Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Benzodiazepines for pediatric epilepsies and their risks in a cohort within the French health care data.

OBJECTIVE: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications. METHODS: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy. RESULTS: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39]). SIGNIFICANCE: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy.

Risk of cancer for patients with rheumatoid arthritis versus general population: a national claims database cohort study.

Background: Older studies uncovered an increased risk of cancer in patients with rheumatoid arthritis between 10% and 30% compared to the general population, with a lack of data concerning infrequent cancers. In recent year, major therapeutic breakthroughs might have affected this risk of cancer by mitigating disease activity or on the contrary by impairing antitumoral immune response. The objectives of this study are to compare cancer risk in patients with treated rheumatoid arthritis to the general population, in all treated patients and according to treatment exposure. Methods: This is a nationwide population-based study within the French national claims database "Système National des Données de Santé" (SNDS) between January 1st 2010 and December 31st 2020, to estimate the age and sex-standardized incidence ratios of cancer (all sites and site specific) of treated rheumatoid arthritis patients, with the French population as reference (by use of the French Network of Population-Based Cancer Registries [FRANCIM]). Findings: During the study period, 257,074 treated patients with rheumatoid arthritis contributed to a total of 2,098,238 person-years for the main analysis. The all-cancer risk was increased in rheumatoid arthritis patients, with a SIR (Standardized Incidence Ratio) of 1.20 (95% CI [1.17-1.23]). This risk was increased particularly for lung (SIR 1.41, 95% CI [1.36-1.46], bladder (SIR 2.38 95% CI [2.25-2.51]), cervix (SIR 1.80, 95% CI [1.62-2.01]), prostate (SIR 1.08, 95% CI [1.04, 1.13]) cancers, melanoma (SIR 1.37, 95% CI [1.29-1.46]), diffuse large B cell lymphoma (SIR 1.79, 95% CI [1.63-1.96], multiple myeloma (SIR 1.42, 95% CI [1.27-1.60]) and Hodgkin's lymphoma (SIR 2.73, 95% CI [2.31-3.23]). Some cancers were less frequent than in the general population such as pancreatic (SIR 0.90, 95% CI [0.83-0.97]) as well as breast and endometrial cancers (SIR 0.91, 95% CI [0.88-0.94] and SIR 0.77, 95% CI [0.71-0.84] respectively). Although we observed a modest but significant relative increase of all-cancer risk over-time in rheumatoid arthritis patients, there was a trend towards a decrease in risk of non-Hodgkin's lymphoma. Patients treated with rituximab were the patients displaying the highest risk of cancer. Interpretation: Compared to the general population, treated rheumatoid arthritis patients were at greater risk of all-cancer and some site specific cancers, except for breast, pancreatic and endometrial cancers which were less frequent than in the general population. Funding: This work was supported by unrestricted grants from the InCA (national institute against cancer) and AP-HP (Assistance Publique des Hôpitaux de Paris).

Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort.

BACKGROUND: Little is known about phototype and the response to systemic treatment in psoriasis. OBJECTIVES: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. METHODS: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1. RESULTS: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V-VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups. CONCLUSIONS: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient.

Levosimendan in patients undergoing extracorporeal membrane oxygenation after cardiac surgery: an emulated target trial using observational data.

BACKGROUND: Retrospective cohorts have suggested that levosimendan may facilitate the weaning of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). We therefore studied this clinical question by emulating a randomized trial with observational data. METHODS: All patients with refractory postcardiotomy cardiogenic shock and assisted with VA-ECMO, admitted to a surgical intensive care unit at La Pitié-Salpêtrière Hospital between 2016 and 2019, were eligible. To avoid immortal-time bias, we emulated a target trial sequentially comparing levosimendan administration versus no levosimendan administration in patients treated with VA-ECMO. The primary outcome was time to successful ECMO weaning. The secondary outcomes were 30-day and 1-year mortality. We performed a multivariable analysis to adjust for confounding at baseline. RESULTS: Two hundred and thirty-nine patients were included in the study allowing building a nested trials cohort of 1434 copies of patients. No association of levosimendan treatment and VA-ECMO weaning was found (HR = 0.91, [0.57; 1.45], p = 0.659 in multivariable analysis), or 30-day mortality (OR = 1.03, [0.52; 2.03], p = 0.940) and 1-year mortality (OR = 1.00, [0.53; 1.89], p = 0.999). CONCLUSIONS: Using the emulated target trial framework, this study did not find any association of levosimendan treatment and ECMO weaning success after postcardiotomy cardiogenic shock. However, the population of interest remains heterogeneous and subgroups might benefit from levosimendan.

Risk of malignancy in rheumatoid arthritis patients initiating biologics: an historical propensity score matched cohort study within the French nationwide healthcare database.

OBJECTIVE: To compare the risk of malignancy between patients with rheumatoid arthritis (RA) initiating their first biological disease-modifying antirheumatic drug (bDMARD) and those continuing conventional synthetic DMARDs (csDMARDs). METHODS: Nine-year historical Propensity Score (PS) matched cohort study within the French national healthcare database (87% of the French population; ~57 million people), including adults RA without malignancy. Exposures started with the first use of any systemic treatment (csDMARDs and/or bDMARDs). Incident users of bDMARDs were matched on a dynamic PS to patients continuing csDMARDs. Their risk of malignancy was compared by Cox model. RESULTS: From 1 January 2007 to 31 December 2014, 83 706 patients with RA started their first systemic treatment (63 837 remained on csDMARDs and 19 869 initiated a bDMARD during follow-up). After dynamic PS matching, 19 727 bDMARD initiators were compared with 19 727 RA remaining on csDMARDs. They did not statistically differ in risk of overall malignancies (HR 0.99 (95% CI 0.86 to 1.14)), solid cancer (HR 0.95 (95% CI 0.82 to 1.11)), nor lymphoma (HR 1.35 (95% CI 0.72 to 2.53)). Results were similar when bDMARDs were given as monotherapy or in association with csDMARDs. Analyses restricted to patients starting TNF inhibitor as first bDMARD compared with matched RA remaining on csDMARDs, provided similar results (HR for overall malignancy 1.03 (95% CI 0.88 to 1.21)). Sensitivity analyses, varying carry-over periods (up to 5 years) to define risk periods, provided similar results. CONCLUSIONS: In this historical cohort study within the French nationwide healthcare database, the risk of overall, solid or haematological malignancies did not significantly differ between patients with RA initiating bDMARD and those continuing csDMARDs.

Dynamic evaluation of MRI-targeted, systematic and combined biopsy for prostate cancer diagnosis through 10 years of practice in a single institution.

PURPOSE: To perform a dynamic evaluation of the prostate cancer (PCa) detection rate according to the biopsy strategy over 10 years of practice in a single institution that pioneered MRI-targeted fusion biopsy (MRI-TB). METHODS: This stage 4 IDEAL study prospectively included all consecutive patients who underwent transrectal prostate biopsy for clinically suspected PCa between January 2010 and November 2020. Patients with positive MRI (PIRADS score ≥ 3) underwent both MRI-TB and systematic biopsy (SB) while those with negative MRI (PIRADS score < 3) underwent SB only. The main outcome was the evolution of the detection rate of clinically relevant PCa (csPCa; grade ≥ 2). The secondary outcome was the change in PCa detection rate according to the biopsy method. RESULTS: A total of 2942 men underwent prostate MRI and a prostate biopsy: 2322 underwent MRI-TB and 620 had SB only. The detection rate of csPCa increased 2.5-fold from 23 to 58%. The detection rate of PCa and csPCa was significantly higher in patients who underwent MRI-TB compared to those who underwent SB only (67% vs. 52% and 40% vs. 32%, respectively (P < 0.001 for both comparisons)). The number of csPCa diagnosed by MRI-TB increased linearly over the study period and represented the majority of PCa diagnoses after 2016. CONCLUSION: Implementation of MRI-TB in patients with positive MRI led to improved detection of csPCa.

Health-related quality of life of COVID-19 two and 12 months after intensive care unit admission.

PURPOSE: To describe health-related quality of life (HRQoL) and dyspnea of COVID-19, 2 and 12 months after an intensive care unit (ICU) stay. METHODS: Patients discharged from the ICU between April and June 2020 and subsequently transferred to an inpatient rehabilitation facility were assessed 2 months and 12 months after ICU admission. HRQoL was assessed by the EuroQoL EQ-5D-3L (visual analog scale and time trade-off normalized to the French population algorithm) and dyspnea was assessed by the modified Medical Research Council (mMRC) dyspnea scale. RESULTS: We enrolled 94 patients. Median EQ-5D-3L time trade-off was 0.80 (interquartile range, 0.36-0.91) at 2 months and 0.91 (0.52-1.00) at 12 months (P = 0.12). EQ-5D-3L visual analog scale was 70 (60-85) at 2 months and 70 (60-85) at 12 months (P = 0.07). The mMRC dyspnea scale was 3 (2-4) at ICU discharge, 1 (0-2), P < 0.001 at 2 months and 1 (1-2) at 12 months. At 12 months, 68 (76%) patients reported at least one symptom that was not present prior to ICU admission and 27 (61%) of the 44 patients who were previously working had returned to work. On multiple linear regression, factors associated with EQ-5D-3L were body mass index on ICU admission, tracheostomy, male gender and active smoking. CONCLUSIONS: Twelve months after ICU admission for COVID-19 and subsequent rehabilitation, a substantial proportion of patients reported alterations of HRQoL, dyspnea and symptoms that were not present prior to admission and a substantial proportion of these patients had not returned to work. Factors associated with a risk of poorer 12-month quality of life, may help to identify at-risk patients.

Novel Composite Endpoint for Assessing Outcomes in Liver Transplantation: Arterial and Biliary Complication-Free Survival.

Transplant and patient survival are the validated endpoints to assess the success of liver transplantation (LT). This study evaluates arterial and biliary complication-free survival (ABCFS) as a new metric. ABC, considered as an event, was an arterial or biliary complication of Dindo-Clavien grade ≥III complication dated at the interventional, endoscopic, or surgical treatment required to correct it. ABCFS was defined as the time from the date of LT to the dates of first ABC, death, relisting, or last follow-up (transplant survival is time from LT to repeat LT or death). Following primary whole LT (n = 532), 106 ABCs occurred and 99 (93%) occurred during the first year after LT. An ABC occurring during the first year after LT (overall rate 19%) was an independent factor associated with transplant survival (hazard ratio [HR], 3.17; P < 0.001) and patient survival (HR, 2.7; P = 0.002) in univariate and multivariate analyses. This result was confirmed after extension of the cohort to split-liver graft, donation after circulatory death, or re-LT (n = 658). Data from 2 external cohorts of primary whole LTs (n = 249 and 229, respectively) confirmed that the first-year ABC was an independent prognostic factor for transplant survival but not for patient survival. ABCFS was correlated with transplant and patient survival (ρ = 0.85 [95% CI, 0.78-0.90] and 0.81 [95% CI, 0.71-0.88], respectively). Preoperative factors known to influence 5-year transplant survival influenced ABCFS after 1 year of follow-up. The 1-year ABCFS was indicative of 5-year transplant survival. ABCFS is a reproducible metric to evaluate the results of LT after 1 year of follow-up and could serve as a new endpoint in clinical trials.

Inappropriate Use of Oral Antithrombotic Combinations in an Outpatient Setting and Associated Risks: A French Nationwide Cohort Study.

With the increase in prevalence of cardiovascular diseases, multimorbidity, and medical progress, oral antithrombotic (AT) combinations are increasingly prescribed. The aims of this study were to estimate the incidence of oral AT combinations, their appropriateness (defined as indications compliant with guidelines), and the related risk of major bleeding (i.e., leading to hospitalization) or death, among new users. We conducted a 5-year historical cohort study, using the French national healthcare database, including all individuals ≥ 45 years old with a first delivery of oral ATs between 1 January 2013 and 31 December 2017. The cumulative incidence of oral AT combinations was estimated with the Fine and Gray method, taking into account the competitive risk of death. We compared the cumulative incidence of major bleeding according to the type of oral AT treatment initiated at study entry (monotherapy or oral AT combinations). During the study period, 22,220 individuals were included (mean (SD) age 68 (12) years). The cumulative incidence of oral AT combinations at 5 years was 27.8% (95% confidence interval (CI) 26.8-28.9). Overall, 64% of any oral AT combinations did not comply with guidelines. The cumulative incidence of major bleeding and death in the whole cohort at 5 years was 4.1% (95% CI 3.7-4.6) and 10.8% (95% CI 10.1-11.6), respectively. Risk of major bleeding increased among individuals with oral AT combinations versus oral AT monotherapy at study entry (subdistribution hazard ratio sHR: 2.16 (1.01-4.63)); with no difference in terms of death. The use of oral AT combinations among oral AT users is frequent, often inappropriately prescribed, and associated with an increased risk of major bleeding.

Progression-free survival as a surrogate for overall survival in oncology trials: a methodological systematic review.

BACKGROUND: Progression-free survival (PFS) is a surrogate endpoint widely used for overall survival (OS) in oncology. Validation of PFS as a surrogate must be done for each indication and each intervention. We aimed to identify all studies evaluating the validity of PFS as a surrogate for OS in oncology, and to describe their methodological characteristics. METHODS: We conducted a systematic review by searching MEDLINE via PubMed and the Cochrane Library with no limitation on time, selected relevant studies and extracted data in duplicate on how surrogacy was evaluated (meta-analytic approach, assessment of correlation and level of evaluation). RESULTS: We identified 91 studies evaluating the validity of PFS as a surrogate for OS in 24 cancer localisations. Although a meta-analytic approach was used in 83 (91%) studies, the methods used to validate PFS as a surrogate of OS were heterogeneous across studies. Of the 47 studies concluding that PFS is a good surrogate for OS, for 15 (32%), there was no quantitative argument for surrogacy. CONCLUSIONS: Although most studies used a meta-analytic approach as recommended, our methodological review highlights heterogeneity in methods and reporting, which stresses the importance of developing and applying clear recommendations in this area.

Cervical cancer screening coverage, management of squamous intraepithelial lesions and related costs in France.

Until 2018, cervical cancer screening in France was an unorganized individual screening, with the exception of some pilot programs in some territories. We aimed to assess, before the implementation of organized cervical cancer screening and human papillomavirus (HPV) nonavalent vaccine introduction in the vaccination schedule in 2018, (i) the individual cervical cancer screening coverage, (ii) the management of squamous intraepithelial lesions (SIL) and (iii) the related costs. We used the Système National des Données de Santé (SNDS) (Echantillon Généraliste de Bénéficiaires [EGB] and Programme de Médicalisation des systèmes d'information [PMSI]) to assess the cervical screening coverage rate in France between January 1st, 2012 and December 31st, 2014, and to describe diagnostic investigations and therapeutic management of SIL in 2013. After extrapolation to the general population, a total of 10,847,814 women underwent at least one smear test over the 3-year study period, corresponding to a coverage rate of 52.4% of the women aged 25 to 64 included. In 2013, 126,095 women underwent HPV test, 327,444 women underwent colposcopy, and 9,653 underwent endocervical curettage; 31,863 had conization and 12,162 had laser ablation. Besides, 34,067 women experienced hospital stays related to management of SIL; 25,368 (74.5%) had high-grade lesions (HSIL) and 7,388 (21.7%) low-grade lesions (LSIL). Conization was the most frequent in-hospital therapeutic procedure: 89.5% (22,704) of women with an in-hospital procedure for HSIL and 64.7% (4,781) for LSIL. Mean cost of smear test, colposcopy and HPV tests were around 50€. Total cost for hospital stays in 2013 was estimated at M41€, or a mean cost of 1,211€ per woman; 76% were due to stays with HSIL. This study highlights the low coverage rate of individual cervical cancer screening and a high burden related to SIL management.

Trajectories of Adherence to Low-Dose Aspirin Treatment Among the French Population.

BACKGROUND: Previous studies have shown that adherence to low-dose aspirin (LDA) is suboptimal. However, these studies were based on an average measure of adherence during follow-up, ignoring its dynamic process over time. We described the trajectories of adherence to LDA treatment among the French population over 3 years of follow-up. METHODS: We identified a cohort of 11 793 new LDA users, aged ≥50 years in 2010, by using the French national health-care database. Patients included had at least 3 years of history in the database before study entry to exclude prevalent aspirin users and to assess baseline comorbidities. They were followed from the first date of LDA supply (the index date) until the first date among death, exit from the database, or 3 years after the index date. Adherence to LDA was assessed every 3 months by using the proportion of days covered (PDC) and dichotomized with a cutoff of PDC of 0.8. We used group-based trajectory modeling to identify trajectories of LDA adherence. Predictors of LDA adherence trajectory membership were identified by multinomial logistics regression. RESULTS: We identified 4 trajectories of adherence among new LDA users: the not-adherents (4737 [40.2%]), the delayed not-adherents (gradual decrease in adherence probability, 1601 [13.6%]), the delayed adherents (gradual increase in adherence probability, 1137 [9.6%]), and the persistent adherents (4318 [36.6%]). The probability of belonging to the not-adherent group was increased with female sex, low socioeconomic status, and polymedication and was reduced with a secondary indication for LDA use, such as diabetes, hypertension, and dementia, at least 4 consultations in the previous year, or 1 hospitalization or a cardiologist consultation in the 3 months before the index date. CONCLUSION: This study provides a dynamic picture of adherence behaviors among new LDA users and underlines the presence of critical trajectories that intervention could target to improve adherence.

Reduced risk of cancer among low-dose aspirin users: Data from French health care databases.

PURPOSE: The effect of chronic use of low-dose aspirin (LDA) on overall cancer is still unclear owing to many controversial results and methodological limitations of studies. This study aimed to assess the effect of LDA use on overall cancer incidence among the French population. METHODS: We conducted a 10-year historical cohort study using the permanent sample of the French national health care databases: the Système National des Données de Santé (SNDS). We used data for 111 025 individuals aged 50 to 80 years at study entry (January 1, 2006) without prevalent cancer or LDA use. Individuals were followed until the earliest of cancer incidence, death from any cause, exit from the database, or end of the study on December 31, 2015. We estimated the effect of LDA on cancer incidence by using a dynamic model to account for the competing risk of death in the presence of time-dependent exposure and risk factors. RESULTS: LDA use was associated with reduced 10-year risk of cancer (subdistribution hazard ratio [SHR] 0.81 [95% CI 0.77-0.86]). The SHRs were 0.88 [0.82-0.94] for men and 0.93 [0.85-1.02] for women. Moreover, each additional year of LDA use was associated with reduced 10-year risk of cancer (SHR 0.93 [0.92-0.95]). LDA use was also associated with reduced 10-year risk of death (SHR 0.86 [0.82-0.91]). CONCLUSIONS: This is the first population-based study to demonstrate a protective effect of LDA on overall cancer incidence and to account for the main methodological issues of previous observational studies.

Evaluation of a prescription support-tool for chronic management of oral antithrombotic combinations in adults using clinical vignettes: protocol of a randomised controlled trial.

INTRODUCTION: Improving the appropriateness of prescriptions of oral antithrombotic (AT) drugs, especially AT combinations, is crucial because these drugs are implicated in bleeding events. We developed a prescription support-tool synthesising guidelines on chronic management of oral AT combinations. Our main objective is to assess the impact of this tool on improving the prescription of oral ATs to comply with guidelines. METHODS AND ANALYSIS: A randomised controlled trial will be conducted among French general practitioners and cardiologists involved in outpatient settings. Physicians will be invited to participate to an online survey by email via physician associations, social networks or word of mouth. They will be randomised to two arms: the experimental arm (access to the prescription support-tool) or the control arm (no prescription support-tool). Then, all participants will be presented three different clinical vignettes illustrating outpatient clinical situations and will be asked to propose prescriptions for each vignette (number of ATs, type, dosage and duration). A computer-generated randomisation scheme implemented in the online survey will be used to allocate physicians to the experimental or control arm and then stratified by medical specialty. The primary outcome will be fully appropriate prescription of oral ATs ie, that comply with the guidelines in terms of number of drugs, drug class, dosage and duration. To demonstrate a 5% increase in this proportion, we will need to include a minimum of 230 physicians per arm. A logistic mixed model with a clinical vignette-effect and a physician-effect nested in the arm of the study will be used. ETHICS AND DISSEMINATION: The Institutional Review Board of Inserm (IRB00003888) approved our research project (no. 18-492). If the prescription support-tool improves the prescription of oral ATs, we will create an interactive web tool and will assess its impact in terms of clinical outcomes in real-life. TRIAL REGISTRATION NUMBER: NCT03630874; Pre-results.

Impact of a population-based asthma management program in France (Sophia Asthme): A matched controlled before-and-after quasi-experimental study using the French health insurance database (SNDS).

PURPOSE: Sophia Asthme (SA) is a chronic disease management program of the French national health insurance for adult patients with asthma. We evaluated the early impact of this intervention. METHODS: We conducted a matched controlled, before-and-after quasi-experimental study within the French Health Insurance Database (Système National Des Données de Santé [SNDS]). The SA program was implemented in a set of 18 Départements in France and targeted 18- to 44-year-old subjects, with at least two reimbursement dates for asthma drug therapy during the 12-month period prior to program targeting. Change in outcomes was assessed from the "before program" period (January-December 2014) to the "after program implementation" period (March 2015-February 2016) in the program group (eligible to SA program in the 18 Départements) and in the matched controlled group. The main outcome measure was the before-after change in proportion of subjects with a controllers/(controllers+relievers) ratio greater than 50%. RESULTS: Of the 99 578 subjects of the program group, 9225 (9.3%) actually participated in SA program. The program had no significant impact on the proportion of subjects with a ratio greater than 50%. However, subjects exposed to SA program were significantly more likely to be dispensed controller medications (OR = 1.04; 95% CI, 1.01-1.07) and to sustain their use of these medications (OR = 1.08; 95% CI, 1.05-1.12). CONCLUSION: We did not demonstrate any significant impact of the program on the primary outcome. The modest yet encouraging findings of this early evaluation suggest the need for reformulation of the program and its evaluation.

Randomised, placebo-controlled, double-blind, double-dummy, multicentre trial comparing electronic cigarettes with nicotine to varenicline and to electronic cigarettes without nicotine: the ECSMOKE trial protocol.

INTRODUCTION: Electronic cigarettes (EC) mainly with nicotine content are widely used worldwide. Although the number of publications about its use is increasing exponentially, evidence-based, unbiased, conclusive, head-to-head comparisons about its efficacy and safety as an aid for smoking cessation are lacking. METHODS AND ANALYSIS: Design: randomised, placebo and reference treatment-controlled, multicentre, double-blind, double-dummy, parallel-group trial. Participants: smokers smoking at least 10 cigarettes/day in the past year and motivated to quit, aged 18-70 years. Interventions: (A) EC without nicotine (ECwoN) plus placebo tablets of varenicline administered by oral route: placebo condition, (B) EC with nicotine (ECwN) plus placebo tablets of varenicline: ECwN condition. Voltage regulated EC will be used with liquid containing 12 mg/mL of nicotine for ad libitum use. Flavour: blond tobacco. (C) Reference: ECwoN plus 0.5 mg varenicline tablets: varenicline condition. Varenicline administered according to the marketing authorisationauthorisation. Treatment duration: 1 week+3 months. Primary outcome: continuous smoking abstinence rate (CAR) (abstinence from conventional/combustible cigarettes) during the last 4 weeks (weeks 9-12) of the treatment period defined as self-report of no smoking during the previous 2 weeks and expired air carbon monoxide ≤8 at visit 4 at week 10 after target quit date (TQD), that is, 11 weeks after treatment initiation AND at visit 5, week 12 after TQD, that is, 13 weeks after treatment initiation. Secondary outcomes: safety profile; point prevalence abstinence rate; CAR confirmed by urinary anabasine concentration; changes in cigarettes/day consumption; craving for tobacco and withdrawal symptoms with respect of baseline. ETHICS AND DISSEMINATION: The ethics committee approval was obtained on 17 April 2018. All data collected about the study participants will be anonymised. Investigators will communicate trial results to participants, health authorities, healthcare professionals, the public and other relevant groups without any publication restrictions. TRIAL REGISTRATION NUMBER: NCT03630614; Pre-results.

Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma.

PURPOSE: The blood-brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. PATIENTS AND METHODS: A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. RESULTS: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. CONCLUSIONS: SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity.See related commentary by Sonabend and Stupp, p. 3750.

Potentially inappropriate prescriptions of antithrombotic therapies in older outpatients: a French multicenter cross-sectional study.

PURPOSE: To assess the prevalence of inappropriate prescriptions of antithrombotic therapies (AT) in older outpatients and examine the associated factors. METHODS: A multicenter cross-sectional study was performed in 75 community pharmacies of 11 French districts. The study included 1178 patients aged ≥ 75 years filling a prescription from a general practitioner (GP) at a community pharmacy (mean [SD] age 83 [± 5.5] years, 59% female, median prescribed drugs 7 [range 5-10]).75 pharmacy students prospectively collected data from structured interviews with patients and from prescriptions into an electronic case report. Updated 2014 STOPP/START criteria regarding AT were applied to each prescription. Factors associated with ≥ 1 AT-STOPP criteria and ≥ 1 AT-START criteria were studied (multivariate analysis). RESULTS: 22.6% patients featured ≥ 1 in AT-STOPP criteria and 12.4% ≥ 1 in AT-START criteria. The most frequent AT-STOPP and AT-START criteria were AT prescription despite a concurrent significant bleeding risk and lack of AT prescription for patients with chronic atrial fibrillation, respectively. Two factors were associated with ≥ 1 AT-STOPP criteria: polymedication (≥ 5 drugs; p < 0.001) and previous hospitalization for a serious adverse drug event (ADE; p = 0.007). The only factor associated with ≥ 1 AT-START criteria was lack of information in the prescription regarding the duration of treatment. CONCLUSION: Suboptimal prescribing of AT is common in GP's prescriptions for older autonomous outpatients. The currently process of prescribing AT to older autonomous patients must be improved. Special attention should be given to those with polymedication and those with a history of severe ADEs.