Long-term care use, hospitalizations and mortality during COVID-19 in Finland and Sweden: A nationwide register-based study in 2020.

AIM: To describe long-term care (LTC) use in Finland and Sweden in 2020, by reporting residential entry and exit patterns including hospital admissions and mortality, compared with the 2018-2019 period and community-living individuals. METHODS: From national registers in Finland and Sweden, all individuals 70+ were included. Using the Finnish and Swedish study populations in January 2018 as the standard population, we reported changes in sex- and age-standardized monthly rates of entry into and exit from LTC facilities, mortality and hospital admission among LTC residents and community-living individuals in 2020. RESULTS: Around 850,000 Finns and 1.4 million Swedes 70+ were included. LTC use decreased in both countries from 2018 to 2020. In the first wave (March/April 2020), Finland experienced a decrease in LTC entry rates and an increase in LTC exit rates, both more marked than Sweden. This was largely due to short-term movements. Mortality rates peaked in April and December 2020 for LTC residents in Finland, while mortality peaked for both community-living individuals and LTC residents in Sweden. A decrease in hospital admissions from LTC facilities occurred in April 2020 and was less marked in Finland versus Sweden. CONCLUSIONS: During the first wave of the pandemic mortality was consistently higher in Sweden. We also found a larger decrease in LTC use and, among LTC residents, a smaller decrease in hospital admissions in Finland than in Sweden. This study calls for assessing the health consequences of the differences observed between these two Scandinavian countries as part of the lessons from the COVID-19 pandemic.

Annual rate of newly treated atrial fibrillation by age and gender in France, 2010-2016.

Few studies are available on atrial fibrillation (AF) burden at a whole country scale. The objective was to estimate the rate of AF patients newly treated with oral anticoagulants (OAC) in France each year between 2010 and 2016 and to describe age and gender differences. We used the French national health data system. For each year between 2010 and 2016, we identified patients aged over 20 initiating OAC. OAC indicated for the treatment of AF was determined by hospitalization diagnoses, specific procedures and registered long-term disease status, or a multiple imputation process for patients with no recorded information as to why they initiated OAC. Among the 421,453 individuals initiating OAC treatment in 2016, the estimated number of newly treated AF patients was 210,131, women accounting for 46%, patients under 65 years old 17%, and 21.4% of patients living in most deprived area. Age-standardized rates reached 400/100,000 inhabitants. Approximately 19% of patients were recently hospitalized for heart failure and 7% for stroke. Age-standardized rates increased by 35% over the study period in both genders, with a marked increase in patients under 55 (+ 41%) and those over 85 years old (+ 60%). Annual rates of AF patients newly treated with OAC increased by 35% between 2010 and 2016. Important differences in rates were observed according to age, gender and the deprivation level of the living area.

Adherence with direct oral anticoagulants in nonvalvular atrial fibrillation new users and associated factors: a French nationwide cohort study.

PURPOSE: Direct oral anticoagulants (DOACs) have been promoted in patients with nonvalvular atrial fibrillation (nv-AF) as a more convenient alternative to vitamin K antagonists. We estimated 1-year dabigatran and rivaroxaban adherence rates in nv-AF patients and assessed associations between baseline patient characteristics and nonadherence. METHODS: This cohort study included OAC-naive nv-AF patients with no contraindications to OAC, who initiated dabigatran and rivaroxaban, using nationwide data from French national health care databases. One-year adherence was defined by the proportion of days covered of 80% or more over a fixed 1-year period after treatment initiation. Associations between nonadherence and baseline patient characteristics were assessed using multivariate logistic regression models. RESULTS: The population was composed of 11 141 dabigatran (women: 48%; mean age: 74 ± 10.7 y; ≥80 y: 34.9%) and 11 126 rivaroxaban (46.5%; 74 ± 10.9 y; 34.8%) new users. One-year adherence was 53.3% in dabigatran-treated and 59.9% in rivaroxaban-treated patients, consistent with numerous subgroup analyses. A switch to vitamin K antagonist was observed in 14.5% of dabigatran and 11.7% of rivaroxaban patients; 10.2% and 5.9% of patients switched to another DOAC, respectively; and 4.3% of patients died in the 2 cohorts. In patients who did not die or switch during the follow-up, 1-year adherence was 69.6% in dabigatran-treated and 72.3% in rivaroxaban-treated patients. Having concomitant ischemic heart diseases was associated with an increased risk of nonadherence in the 2 cohorts. CONCLUSION: In this real-life study, 1-year adherence to DOAC is poor in nv-AF new users. Despite the introduction of DOAC, adherence to OACs may remain a significant challenge in AF patients.

Identifying atrial fibrillation in outpatients initiating oral anticoagulants based on medico-administrative data: results from the French national healthcare databases.

PURPOSE: Identifying atrial fibrillation (AF) in outpatients treated with oral anticoagulants (OACs) from claims databases is challenging when the outpatient indication is not available, as OACs are also prescribed for deep vein thrombosis/pulmonary embolism (DVT/PE) that may be treated in the ambulatory setting. An algorithm was developed to identify AF in outpatients initiating OAC from medico-administrative data. METHODS: Among patients initiating OAC in 2013 in the French healthcare databases, those treated for orthopaedic indications were excluded. Patients with a history of AF or DVT/PE directly identified from available medical data, mainly hospital discharge diagnoses, were considered to be 'confirmed AF or DVT/PE patients'. Demographics of these patients and their healthcare utilization data prior to OAC initiation were then included in a logistic regression model discriminating AF versus DVT/PE indications. The final model selected, comparing c-index, provided an algorithm identifying AF from among initially unclassified patients assumed to be either AF or DVT/PE outpatients. RESULTS: Among 256 418 patients initiating OAC, 37 388 were excluded; 61 329 AF and 59 859 DVT/PE patients were directly identified, leaving 88 488 unclassified patients. The final model (c-index: 0.93) included demographics, cardiologist prescriber, hospitalization for stroke, use of antiarrhythmics/beta-blockers/antihypertensive drugs and undergoing a Holter/echocardiography procedure, thyroid function tests, but no D-dimer tests. With a specificity of 95% (sensitivity: 65%), 41% of the unclassified patients were assumed to be AF outpatients. Similar results were obtained on 250 159 new users in 2014. CONCLUSION: This algorithm combining inpatient and outpatient claims data performed relatively well to identify AF outpatients initiating OAC. Copyright © 2017 John Wiley & Sons, Ltd.

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.

Comparative effectiveness of rosuvastatin versus simvastatin in primary prevention among new users: a cohort study in the French national health insurance database.

PURPOSE: Using the French claims database (Système National d'Information Inter-Régimes de l'Assurance Maladie) linked to the hospital discharge database (Programme de Médicalisation des Systèmes d'Information), this observational study compared the effectiveness of rosuvastatin and simvastatin prescribed at doses with close LDL-cholesterol-lowering potency on all-cause mortality and cardiovascular and cerebrovascular diseases (CCDs) in primary prevention. METHODS: This historical cohort included patients with no prior CCD, aged 40-79 years, who initiated statin therapy with rosuvastatin 5 mg or simvastatin 20 mg in 2008-2009 in general practice. Follow-up started after a 1-year period used to select patients who regularly received the initial treatment. In an intention-to-treat analysis, patients were followed up to December 2011. In a per-protocol analysis, they were censored prematurely when they discontinued their initial treatment. Adjustment for baseline covariates (age, deprivation index, comedications, comorbidities, prior hospital admissions) was carried out by a Cox proportional hazards model. In the per-protocol analysis, estimation was done by "inverse probability of censoring weighting" using additional time-dependent covariates. Analyses were gender-specific. RESULTS: A total of 106941 patients initiated statin therapy with rosuvastatin 5 mg and 56860 with simvastatin 20 mg. Mean follow-up was 35.8 months. For both genders and both types of analyses, the difference in incidence rates of mortality and/or CCD between rosuvastatin 5 mg and simvastatin 20 mg users was not statistically significant after adjustment (e.g., for CCD and/or mortality in men, in intention-to-treat analysis HR=0.94 [95% CI=0.85-1.04], in per-protocol analysis HR=0.98 [0.87-1.10]). CONCLUSIONS: The results of this real-life study based on medico-administrative databases do not support preferential prescription of rosuvastatin compared to simvastatin for primary prevention of CCD.

Spousal bereavement and four-year trajectories of medication use: A nationwide register-based study in Swedish older adults.

BACKGROUND: Medication use around widowhood has been poorly described for most medication classes. Medication use patterns can reflect health consequences of spousal loss, as previously shown for psychotropic drugs. METHODS: We used data from nationwide health registers (2008-2020) to describe the patterns of use of dispensed medications in all widowed Swedes aged ≥65 years followed between 2 years before and 2 years after spousal death. All prescription drugs used by at least 5% of the cohort were considered according to their therapeutic subgroups (Anatomical Therapeutic Chemical [ATC] classification system 2nd level). We used group-based trajectory models to cluster widowed individuals into up to 4 distinct longitudinal patterns of monthly medication use. We ranked the therapeutic subgroups with similar patterns according to their plausibility to reflect potential health effects of spousal loss, compared to those of psycholeptics (mainly anxiolytics, hypnotics) and psychoanaleptics (mainly antidepressants) as the references. RESULTS: From 212,111 widowed adults included (68% female and 70% aged ≥75 years), we observed a significant increasing trend in medication use, especially after spousal death, for 21 out of the 39 different therapeutic subgroups that were used by at least 5% (most represented pharmacological groups: cardiovascular system, nervous system, and alimentary tract and metabolism). This increasing trend often concerned only a small proportion of individuals, with varying magnitude and speed of change in medication use across therapeutic subgroups. The patterns of use of antiepileptics, laxatives, skin emollients/protectives, analgesics, and drugs for anemia, constipation, or peptic ulcers, were the closest to those of references, displaying the largest changes in use, and were therefore ranked as the most likely to reflect health effects of spousal loss. CONCLUSION: Our results confirmed the increase in psychotropic medications' use in widowed older adults and identified several potential physical health effects of spousal loss that warrant further research.

Cholinesterase inhibitors and non-steroidal anti-inflammatory drugs and the risk of peptic ulcers: A self-controlled study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with caution in adults aged 65 years and older. Their gastrointestinal adverse event risk might be further reinforced when using concomitant cholinesterase inhibitors (ChEIs). We aimed to investigate the association between NSAIDs and ChEI use and the risk of peptic ulcers in adults aged 65 years and older. METHODS: Register-based self-controlled case series study including adults ≥65 years with a new prescription of ChEIs and NSAIDs, diagnosed with incident peptic ulcer in Sweden, 2007-2020. We identified persons from the Total Population Register individually linked to several nationwide registers. We estimated the incidence rate ratio (IRR) of peptic ulcer with a conditional Poisson regression model for four mutually exclusive risk periods: use of ChEIs, NSAIDs, and the combination of ChEIs and NSAIDs, compared with the non-treatment in the same individual. Risk periods were identified based on the prescribed daily dose, extracted via a text-parsing algorithm, and a 30-day grace period. RESULTS: Of 70,060 individuals initiating both ChEIs and NSAIDs, we identified 1500 persons with peptic ulcer (median age at peptic ulcer 80 years), of whom 58% were females. Compared with the non-treatment periods, the risk of peptic ulcer substantially increased for the combination of ChEIs and NSAIDs (IRR: 9.0, [6.8-11.8]), more than for NSAIDs alone (5.2, [4.4-6.0]). No increased risks were found for the use of ChEIs alone (1.0, [0.9-1.2]). DISCUSSION: We found that the risk of peptic ulcer associated with the concomitant use of NSAIDs and ChEIs was over and beyond the risk associated with NSAIDs alone. Our results underscore the importance of carefully considering the risk of peptic ulcers when co-prescribing NSAIDs and ChEIs to adults aged 65 years and older.

Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts.

Bevacizumab is one of the rare drugs that could improve high-grade glioma outcome after failure of chemoradiotherapy. However, to date, there is no biomarker predictive for efficacy of bevacizumab therapy in terms of survival improvement for patients with high-grade glioma. We performed a retrospective analysis of clinical factors associated with patient survival using a training cohort of 110 consecutive patients treated with bevacizumab for recurrent high-grade glioma and an independent validation cohort of 109 patients. In the training cohort, 110 consecutive patients received bevacizumab-based therapy. The number of chemotherapy cycles delivered was 1,411. Median follow-up was 12 months. Thirty-four patients (31%) had objective partial response and 24% had stable disease on magnetic resonance imaging evaluation. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 9.2 months, respectively. On univariate analysis, among classical prognosis factors, only Karnofsky status ≥70% was associated with improved outcome. Surprisingly, patients with low bevacizumab dose intensity (<5 mg/kg/week) had better PFS (12 vs. 2 months, P < 0.0001) and OS (16 vs. 6 months, P = 0.0002). On multivariate analysis, low bevacizumab dose intensity was the most significant independent prognostic factor of survival. Analysis of the validation cohort yielded similar results, externally validating this observation. This large retrospective study using two independent cohorts of high-grade glioma suggests that the currently recommended dosage of bevacizumab (5 mg/kg/week) is not optimal. Further prospective randomized trials using lower dosages are warranted.

Dispensing of Potentially Harmful Prescription Drugs in 1.8 Million Pregnant Women in France: A Nationwide Study Based on Two Risk Classification Systems.

INTRODUCTION: Nationwide prevalence of potentially harmful drug prescribing during pregnancy is unknown in France, and several risk classification systems (RCS) exist to guide prescribers. OBJECTIVE: The aim of this study was to estimate the nationwide prevalence of potentially harmful drug prescribing during pregnancy in France and to describe maternal characteristics associated with this prescription. METHODS: This drug utilisation study, conducted on the French health databases (67 million beneficiaries), included all pregnancies beginning in 2016-2017, regardless of pregnancy outcome. Potentially harmful drug prescribing was defined as at least one reimbursement during pregnancy of Swedish RCS category D drugs, Australian RCS category D/X drugs, or contraindicated drugs in France for drugs not listed in these two RCSs. Maternal characteristics associated with potentially harmful drug prescribing were described using a univariate logistic regression analysis. RESULTS: Among the 1,844,447 pregnant women identified, the prevalence of potentially harmful drug prescribing was higher according to the Australian RCS (3.9%) than according to the Swedish RCS (2.2%), with good agreement between the two RCSs (Kappa = 0.81 [0.74-0.87]). This prevalence increased to 9.2% and 6.9%, respectively, when considering contraindications in France. Prescribing of teratogenic drugs, including retinoids and valproate, was highest during the first trimester, whereas prescribing of foetotoxic drugs decreased after the first trimester but remained high for nonsteroidal anti-inflammatory drugs (N = 10,021). In women with no chronic diseases, polymedication (five or more drugs) was the strongest maternal characteristic associated with potentially harmful drug prescribing in both RCSs. CONCLUSIONS: Potentially harmful drug prescribing during pregnancy is not uncommon in France. This study supports the comparative analysis of RCS to assess potentially harmful drug prescribing in claims databases.

Oral anticoagulants and risk of acute liver injury in patients with nonvalvular atrial fibrillation: a propensity-weighted nationwide cohort study.

Insufficient real-world data on acute liver injury (ALI) risk associated with oral anticoagulants (OACs) exist in patients with nonvalvular atrial fibrillation (NVAF). Using the French national healthcare databases, a propensity-weighted nationwide cohort study was performed in NVAF patients initiating OACs from 2011 to 2016, considering separately those (1) with no prior liver disease (PLD) as main population, (2) with PLD, (3) with a history of chronic alcoholism. A Cox proportional hazards model was used to estimate the hazard ratio with 95% confidence interval (HR [95% CI]) of serious ALI (hospitalised ALI or liver transplantation) during the first year of treatment, for each non-vitamin K antagonist (VKA) oral anticoagulant (NOAC: dabigatran, rivaroxaban, apixaban) versus VKA. In patients with no PLD (N = 434,015), only rivaroxaban new users were at increased risk of serious ALI compared to VKA initiation (adjusted HR: 1.41 [1.05-1.91]). In patients with chronic alcoholism history (N = 13,173), only those initiating dabigatran were at increased risk of serious ALI compared to VKA (2.88 [1.74-4.76]) but an ancillary outcome suggested that differential clinical follow-up between groups might partly explain this association. In conclusion, this study does not suggest an increase of the 1-year risk of ALI in NOAC versus VKA patients with AF.

Oral anticoagulation therapy use in patients with atrial fibrillation after the introduction of non-vitamin K antagonist oral anticoagulants: findings from the French healthcare databases, 2011-2016.

OBJECTIVES: To describe (i) the trend in oral anticoagulant (OAC) use following the introduction of non-vitamin K antagonist oral anticoagulant (NOAC) therapy for stroke prevention in atrial fibrillation (AF) patients and (ii) the current patterns of use of NOAC therapy in new users with AF in France. DESIGN: (i) Repeated cross-sectional study and (ii) population-based cohort study. SETTING: French national healthcare databases (50 million beneficiaries). PARTICIPANTS: (i) Patients with identified AF in 2011, 2013 and 2016 and (ii) patients with AF initiating OAC therapy in 2015-2016. PRIMARY AND SECONDARY OUTCOME MEASURES: (i) Trend in OAC therapy use in patients with AF and (ii) patterns of use of NOAC therapy in new users with AF. RESULTS: Between 2011 and 2016, use of OAC therapy moderately increased (+16%), while use of antiplatelet therapy decreased (-22%) among all patients with identified AF. In 2016, among the 1.1 million AF patients, 66% used OAC therapy and were more likely to be treated by vitamin K antagonist (VKA) than NOAC therapy, including patients at higher risk of stroke (63.5%), while 33% used antiplatelet therapy. Among 192 851 new users of OAC therapy in 2015-2016 with identified AF, NOAC therapy (66.3%) was initiated more frequently than VKA therapy, including in patients at higher risk of stroke (57.8%). Reduced doses were prescribed in 40% of NOAC new users. Several situations of inappropriate use at NOAC initiation were identified, including concomitant use of drugs increasing the risk of bleeding (one in three new users) and potential NOAC underdosing. CONCLUSIONS: OAC therapy use in patients with AF remains suboptimal 4 years after the introduction of NOACs for stroke prevention in France and improvement in appropriate prescribing regarding NOAC initiation is needed. However, NOAC therapy is now the preferred drug class for initiation of OAC therapy in patients with AF, including in patients at higher risk of stroke.

Conventional mood stabilizers and/or second-generation antipsychotic drugs in bipolar disorders: A population-based comparison of risk of treatment failure.

BACKGROUND: The study compared treatment failure when using three therapeutic strategies in bipolar disorders: (i) mood stabilizers (MSs: lithium, valpromide, divalproate, carbamazepine, lamotrigine) without second-generation antipsychotic (SGAP); (ii) SGAPs (aripiprazole, olanzapine, risperidone, quetiapine) without MS; (iii) combination of MSs and SGAPs. METHODS: A historical cohort study was conducted using the French national healthcare databases in 20,086 outpatients aged 21+, newly treated with one of the three treatment strategies in 2011-2012, and diagnosed with a bipolar disorder. A composite outcome was based on indicators of treatment failure identified over 12 months: treatment discontinuation, switch or addition, psychiatric hospitalisation, suicide attempt, and death. For each strategy, the cumulative incidence of treatment failure was calculated while adjusting for covariates by propensity score weighting. RESULTS: A total of 8,225 patients (40.9%) were newly dispensed MSs, 9,342 (46.5%) SGAPs, and 2,519 (12.5%) both MSs and SGAPs. The one-year adjusted cumulative incidence of treatment failure was 75.7% (95%CI 74.9;76.3) in patients using MSs, 75.3% (74.6;76.0) in patients using SGAPs, and 60.5% (58.3;62.6) in patients with the combination. The adjusted difference in incidence for SGAPs compared with MSs was -0.40% (-1.4;0.6 p = 0.4) in the whole population, -2.2% (-3.3; -1.2 p < 0.002) in patients under 65 years and +6.7% (4.1;9.1 p < 0.002) in patients 65 years and over. LIMITATIONS: Combinations of MSs and SGAPs could not be directly compared with MS or SGAP monotherapies. CONCLUSIONS: One-year treatment failure was high. Overall, no difference in treatment failure was observed between MS or SGAP strategy but differences might exist depending on age.

Cervical cancer screening and subsequent procedures in women under the age of 25 years between 2007 and 2013 in France: a nationwide French healthcare database study.

Cervical cancer screening in young women may lead to the detection of lesions with a high potential for spontaneous regression and no benefit of surgery. French guidelines recommend initiating cervical cancer screening by the Pap test from the age of 25 years. To date, no French nationwide study has assessed cervical cancer screening in young women and the related subsequent work-up and surgical procedures among screen-positive women. Using data from the French national healthcare databases (around 50 million beneficiaries), annual and 3-year Pap test screening rates were calculated among women aged 15-24 years between 2007 and 2013. Cervical excisional procedures were assessed during the 15-month period following a first Pap test in women aged 20-24 years in 2007 and 2012. About 10% of the almost six million women aged 15-65 years with at least one annual Pap test were under the age of 25, mainly women aged 20-24 years, in whom the 3-year screening coverage was 35.5% in 2013. In screened women aged 20-24 years, human papillomavirus testing rates increased markedly over the study period (+105%) and surgical management became less conservative with an increased rate of both conization (+16.5%) and other excisional treatments (+74.5%). Nevertheless, because of the overall decrease in screening coverage, the absolute yearly number of women who underwent conization decreased from 1974 to 1766 between 2007 and 2012. Higher adherence to guidelines is needed to reduce the burden of surgical treatment that is potentially associated with adverse obstetric outcomes among women under the age of 25 years.

Comparison of Treatment Persistence with Dabigatran or Rivaroxaban versus Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients: A Competing Risk Analysis in the French National Health Care Databases.

BACKGROUND: Direct oral anticoagulants (DOACs) have been proposed as a more convenient alternative to vitamin K antagonists (VKAs), which are commonly associated with poor treatment persistence in non-valvular atrial fibrillation (nv-AF). METHODS: Using data from the French national health care databases (Régime Général, 50 million beneficiaries), a cohort study was conducted to compare the 1-year non-persistence rates in nv-AF patients initiating dabigatran (N=11,141) or rivaroxaban (N=11,126) versus VKA (N=11,998). Treatment discontinuation was defined as a switch between oral anticoagulant (OAC) classes or a 60-day gap with no medication coverage, with the additional criterion of no reimbursement for international normalized ratio monitoring during this gap for VKA patients. Considering death as a competing risk, differences between 1-year discontinuation rates were used to compare each DOAC versus VKA. The 95% confidence intervals (CIs) were estimated via bootstrapping. Baseline patient characteristics were adjusted using inverse probability of treatment weighting. Subgroup analyses considered DOAC dose at initiation, age, risk of stroke, and bleeding. RESULTS: Adjusted 1-year discontinuation rates were higher for dabigatran than for VKA new users (36.8% vs 30.2%; difference: 6.6% [95% CI, 5.5-7.6]) and for rivaroxaban versus VKA new users (33.4% vs 30.4%; 3.0% [1.9-4.1]). Similar differences were found in all subgroup analyses, except in dabigatran and rivaroxaban patients <75 years (dabigatran vs VKA: 0.3% [-1.4 to 1.8]; rivaroxaban vs VKA: -2.6% [-4.3 to -0.9]) and dabigatran 150 mg new users (-1.1% [-3.1 to 0.7]). Consistent results were obtained when considering both switches between OAC classes and death as competing risks of treatment discontinuation. CONCLUSION: Results from this nationwide cohort study showed high non-persistence levels with all OACs and suggest that persistence with both dabigatran and rivaroxaban therapy is not better than persistence with VKA therapy. Hospitalizations for bleeding among non-persistent patients were unlikely to explain these high non-persistence rates.

Clinical Events After Discontinuation of ß-Blockers in Patients Without Heart Failure Optimally Treated After Acute Myocardial Infarction: A Cohort Study on the French Healthcare Databases.

BACKGROUND: ß-blockers have been among the first medications shown to improve outcomes after acute myocardial infarction (AMI). With the advent of reperfusion therapy and other secondary-prevention medications, their role has become uncertain, and large-scale experience after AMI in the contemporary era is lacking. In particular, the effect of stopping ß-blockers in patients initially treated after AMI is unknown. METHODS AND RESULTS: Using the French healthcare databases, 73 450 patients (<80 years of age), admitted for AMI in 2007 to 2012, without acute coronary syndrome (ACS) in the previous 2 years and no evidence of heart failure, having received optimal treatment with myocardial revascularization and all recommended medications in the 4 months after index admission, and not having discontinued ß-blockers before 1 year, were followed for 3.8 years on average. ß-Blocker discontinuation was defined as 4 consecutive months without exposure. If ß-blocker treatment was resumed later on, follow-up was stopped. Both the risk of the composite outcome of death or admission for ACS and the risk of all-cause mortality were assessed in relation with ß-blocker discontinuation during follow-up. Adjusted hazard ratios were estimated using marginal structural models accounting for time-varying confounders affected by previous exposure. A similar analysis was performed with statins. Of 204 592 patient-years, 12 002 (5.9%) corresponded to discontinued ß-blocker treatment. For ß-blocker discontinuation, the adjusted hazard ratio for death or ACS was 1.17 (95% confidence interval, 1.01-1.35); for all-cause death, the adjusted hazard ratio was 1.13 (95% confidence interval, 0.94-1.36). In contrast, for statin discontinuation, the adjusted hazard ratios for death or ACS and for all-cause death were 2.31 (95% confidence interval, 2.01-2.65) and 2.57 (95% confidence interval, 2.19-3.02), respectively. CONCLUSIONS: In routine care of patients without heart failure, revascularized and optimally treated after AMI, discontinuation of ß-blockers beyond 1 year after AMI was associated with an increased risk of death or readmission for ACS, while statistical significance was not reached for the association with all-cause mortality. A contemporary randomized clinical trial is needed to precise the role of ß-blockers in the long-term treatment after AMI.

Non-bleeding Adverse Events with the Use of Direct Oral Anticoagulants: A Sequence Symmetry Analysis.

INTRODUCTION: Postmarketing pharmacovigilance reports have raised concerns about non-bleeding adverse events associated with direct oral anticoagulants (DOACs), but only limited results are available from large claims databases. OBJECTIVE: The aim of this study was to assess the potential association between DOAC initiation and the onset of four types of non-bleeding adverse events by sequence symmetry analysis (SSA). METHODS: SSA was performed using nationwide data from the French National Healthcare databases (Régime Général, 50 million beneficiaries) to assess a cohort of 386,081 DOAC new users for the first occurrence of four types of non-bleeding outcomes: renal, hepatic, skin outcomes identified by using hospitalization discharge diagnoses, and gastrointestinal outcomes by using medication reimbursement. Asymmetry in the distribution of each investigated outcome occurring before and after initiation of DOAC therapy was used to test the association between DOAC therapy and these outcomes. SSA inherently controls for time-constant confounders, and adjusted sequence ratios were computed after correcting for temporal trends. Negative (glaucoma) and positive (bleeding, depressive disorders) control outcomes were used and analyses were replicated on a cohort of 310,195 patients initiating a vitamin K antagonist (VKA). RESULTS: This study demonstrated the expected positive association between either DOAC or VKA therapy and hospitalised bleeding and initiation of antidepressant therapy, while no association was observed between either DOAC or VKA therapy and initiation of antiglaucoma medications. For DOAC therapy, signals were the associations with hepatic outcomes, including acute liver injury [for the 3-month time window, aSR3 = 2.71, 95% confidence interval (CI) 1.79-4.52]; gastrointestinal outcomes, including initiation of drugs for constipation and antiemetic drugs (aSR3 = 1.31, 95% CI 1.27-1.36; and 1.17, 95% CI 1.12-1.22, respectively); and kidney diseases (aSR3 = 1.33, 95% CI 1.29-1.37). CONCLUSION: Results of this nationwide study suggest that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders. A low risk of kidney injury with DOAC therapy can also not be excluded.

Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases.

BACKGROUND: The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence. METHODS: We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends. FINDINGS: 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3-18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries. INTERPRETATION: Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults. FUNDING: None.

Prevalence and mortality of patients with multiple sclerosis in France in 2012: a study based on French health insurance data.

Data on the prevalence of multiple sclerosis (MS) in France are scarce. National and regional updated estimates are needed to better plan health policies. In this nationwide study, we provided estimates of the prevalence of MS in France in 2012 and mortality rate in 2013. MS cases were identified in the French national health insurance database (SNIIRAM-PMSI) using reimbursement data for disease-modifying treatment, long-term disease status for MS, disability pension for MS, and hospitalisation for MS (MS ICD-10 code: G35). We identified 99,123 MS cases, corresponding to an overall crude prevalence rate of 151.2 per 100,000 inhabitants [95% confidence interval (CI) 150.3-152.2]: 210.0 per 100,000 in women (95% CI 208.4-211.5) and 88.7 per 100,000 in men (95% CI 87.6-89.7). The overall prevalence rate was 155.6 per 100,000 inhabitants (95% CI 154.7-156.6) after standardization on the 2013-European population. We observed a prevalence gradient with a higher prevalence (190-200 per 100,000) in North-Eastern France and a lower prevalence in Southern and Western France (126-140). The crude mortality rate in 2013 was 13.7 per 1,000 MS cases (11.4 in women and 20.3 in men). The standardized mortality ratio was 2.56 (95% CI 2.41-2.72). Our results revise upwards the estimation of MS prevalence in France and confirm the excess mortality of MS patients compared to the general population.

Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study.

BACKGROUND: Patients with non-valvular atrial fibrillation who are receiving or have been previously exposed to a vitamin K antagonist could be switched to a non-vitamin K-antagonist oral anticoagulant (NOAC) but little information is available about the risk of bleeding and arterial thromboembolism after such a switch. We aimed to compare the risk of bleeding between individuals who switched and those who remained on a vitamin K antagonist (non-switchers) in real-world conditions. METHODS: We did a matched-cohort study with information from French health-care databases. We extracted data for adults (aged ≥18 years) with non-valvular atrial fibrillation who received their first prescription for a vitamin K antagonist (fluindione, warfarin, or acenocoumarol) between Jan 1, 2011, and Nov 30, 2012, and who were either switched to a NOAC (dabigatran or rivaroxaban) or maintained on the vitamin K antagonist. Each switcher was matched with up to two non-switchers on the basis of eight variables, including sex, age, and international normalised ratio number. The primary endpoint was incidence of bleeding (intracranial haemorrhage, gastrointestinal haemorrhage, or other) in switchers versus non-switchers, and switchers stratified by type of NOAC versus non-switchers, noted from databases of hospital admissions. Each patient was followed up to 1 year; the study closed on Oct 1, 2013. FINDINGS: Of 17,410 participants, 6705 switched to a NOAC (switchers) and 10,705 remained on vitamin K-antagonist therapy (non-switchers). Median age of participants was 75 years (IQR 67-82), 8339 (48%) were women, and the median duration of vitamin K-antagonist exposure before a switch was 8.1 months (IQR 3.9-14.0). After a median follow-up of 10.0 months (IQR 9.8-10.0), we noted no difference between groups for bleeding events (99 [1%] in switchers vs 193 [2%] in non-switchers, p=0.54). In adjusted multivariate analyses, the risk of bleeding in switchers was not different from that in non-switchers (hazard ratio [HR] 0.87; 95% CI 0.67-1.13, p=0.30). Additionally, no differences were noted when the risk of bleeding was compared between switchers from a vitamin K antagonist to dabigatran (HR 0.78, 95% CI 0.54-1.09, p=0.15), switchers from a vitamin K antagonist to rivaroxaban (HR 1.04, 95% CI 0.68-1.58, p=0.86), and non-switchers. INTERPRETATION: In this matched-cohort study, our findings suggest that patients with non-valvular atrial fibrillation who switch their oral anticoagulant treatment from a vitamin K antagonist to a non-vitamin K antagonist are not at increased risk of bleeding. Future studies with longer follow-up might be needed. FUNDING: None.