Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study).

Background: The only disease-modifying treatment currently available for allergic rhinitis (AR) is allergen immunotherapy (AIT). The main objective of the EfficAPSI real-world study (RWS) was to evaluate the impact of liquid sublingual immunotherapy (SLIT-liquid) on asthma onset and evolution in AR patients. Methods: An analysis with propensity score weighting was performed using the EfficAPSI cohort, comparing patients dispensed SLIT-liquid with patients dispensed AR symptomatic medication with no history of AIT (controls). Index date corresponded to the first dispensation of either treatment. The sensitive definition of asthma event considered the first asthma drug dispensation, hospitalisation or long-term disease (LTD) for asthma, the specific one omitted drug dispensation and the combined one considered omalizumab or three ICS ± LABA dispensation, hospitalisation or LTD. In patients with pre-existing asthma, the GINA treatment step-up evolution was analysed. Findings: In this cohort including 112,492 SLIT-liquid and 333,082 controls, SLIT-liquid exposure was associated with a significant lower risk of asthma onset vs. control, according to all definitions (combined: HR [95% CI] = 0.62 [0.60-0.63], sensitive: 0.77 [0.76-0.78], and specific: 0.67 [0.61-0.72]). Exposure to SLIT was associated with a one-third reduction in GINA step-up regardless baseline steps. Interpretation: In this national RWS with the largest number of person-years of follow-up to date in the field of AIT, SLIT-liquid was associated with a significant reduction in the risk of asthma onset or worsening. The use of three definitions (sensitive or specific) and GINA step-up reinforced the rigorous methodology, substantiating SLIT-liquid evidence as a causal treatment option for patients with respiratory allergies. Funding: Stallergenes Greer.

A successful linkage of a named patient products of sublingual immunotherapy-dispensing registry to French healthcare insurance database (SNDS): methodological constitution of the EfficAPSI cohort.

BACKGROUND: The only causal treatment for allergic rhinitis (AR) is allergen immunotherapy (AIT) including personalized liquid sublingual AIT (SLIT). We present the methodology for establishing the EfficAPSI cohort to further evaluate the real-life effectiveness and use of SLIT liquid. RESEARCH DESIGN AND METHODS: The EfficAPSI cohort was constituted by deterministic linkage of Stallergenes Greer dispensing and nationwide French healthcare insurance system (SNDS) databases. Data from 2006 to 2018 were extracted. All patients who initiated Stallergenes Greer SLIT liquid between 2010 and 2013 were considered as exposed and those dispensed with AR symptomatic treatment only as control. To limit the impact of confounding, the models will be weighted using the inverse probability of treatment weighting (IPTW). RESULTS: A total of 445,574 patients were included; median age was 38 years; 59.1% were female. Exposed patients (n = 112,492) were significantly younger, more frequently males, and less likely to have comorbidities than controls (n = 333,082). After IPTW, patients' characteristics from both groups were similar. CONCLUSIONS: To date, the EfficAPSI cohort has the largest number of person-years of follow-up in the field of AIT. The completeness of the data allows to evaluate SLIT liquid effectiveness with rigorous methodology, leading to important insights on personalized medicine in real-life.

Management of diabetic macular oedema in France from 2012 to 2018: The nationwide LANDSCAPE study.

OBJECTIVE: To describe the management of diabetic macular oedema (DME) patients from the entire French population between 2012 and 2018. METHODS: In this retrospective longitudinal study, we identified adults treated for DME from the French population using the exhaustive French National Health Information database (SNDS), and an algorithm based on diagnosis and procedure codes, and reimbursed treatments. RESULTS: Between 2012 and 2018, we identified 53 584 treated DME patients, who were followed for up to 7 years from DME treatment initiation. Optical coherence tomography (OCT) became the predominant imaging tool to diagnose DME. Only 14% of patients consulted a diabetologist or endocrinologist in the 3 months prior to initiating DME treatment, whereas 84% consulted a general practitioner. The percentage of patients consulting an ophthalmologist declined over time, from 97% of patients in Year 1 (median of 9 consultations), to 46% in Year 7 (median of 7 consultations). The median DME treatment duration with an anti-VEGF and/or dexamethasone implant treatment was 9 months; 54% of patients had a treatment duration less than 1 year. First-line treatment was more common with ranibizumab (55% of patients) than with aflibercept (30%), or dexamethasone implant (15%). About 25% of patients who initiated anti-VEGF treatment switched treatment at least once, while 30% of patients who initiated dexamethasone implant switched to anti-VEGF treatment at least once. CONCLUSIONS: French DME patients seem well-monitored by their ophthalmologist, but median DME treatment duration was just 9 months. These results emphasise the challenge to manage and treat patients with DME over the long term.

Management of Neovascular Age-Related Macular Degeneration Treatment in France from 2008-2018: The Nationwide LANDSCAPE Study.

INTRODUCTION: The aim of this study was to describe the management of neovascular age-related macular degeneration (nAMD) in French patients between 2008 and 2018. METHODS: This was a retrospective longitudinal cohort study using exhaustive nationwide health records from the French National Health Information database. Enrollment criteria were adults aged ≥ 50 years, nAMD diagnosis, or reimbursement for nAMD treatments (anti-vascular epithelial growth factor [VEGF] injection or dynamic phototherapy with verteporfin). Exclusion criteria were high myopia, diagnosis of other retinal diseases, and treatments for other macular diseases (dexamethasone implant, laser). Main outcome measures were consumption of medical care and nAMD treatments per calendar year and number of years of follow-up. RESULTS: Between 2008 and 2018, we identified 342,961 patients who have been treated for nAMD. Median duration of ophthalmological follow-up exceeded 7 years (90 months). The median annual number of ophthalmology consultations decreased from nine visits in year 1 after treatment initiation to four visits from year 7 onwards. The median duration of nAMD treatment was 10.1 months for all patients, with 48.5% of patients undergoing treatment for < 1 year. Only 24.4% of patients had maintained treatment at year 11. Patients remaining under treatment had a median of four anti-VEGF treatments per year throughout the 10-year study period. Ranibizumab was the more common first-line treatment (67.5% of patients) compared to aflibercept (32.4%). About 20% of patients who initiated treatment switched treatment at least once. CONCLUSIONS: LANDSCAPE provides exhaustive nationwide data on the real-world management of nAMD in France over a 10-year period. Further investigation into short treatment duration is required, especially in terms of understanding its relation to visual outcomes.

Real-world effectiveness of long-acting injectable antipsychotic treatments in a nationwide cohort of 12,373 patients with schizophrenia-spectrum disorders.

This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015-December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18-34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = -0.19, -0.26 and -0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = -0.20, -0.24, -0.21, respectively) and ED admissions (SMD = -0.15, -0.13, -0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.

How can we improve the care of patients with schizophrenia in the real-world? A population-based cohort study of 456,003 patients.

An important step to improve outcomes for patients with schizophrenia is to understand treatment patterns in routine practice. The aim of the current study was to describe the long-term management of patients with schizophrenia treated with antipsychotics (APs) in real-world practice. This population-based study included adults with schizophrenia and who had received ≥3 deliveries of an AP from 2012-2017, identified using a National Health Data System. Primary endpoints were real-life prescription patterns, patient characteristics, healthcare utilization, comorbidities and mortality. Of the 456,003 patients included, 96% received oral APs, 17.5% first-generation long-acting injectable APs (LAIs), and 16.1% second generation LAIs. Persistence rates at 24 months after treatment initiation were 23.9% (oral APs), 11.5% (first-generation LAIs) and 20.8% (second-generation LAIs). Median persistence of oral APs, first-generation LAIs and second-generation LAIs was 5.0, 3.3, and 6.1 months, respectively. Overall, 62.1% of patients were administered anxiolytics, 45.7% antidepressants and 28.5% anticonvulsants, these treatments being more frequently prescribed in women and patients aged ≥50 years. Dyslipidemia was the most frequent metabolic comorbidity (16.2%) but lipid monitoring was insufficient (median of one occasion). Metabolic comorbidities were more frequent in women. Standardized patient mortality remained consistently high between 2013 and 2015 (3.3-3.7 times higher than the general French population) with a loss of life expectancy of 17 years for men and 8 years for women. Cancer (20.2%) and cardiovascular diseases (17.2%) were the main causes of mortality, and suicide was responsible for 25.4% of deaths among 18-34-year-olds. These results highlight future priorities for care of schizophrenia patients. The global persistence of APs used in this population was low, whereas rates of psychiatric hospitalization remain high. More focus on specific populations is needed, such as patients aged >50 years to prevent metabolic disturbances and 18-34-year-olds to reduce suicide rates.

Epidemiology of Treated Diabetes Ocular Complications in France 2008-2018-The LANDSCAPE French Nationwide Study.

AIM: LANDSCAPE aimed to estimate the annual incidence and prevalence of treated diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) between 2008 and 2018. METHODS: This French nationwide observational study used data from the French National Health Insurance Databases covering 99% of the French population. Data about healthcare consumption were used to identify adults treated with anti-VEGFs or dexamethasone implants (for DME) and with pan-retinal photocoagulation (for PDR). All French patients newly treated between 2008 and 2018 were included. Incidence and prevalence of treated DME and PDR were estimated for the age-matched general population and the population with diabetes in France. Sociodemographic characteristics and medical history were described in both populations. RESULTS: We identified 53,584 treated DME patients and 127,273 treated PDR patients between 2008 and 2018, and 11,901 DME and 11,996 PDR new incident patients in 2018. The treated DME incidence in 2018 was 2.5 per 10,000 in the general population and 37.3 per 10,000 in the population with diabetes. Prevalence in 2018 was 9.5 and 143.7 per 10,000 in the respective populations. Treated PDR incidence in 2018 was 2.3 per 10,000 in the general population and 31.2 per 10,000 in the population with diabetes. Prevalence in 2018 was 19.9 and 270.3 per 10,000 in the respective populations. Incidence and prevalence were not age-dependent. Incidence of treated PDR incidence was relatively stable from 2008-2018. Incidence of treated DME incidence rose from 2012-2018, probably due to widening access to newly available treatments, such as anti-VEGFs. CONCLUSIONS: We provide exhaustive nationwide data on the incidence and prevalence of treated diabetic ocular complications in France over a 10-year period.

The Economic Burden of Severe Osteoporotic Fractures in the French Healthcare Database: The FRACTOS Study.

Osteoporosis carries a high medical, economic, and societal burden principally because of the risk of severe fractures. The objective of this cost-of-illness study was to describe health resource utilization and associated costs in all patients aged ≥50 years hospitalized for a severe osteoporotic fracture over a 6-year period (2009 to 2014) in France. Data were extracted from the French national healthcare database (SNDS) on all health care resource utilization between the index date (date of hospitalization for first fracture during the enrollment period) and study end (December 31, 2016) or until the patient died. Costing was restricted to direct costs and determined from the payer perspective. Variables related to costs were identified through multivariate logistic regression analysis. A total of 356,895 patients were included (median follow-up 39.1 months). In the year after the index fracture, 36,622 patients (10.5%) were rehospitalized for a fracture-related reason. Only 18,474 (5.3%) underwent bone densitometry and 58,220 (16.7%) received a specific treatment. The total annual per capita osteoporosis-related cost in the year after the index severe osteoporotic fracture was €18,040 (from €8598 for multiple ribs to €21,085 for hip fracture) of which €17,905 was incurred by fracture-related costs. The cost incurred by management of osteoporosis was €135. Over years 2 to 5, the mean annual per capita costs of fracture treatment (€806, mostly attributable to the treatment of refractures) continued to dominate those of osteoporosis management (€99). Total annual cost of care was €1260 million (year 2014). Variables associated with higher cost were older age, male sex, site of fracture, a history of prior osteoporotic fracture, and the number of refracture events. The 5-year cost of severe osteoporotic fractures to the French health care system is high and mostly attributable to the treatment of refractures. Improved fracture prevention measures in patients with osteoporosis is crucial to reduce the economic burden of the disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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

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

Tamper-resistant prescription forms for narcotics in France: Should we generalize them?

In France, prescription of narcotics must be written on a tamper-resistant prescription form with specific technical particularities. Dosage and daily dose of medicines shall be written out entirely in letters. These prescription forms are also mandatory for buprenorphine, clorazepate, clonazepam, tianeptine, buccal midazolam and zolpidem owing to traffic, abuse or diversion. In 2012, to assess the use of standard and tamper-resistant prescription forms and the acceptability of the generalization of the latter to all medicines, a national opinion survey was performed, with a postal questionnaire, within three randomized samples of 1500 prescribers (physicians, dentists and midwives). Of the 403 participating prescribers (participation rate of 26.8%), 373 were physicians, 14 dentists and 16 midwives. Tamper-resistant prescription forms were used by 76.2% of prescribers, but only by 5.1% in a computerized version, whereas for standard prescription forms, 61% used computer assisted prescription software. The main reason was the inability of the prescription software to print these forms or to respect the mandatory prescription rules for narcotics. Theft and falsification of prescriptions had ever occurred (working life). Most prescribers (62.5%) were against the generalization of tamper-resistant prescription forms. Those in favour were for a generalization to all medicines (65%) and not only to psychotropic agents. Generalization of tamper-resistant prescription forms is not a consensual solution to prevent medicines' diversion. Some prescribers alluded to the possibility of dematerialization and electronic transmission of prescription forms, which could avoid theft, forgery or falsification.

Human papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of over 2million young girls in France.

BACKGROUND: Whether human papillomavirus (HPV) vaccination could induce or trigger autoimmune diseases (AID) has been questioned, and potentially contributes to low immunization coverage in France. This study evaluated the association between HPV vaccination and the risk of AID using routinely collected data sources. METHODS: All girls aged 13-16years between 2008 and 2012, covered by the general health insurance scheme and without history of HPV vaccination or AID, were included and followed using French nationwide databases. Fourteen neurological, rheumatological, haematological, gastrointestinal or endocrine AID, were identified from ICD-10 codes allocated to hospital stays and long-term illnesses or by marker drugs. Their incidence was compared between girls exposed and non-exposed to HPV vaccination, using a Cox model adjusted for inclusion year, geographic area, socio-economic indicators, healthcare use level and other immunizations. RESULTS: Among 2,252,716 girls, 37% received HPV vaccine and 4,096 AID occurred during a mean follow-up time of 33months. The incidence of AID was not increased after exposure to HPV vaccination, except for Guillain-Barré syndrome (GBS) (incidence rate of 1.4 among exposed [20 cases] versus 0.4 per 100,000 PY among unexposed [23 cases]; adjusted HR: 3.78 [1.79-7.98]). This association persisted across numerous sensitivity analyses and was particularly marked in the first months following vaccination. Under the hypothesis of a causal relationship, this would result in 1-2 GBS cases attributable to HPV vaccine per 100,000 girls vaccinated. CONCLUSIONS: Our study provides reassuring results regarding the risk of AID after HPV vaccination, but an apparently increased risk of GBS was detected. Further studies are warranted to confirm this finding.

Association between Exposure to Benzodiazepines and Related Drugs and Survivorship of Total Hip Replacement in Arthritis: A Population-Based Cohort Study of 246,940 Patients.

BACKGROUND: Total hip replacement (THR) is successful in treating hip arthritis. Prosthetic survivorship may depend on the medications taken by the patient; particularly, the role of benzodiazepines and related drugs (Z-drugs) with THR revision has been poorly investigated. Our objective was to compare THR short-term survivorship according to level of exposure to benzodiazepine and Z-drugs. DESIGN, SETTING AND PARTICIPANTS: All French patients aged 40 years or older, having undergone primary THR from January 1, 2009, through December 31, 2012, for arthritis according to French national health insurance databases were included in the cohort. Outcome of interest was THR revision, including any surgical procedure in which the implant or any component was changed or removed. Follow-up started the day the primary THR was performed. Observations were right-censored on December 31, 2014, if neither revision nor death had yet occurred. Exposure of interest was the cumulative defined daily doses per day (cDDD/day) of benzodiazepines and Z-drugs dispensed within 6 months before or after inclusion. We defined four exposure groups; cDDD/d = 0: unexposed; <0.08: low exposure;] 0.08-0.38]: medium exposure; >0.38: high exposure. THR survivorship was assessed according to level of exposure to benzodiazepines and Z-drugs in univariate and multivariate Cox models adjusted for patient, THR and implanting center characteristics. RESULTS: The study cohort comprised 246,940 individuals: mean age at baseline, 69.9 years; women, 57.9%; unexposed: 51.7%; low exposure: 16.7%; medium exposure: 15.9%; and high exposure: 15.7%. During the median 45-month follow-up, 9043 individuals underwent prosthetic revision. Adjusted hazard ratios in low, medium and high exposed groups were 1.18 (95%CI, 1.12-1.26; P<0.001), 1.32 (95%CI, 1.24-1.40; P<0.001) and 1.37 (95%CI, 1.29-1.45; P<0.001), respectively, compared to unexposed. CONCLUSION AND RELEVANCE: Exposure to benzodiazepines and Z-drugs is associated with an increased risk of THR revision, with a dose-response relationship. Cautious prescribing might be needed as well as careful history examination and assessment of risk for patients with a hip prosthesis.

Association Between Total Hip Replacement Characteristics and 3-Year Prosthetic Survivorship: A Population-Based Study.

IMPORTANCE: Total hip replacement (THR) is successful in treating hip arthritis. Prosthetic survivorship may depend on characteristics of the implant, notably THR fixation technique and bearing surface type. OBJECTIVE: To compare THR short-term survivorship according to cement type and bearing surface. DESIGN, SETTING, AND PARTICIPANTS: The cohort included all French patients aged 40 years or older covered by the general scheme of the French national health insurance system who had undergone THR from April 1, 2010, through December 31, 2011, for arthritis, according to French national health insurance databases. The cohort was followed up until December 31, 2013. The THR survivorship was assessed according to cement type and bearing surface in univariate and multivariate Cox proportional hazards regression models adjusted for patient and implanting center characteristics. EXPOSURES: Antibiotic-free cemented THRs and antibiotic-impregnated cemented THRs were compared with uncemented THRs. Ceramic-on-ceramic (CoC), ceramic-on-polyethylene (CoP), and metal-on-metal (MoM) THRs were compared with metal-on-polyethylene (MoP) THRs. MAIN OUTCOMES AND MEASURES: Revision, including any surgical reintervention in which the implant or any of its components was changed or removed. RESULTS: The study cohort comprised 100 191 individuals: mean age at baseline, 69.5 years; women, 56.6%; uncemented THR, 74.8%; antibiotic-free cemented THR, 3.8%; antibiotic-impregnated cemented THR, 21.4%; CoC, 40.9%; MoP, 33.9%; CoP, 20.8%; and MoM, 4.4%. During the median 33-month follow-up period, 3142 individuals underwent prosthetic revision. Antibiotic-impregnated cemented THRs had a better prognosis than uncemented THRs: cumulative revision rates were 2.4% and 3.3%, respectively (P < .001), and the multivariate adjusted hazard ratio was 0.75 (95% CI, 0.67-0.84; P < .001). This association was particularly significant in women. The CoP and CoC THRs were no different from the MoP THR. The MoM THR had slightly shorter survivorship compared with the MoP THR (adjusted hazard ratio, 1.20; 95% CI, 1.01-1.43; P < .001). CONCLUSIONS AND RELEVANCE: Characteristics of THR are related to early prosthetic revision: antibiotic-impregnated cemented THRs have a better prognosis and MoM THRs a worse one. These findings are useful in helping surgeons select a THR fixation technique and helpful for both patient and surgeon in the decision-making process.

Designing a tool allowing for a standardized assessment of resistance to drug diversion.

OBJECTIVES: Drug diversion is a growing problem in numerous countries. Some laboratories have developed tamper-resistant formulations. The problem for healthcare authorities is now to assess new formulations developed to limit the risk of diversion for administration by another mode and intended mode. It would be helpful to have a pertinent panel of in vitro tests allowing assessment of how a formulation may be altered, both for healthcare authorities and for laboratories, so as to implement adequate sanitary measures. We designed a methodology/tool allowing assessment, in a standardized manner, of the formulation's resistance to drug diversion. We present the various steps leading to the construction of the scale and to its first use. METHODS: Creating a Steering Committee - Choosing assays or parameters - standardized by a monograph of the European Pharmacopoeia and pragmatic assays related to users' behaviors - for the assessment of formulation resistance to drug diversion. Designing a scale: i) applying all these tests to a panel of formulations; ii) applying a score by drug and by test; and iii) attribution of weighting per test and calculating the total score for a drug. RESULTS: Eight tests or parameters and 14 drugs (diverted drugs and controls) were chosen. Buprenorphine Subutex® had the lowest score and flunitrazepam Rohypnol® the highest. CONCLUSIONS: Our tool allowed classification of the various drugs selected. This classification correlated with results of postmarketing authorization assessment. Rohypnol®, which was the object of many measures, including formulation changes, obtained the highest score in our study.

Estimate of venous thromboembolism and related-deaths attributable to the use of combined oral contraceptives in France.

PURPOSE: To estimate the number of venous thromboembolic events and related-premature mortality (including immediate in-hospital lethality) attributable to the use of combined oral contraceptives in women aged 15 to 49 years-old between 2000 and 2011 in France. METHODS: French data on sales of combined oral contraceptives and on contraception behaviours from two national surveys conducted in 2000 and 2010 were combined to estimate the number of exposed women according to contraceptives generation and age. Absolute risk of first time venous thromboembolism in non-users of hormonal contraception and increased risk of thromboembolism in users vs. non-users of hormonal contraception were estimated on the basis of literature data. Finally, immediate in-hospital lethality due to pulmonary embolism and premature mortality due to recurrent venous thromboembolism were estimated from the French national database of hospitalisation and literature data. RESULTS: In France, more than four million women are daily exposed to combined oral contraceptives. The mean annual number of venous thromboembolic events attributable to their use was 2,529 (778 associated to the use of first- and second-generation contraceptives and 1,751 to the use of third- and fourth-generation contraceptives), corresponding to 20 premature deaths (six with first- and second-generation contraceptives and fourteen with third- and fourth-generation contraceptives), of which there were eight to nine immediate in-hospital deaths. As compared to the use of first- and second-generation contraceptives, exposure to third- and fourth-generation contraceptives led to a mean annual excess of 1,167 venous thromboembolic events and nine premature deaths (including three immediate in-hospital deaths). CONCLUSIONS: Corrective actions should be considered to limit exposure to third- and fourth-generation contraceptives, and thus optimise the benefit-risk ratio of combined oral contraception.

Long-term changes in arterial structure and function and left ventricular geometry after enzyme replacement therapy in patients affected with Fabry disease.

AIMS: Fabry disease is a lysosomal storage disorder due to deficient alpha-galactosidase A activity, characterised by glycosphingolipids deposition in tissues. Patients have a common arterial involvement and contract progressive renal and cardiac disease. Although short-term effects of enzyme replacement therapy (ERT) on target organs have been established, no data are available on the long-term outcome. METHODS AND RESULTS: We studied the effects of ERT (agalsidase beta, 1 mg/kg/14 days) on arterial and cardiac structure and function during a longitudinal study beginning in 1999, with 4.5 ± 0.4 years follow-up (four visits) in 30 patients (age: 33 ± 12 years). In addition, we studied 16 untreated Fabry patients during 2.6 ± 1.6 years (two visits). Aortic stiffness was determined by carotid-femoral pulse wave velocity, central pulse pressure by aplanation tonometry, and carotid and radial intima-media thickness and diameter by high definition echotracking device. Left ventricular mass was determined by MRI. A significant decrease in aortic stiffness (-0.56 ± 0.13 m/s/yr, p = 0.0002) was observed after ERT whereas central pulse pressure did not change. Carotid intima-media thickness (IMT) increased (+18 ± 6 µm/yr; p < 0.005) whereas radial IMT remained stable. Radial artery diameter decreased (-50 ± 20 µm/years, p < 0.05) whereas carotid diameter did not change. Carotid circumferential wall stress was reduced (-1.7 ± 0.6 kPa/yrs, p < 0.01). Left ventricular mass index significantly decreased (-7.8 ± 2.3 g/m(2)/yr, p < 0.005). CONCLUSION: A sustained reduction in aortic stiffness and left ventricular hypertrophy, and a limited radial artery wall thickening were observed after long-term enzyme replacement therapy. There was no significant benefit of treatment on carotid hypertrophy.

Association of central and peripheral pulse pressure with intermediate cardiovascular phenotypes.

OBJECTIVE: We assessed the relationship between pulse pressure and intermediate cardiovascular phenotypes in a middle-aged cohort with high prevalence of hypertension. BACKGROUND: It has been suggested that central pulse pressure (cPP) is a better predictor of cardiovascular outcome than peripheral pulse pressure (pPP), particularly in the elderly. Yet, it is unclear if cPP provides additional prognostic information to pPP in younger individuals. METHODS: In 535 individuals we assessed cPP and pPP as well as the intermediate cardiovascular phenotypes pulse wave velocity (PWV; SphygmoCor, Complior, PulsePen), carotid intima-media thickness (C-IMT; carotid ultrasound), left-ventricular mass index (LVMI; echocardiography) and urinary albumin : creatinine ratio (ACR). cPP was derived noninvasively from brachial blood pressure by pulse wave analysis (PWA; SphygmoCor) based on radial pulse wave tonometry and a validated transfer function. RESULTS: The cohort contained 331 hypertensive participants of whom 84% were treated. The average age was 46 ±â€Š16 years. When compared to pPP, cPP had stronger associations with PWV (r = 0.471 vs. r = 0.372; P < 0.01), C-IMT (r = 0.426 vs. r = 0.235; P < 0.01) and LVMI (r = 0.385 vs. r = 0.189; P < 0.01), but equal association with ACR (r = 0.236 vs. r = 0.226; P = n.s.). In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between cPP and pPP for prediction of PWV (adjusted R, 0.399 vs. 0.413; P = 0.066), C-IMT (adjusted R, 0.399 vs. 0.413; P = 0.487) and LVMI (adjusted R, 0.181 vs. 0.170; P = 0.094) in multivariate analysis. CONCLUSION: In our middle-aged cohort with high prevalence of hypertension cPP is more closely correlated with cardiovascular phenotypes than pPP. When adjusted for relevant cofactors, however, cPP does not provide additional information beyond pPP.

Arterial remodeling associates with CKD progression.

In CKD, large arteries remodel and become increasingly stiff. The greater pulsatile pressure reaching the glomerulus as a result of increased aortic stiffness could induce renal damage, suggesting that the stiffening and remodeling of large arteries could affect the progression of CKD. We measured carotid-femoral pulse wave velocity, aortic pressure and carotid remodeling and stiffness parameters in 180 patients with CKD (mean measured GFR, 32 ml/min per 1.73 m(2)) and followed them prospectively for a mean of 3.1 years. During follow-up, carotid stiffness significantly increased (+0.28 ± 0.05 m/s; P<0.0001) but aortic stiffness did not. Carotid intima-media thickness decreased significantly during follow-up and the internal diameter of the carotid increased, producing increased circumferential wall stress (+2.08 ± 0.43 kPa/yr; P<0.0001). In a linear mixed model, circumferential wall stress significantly associated with faster GFR decline after adjustment for risk factors of cardiovascular disease and progression of CKD. In a multivariable Cox model, carotid circumferential wall stress and pulse pressure independently associated with higher risk for ESRD. None of the arterial stiffness parameters associated with progression of CKD. In conclusion, maladaptive remodeling of the carotid artery and increased pulse pressure independently associate with faster decline of renal function and progression to ESRD.

Long-term reduction in aortic stiffness: a 5.3-year follow-up in routine clinical practice.

BACKGROUND: Whether a direct blood pressure-independent reduction in aortic stiffness can occur after several years of antihypertensive treatment has never been unequivocally demonstrated. METHOD: In this observational study, performed under conditions of routine clinical practice, we included 97 patients (age 63 ± 11 years) with treated essential hypertension who attended the outpatient hypertension clinic of a university hospital, had a significant blood pressure (BP) lowering under treatment before the first measurement of aortic stiffness, and had at least one additional measurement of aortic stiffness during follow-up. Aortic stiffness and carotid pulse pressure (PP) were determined through carotid-femoral pulse wave velocity (PWV) and applanation tonometry, respectively. RESULTS: A linear mixed model showed that the reduction in PWV (from 14.2 ± 4.2 to 11.0 ± 2.4 m/s; P < 0.0001) over a long follow-up (mean delay 5.3 ± 1.3 years) was associated with a significant reduction in central SBP (from 132 ± 22 to 122 ± 16 mmHg; P < 0.0001) and central PP (from 59 ± 22 to 54 ± 14; P < 0.001), contrasting with a smaller change in brachial SBP (from 132 ± 17 to 129 ± 16 mmHg; P < 0.02) and no change in brachial PP. In multivariate analysis, the decrease in PWV (-0.70 ± 0.07 m/s per year; P < 0.0001) was only slightly explained by the reduction in mean blood pressure. By contrast, the decrease in central PP (-0.83 ± 0.41 mmHg per year; P = 0.043) was largely explained by the reduction in PWV. CONCLUSION: These results indicate that a large and sustained decrease in aortic stiffness can be obtained in treated hypertensive patients under conditions of routine clinical practice. These changes likely represent a delayed response to the long-term normalization of BP and cardiovascular risk factors, through arterial remodeling.

Age-independent association between arterial and bone remodeling in mild-to-moderate chronic kidney disease.

BACKGROUND: Damages to large arteries are related to bone disease in end-stage renal disease and contribute to cardiovascular mortality. An outward remodeling and stiffening of carotid artery already exist at an earlier stage of chronic kidney disease (CKD). We made the hypothesis that bone disease could be associated with the carotid outward remodeling in parallel with the decline of renal function in this population. METHODS: One hundred and seven patients (60.4 +/- 14.6 years) with CKD (mean glomerular filtration rate = 34 +/- 17 mL/min/1.73 m(2)) were included in this cross-sectional study. Common carotid artery diameter, intima-media thickness and carotid stiffness were determined with an echotracking system. Bone evaluation was performed by bone densitometry and the measurement of a bone-remodeling marker, bone-specific alkaline phosphatase (BSALP). RESULTS: After adjustment for age, sex, mean blood pressure, carotid pulse pressure and glomerular filtration rate, bone mineral densities measured at the radius, hip and lumbar spine were significantly and negatively correlated with carotid internal diameter (P = 0.0001, P = 0.0003, P = 0.01, respectively). This association exists only in patients with glomerular filtration rate < or =38 mL/min/ 1.73 m(2). BSALP was independently and positively correlated with carotid internal diameter and explained 13% of the variance. CONCLUSIONS: Bone mineral density and serum marker of bone remodeling are independently correlated with arterial remodeling in CKD patients suggesting a crosstalk between kidney, arterial wall and bone.