EvaluatioN of ApiXaban in strOke and systemic embolism prevention in patients with non-valvular atrial fibrillation in clinical practice Setting in France, rationale and design of the NAXOS: SNIIRAM study.

Non-vitamin K antagonists oral anticoagulants (NOACs) have recently challenged vitamin-K antagonists (VKAs) for stroke and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation (NVAF). Nevertheless, little information is available in routine clinical practice for France. The aim of this study is to describe the effectiveness and safety of apixaban, rivaroxaban, dabigatran or VKAs in routine clinical practice in adult NVAF patients for the prevention of stroke and systemic embolism in France. The NAXOS study is a nationwide observational retrospective cohort generated from the French national healthcare insurance database (SNIIRAM-a comprehensive in- and outpatient healthcare consumption database), consisting of eight distinct sub-cohorts of anticoagulant-naive or anticoagulant-experienced patients diagnosed with NVAF, newly initiated with either NOACs (dabigatran, rivaroxaban or apixaban) or VKAs. Patients will be included if initiating a new anticoagulant treatment for AF during the study period from 1 January 2014 to 31 December 2016. Primary effectiveness outcome will be the incidence of stroke or systemic thromboembolic events; primary safety outcome will be the incidence of major bleeding during the exposure period. The NAXOS study will provide routine clinical practice data on the effectiveness and safety profiles of apixaban vs other NOACs and VKAs in the prevention of stroke and systemic embolism in adult patients with NVAF in clinical practice conditions in France.

Changes in Persistent Asthma Care and Outcomes From 2006 to 2016 in France.

BACKGROUND: Changes in asthma care need to be documented at arrival of biotherapies. OBJECTIVES: To characterize changes in asthma care and outcomes in patients with persistent asthma. METHODS: Repeated transversal analyses were conducted on a historical cohort using the French national claims data over 10 years. Patients aged 18 to 40 years with either 1 or more (any-use population) or 4 or more (high-use population) yearly dispensings of controller therapy were selected. Clinical and demographic features were characterized, and comparisons were made between 2006 and 2016 to assess temporal changes in asthma therapy, health care resource utilization, and outcomes. RESULTS: In 2016, prevalent use of controller therapy was 5.2% (any-use population) and 0.8% (high-use population) of the population aged 18 to 40 years. In the any-use population, the use of long-acting ß2-agonists in monotherapy, and inhaled corticosteroids decreased (1.7% and 40.3% in 2016, respectively), whereas the use of fixed-dose combinations increased (56.4%). In both populations, visits to respiratory or hospital physicians and pulmonary function testing increased with time, in parallel to a decreasing number of general practitioner visits; in addition, oral corticosteroid use and incidence of emergency room visits increased. However, asthma hospitalizations and mortality remained low in both populations. CONCLUSIONS: Changes in persistent asthma care included replacement of inhaled corticosteroids by fixed-dose combinations, decreased use of long-acting ß2-agonists as a monotherapy, and increased involvement of secondary care physicians. In parallel, despite low figures for hospital admissions and mortality, overall use of oral corticosteroids and incidence of emergency room visits have increased over the last decade.

Impact of bisphosphonate compliance on the risk of osteoporotic fracture in France.

Limited information is available on the impact of bisphosphonate compliance levels on fracture risk in osteoporosis patients in France. The results of this nested case-control, retrospective study suggest that fracture risk did not significantly change with bisphosphonate compliance levels, except for highly compliant patients. PURPOSE/INTRODUCTION: This was the first study conducted in France to evaluate the impact of compliance levels for bisphosphonates, the most frequently prescribed first-line anti-osteoporotic treatment, on fracture risk. METHODS: This retrospective nested case-control study included patients ≥ 50 years old, who were recorded in a random sample of French claims data, did not die between 2006 and 2013, and received ≥ 1 reimbursement for anti-osteoporotic treatment between 2007 and 2013. Cases (patients hospitalised for osteoporosis-related fractures) were matched to 1-3 controls (patients hospitalised for other reasons). Patients hospitalised for fractures within 12 months preceding the first delivery of anti-osteoporotic treatment or during the first 24 months of follow-up were excluded. Bisphosphonate compliance during the 24 months preceding hospitalisation was calculated by the Continuous measure of Medication Acquisition version 7 (CMA7). We evaluated the impact of bisphosphonate compliance (CMA7 ≥ 80%) and very good compliance levels (CMA7 > 90%) on fracture risk. RESULTS: In the main analysis, the mean CMA7 values during the 24 months preceding hospitalisation were 48.4% for the 434 cases and 51.3% for the 1123 age-matched controls. An adjusted conditional logistic regression showed no significant impact (odds ratio: 0.851 [95% confidence interval: 0.668, 1.084]) of bisphosphonate compliance on fracture occurrence. In the sensitivity analysis, including one randomly selected control per case and only controls with CMA7 values > 90%, occurrence of fractures was lower (odds ratio: 0.741 [95% confidence interval: 0.608, 0.903]) among the 119 controls. CONCLUSION: In conclusion, this study suggested that very high levels of compliance with bisphosphonates are necessary to induce significant decreases in fracture risk.

Long-Term Inhaled Corticosteroid Adherence in Asthma Patients with Short-Term Adherence.

BACKGROUND: Although the use of inhaled corticosteroids (ICS) in asthma is known to be overall erratic, the long-term use of ICS by patients selected during an episode of regular use is poorly documented. OBJECTIVE: In a cohort of patients with asthma regularly acquiring ICS therapy over several months, we verified whether these patients remained treated in the following 12 months. The correlates of regular ICS use over this period were investigated. METHODS: A historical cohort of patients with asthma was identified from the Echantillon généraliste de bénéficiaires national French health care reimbursement data (2007-2012). Patients (6-40 years) were selected during a regular ICS use episode, with 3 or more ICS refills within 120 days. Continuous multiple-interval measures of medication availability (CMA) were computed for the 12 months after the third dispensation, and the factors associated with a CMA value of 80% or more (adherent patients) were identified. RESULTS: Among 5096 patients (42.1% children/teenagers, 48.8% females), only 24.0% had a CMA value of 80% or more (mean CMA = 54.4%) over the 12 months following the ICS selection period. Achieving a CMA value of 80% or more was primarily associated with being a child/teenager (P = .002), having more severe or less controlled asthma (P = .007), more previous dispensing of short-acting beta agonists (P < .0001), and receiving devices with 200 unit doses (P < .0001). Adherent patients had more frequent general practitioner visits (P < .0001), more distinct prescribers of respiratory therapy (P = .0002), and more frequent switches of ICS (P < .0001). CONCLUSIONS: Most patients with asthma selected during an episode of regular ICS use did not maintain therapy over the following months. Adherence should be repeatedly monitored, and the reasons for discontinuation should be investigated, at prescriber and patient levels.

Frequency of comorbidities in chronic obstructive pulmonary disease, and impact on all-cause mortality: A population-based cohort study.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), the role of specific comorbidities on all-cause mortality is of major interest particularly with a database representative of the beneficiaries covered by the French health system. We investigated the frequency and the role of major comorbidities on all-cause mortality in a population-based cohort of COPD patients, and whether this impact was modulated by gender. METHODS: A historical cohort was identified in the French claims data. Patients aged ≥45 years were selected in 2006 from the French national claims data (1/97(th) random sample) by at least one of the following criteria: (a) COPD-related hospitalisations, (b) long-term disease status for COPD, (c) dispensations of bronchodilators. Cardiovascular diseases, diabetes, depression and cancer were defined by specific therapy and/or long-term disease status. The impact of comorbidities on mortality was investigated during a seven-year follow-up period (2007-2013), using Cox models. RESULTS: In 4,237 patients (mean age 68 years, 55% males, mean annual death-rate 4.9%), cardiovascular diseases, diabetes, depression and cancers were identified in 68.7%, 15.2%, 14.2% and 10.6% of patients, respectively. Associations with mortality were significant for cardiovascular diseases (HR = 1.2, 95%CI = [1.0-1.4]), diabetes (HR = 1.2, 95%CI = [1.0-1.4]), depression (HR = 1.4, 95%CI = [1.2-1.6]) and cancers (HR = 1.6, 95%CI = [1.4-1.9]), with no difference between genders. CONCLUSIONS: In the French population, major comorbidities are common in COPD, particularly cardiovascular diseases that occur in over two thirds of patients. The impact of comorbidities on mortality was not related to their prevalence, with cancer having the largest impact.

Level of Asthma Controller Therapy Before Admission to the Hospital.

BACKGROUND: In asthma, choice of controller therapy and adherence to treatment can affect the risk of future severe exacerbations leading to hospitalization. OBJECTIVE: Our objective was to characterize treatment dispensation profiles before hospital admission for asthma. METHODS: Using a 1/97th random sample of the national French claims data, patients with asthma aged 6 to 40 years were identified between 2006 and 2014. Patients with subsequent asthma-related hospitalization were selected. On the basis of controller therapy dispensed in the 12 months before admission, treatment profiles were categorized into clusters, using Ward's minimum-variance hierarchical clustering method. RESULTS: Of 17,846 patients with asthma, we identified 275 patients (1.5%) with an asthma-related hospitalization. Three distinct clusters were identified. The first cluster (63.6%) included patients with few dispensations of any controller medication (<1 unit). The second cluster (32.4%) consisted of patients with frequent dispensations of long-acting beta agonists (LABAs)/inhaled corticosteroids (ICS) in fixed-dose combinations. The third cluster (4%) comprised patients receiving free combinations of ICS and LABAs, with more dispensations of LABAs than of ICS. CONCLUSIONS: In France, before an asthma-related hospitalization, more than 60% of patients received little controller therapy and 4% were exposed to higher dispensation of LABAs than of ICS. These results indicate that a large fraction of asthma-related hospitalizations can potentially be prevented with better pharmacotherapy.

Recurrent Wheezing in Infants: A Population-Based Study.

Recurrent wheezing (RW) has a significant impact on infants, caregivers, and society, but morbidity and related medical resource utilization (MRU) have not been thoroughly explored. The burden of RW needs to be documented with population-based data. The objective was to assess the characteristics, medical management, and MRU of RW infants identified from national claims data. Infants aged from 6 to 24 months, receiving ≥2 dispensations of respiratory drugs within 3 months, and presenting a marker of poor control (index date), were selected. During the 6 months after index date, MRU was described in the cohort and among 3 subgroups with more severe RW, defined as ≥4 dispensations of respiratory drugs, ≥3 dispensations of oral corticosteroids (OCS), or ≥1 hospitalization for respiratory symptoms. A total of 115,489 infants had RW, corresponding to 8.2% of subjects in this age group. During follow-up, 68.7% of infants received inhaled corticosteroids, but only 1.8 U (unit) were dispensed over 6 months, suggesting discontinuous use. Control was mostly inadequate: 61.7% of subjects received OCS, 80.2% antibiotics, and 71.2% short-acting beta-agonists, and medical/paramedical visits were numerous, particularly for physiotherapy. Severe RW concerned 39.0% of the cohort; 32.8% and 11.7% of infants had repeated use of respiratory drugs and OCS, respectively, and 5.5% were hospitalized for respiratory symptoms. In this real-life nation-wide study, RW was common and infants had poor control and high MRU. Interventions are needed to support adequate use of controller therapy, and to improve medical care.

Influence of vectors' risk-spreading strategies and environmental stochasticity on the epidemiology and evolution of vector-borne diseases: the example of Chagas' disease.

Insects are known to display strategies that spread the risk of encountering unfavorable conditions, thereby decreasing the extinction probability of genetic lineages in unpredictable environments. To what extent these strategies influence the epidemiology and evolution of vector-borne diseases in stochastic environments is largely unknown. In triatomines, the vectors of the parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, juvenile development time varies between individuals and such variation most likely decreases the extinction risk of vector populations in stochastic environments. We developed a simplified multi-stage vector-borne SI epidemiological model to investigate how vector risk-spreading strategies and environmental stochasticity influence the prevalence and evolution of a parasite. This model is based on available knowledge on triatomine biodemography, but its conceptual outcomes apply, to a certain extent, to other vector-borne diseases. Model comparisons between deterministic and stochastic settings led to the conclusion that environmental stochasticity, vector risk-spreading strategies (in particular an increase in the length and variability of development time) and their interaction have drastic consequences on vector population dynamics, disease prevalence, and the relative short-term evolution of parasite virulence. Our work shows that stochastic environments and associated risk-spreading strategies can increase the prevalence of vector-borne diseases and favor the invasion of more virulent parasite strains on relatively short evolutionary timescales. This study raises new questions and challenges in a context of increasingly unpredictable environmental variations as a result of global climate change and human interventions such as habitat destruction or vector control.

Adaptive developmental delay in Chagas disease vectors: an evolutionary ecology approach.

BACKGROUND: The developmental time of vector insects is important in population dynamics, evolutionary biology, epidemiology and in their responses to global climatic change. In the triatomines (Triatominae, Reduviidae), vectors of Chagas disease, evolutionary ecology concepts, which may allow for a better understanding of their biology, have not been applied. Despite delay in the molting in some individuals observed in triatomines, no effort was made to explain this variability. METHODOLOGY: We applied four methods: (1) an e-mail survey sent to 30 researchers with experience in triatomines, (2) a statistical description of the developmental time of eleven triatomine species, (3) a relationship between development time pattern and climatic inter-annual variability, (4) a mathematical optimization model of evolution of developmental delay (diapause). PRINCIPAL FINDINGS: 85.6% of responses informed on prolonged developmental times in 5(th) instar nymphs, with 20 species identified with remarkable developmental delays. The developmental time analysis showed some degree of bi-modal pattern of the development time of the 5(th) instars in nine out of eleven species but no trend between development time pattern and climatic inter-annual variability was observed. Our optimization model predicts that the developmental delays could be due to an adaptive risk-spreading diapause strategy, only if survival throughout the diapause period and the probability of random occurrence of "bad" environmental conditions are sufficiently high. CONCLUSIONS/SIGNIFICANCE: Developmental delay may not be a simple non-adaptive phenotypic plasticity in development time, and could be a form of adaptive diapause associated to a physiological mechanism related to the postponement of the initiation of reproduction, as an adaptation to environmental stochasticity through a spreading of risk (bet-hedging) strategy. We identify a series of parameters that can be measured in the field and laboratory to test this hypothesis. The importance of these findings is discussed in terms of global climatic change and epidemiological consequences.