial. Eligible participants (free of symptomatic chronic diseases and apparently healthy) were randomly allocated to daily receive either a combination of antioxidants (120 mg vitamin C, 30 mg vitamin E, 6 mg beta carotene, 100 microg selenium, and 20 mg zinc) or placebo and followed-up over an average of 7.2+/-0.3 years. At the end-trial examination, the carotid ultrasound examination and carotid-femoral pulse-wave velocity (PWV) measurement were performed blindly in 1162 subjects aged older than 50 years and living in the Paris area. The percentage of subjects with carotid plaques was higher in the intervention group compared with the placebo group (35.2% versus 29.5%, P=0.04). Common carotid intima-media thickness (mean+/-SD) was not different between the 2 groups (0.70+/-0.08 versus 0.70+/-0.08 mm, P=0.38). Mean PWV tended to be lower (indicating less stiff aortic arteries) in the intervention group but the difference did not reach statistical significance (P=0.13). CONCLUSIONS: These results suggest no beneficial effects of long-term daily low-dose supplementation of antioxidant vitamins and minerals on carotid atherosclerosis and arterial stiffness.