Design and validation of algorithms to identify venous thromboembolism in the French National Healthcare Database.

PURPOSE: This paper aims to introduce an algorithm designed to identify Venous Thromboembolism (VTE) in the French National Healthcare Database (SNDS) and to estimate its positive predictive value. METHODS: A case-identifying algorithm was designed using SNDS inpatient and outpatient encounters, including hospital stays with discharge diagnoses, imaging procedures and drugs dispensed, of French patients aged at least 18 years old to whom baricitinib or Tumor Necrosis Factor Inhibitors (TNFi) were dispensed between September 1, 2017, and December 31, 2018. An intra-database validation study was then conducted, drawing 150 cases identified as VTE by the algorithm and requesting four vascular specialists to assess them. Patient profiles used to conduct the case adjudication were reconstituted from de-identified pooled and formatted SNDS data (i.e., reconstituted electronic health records-rEHR) with a 6-month look-back period prior to the supposed VTE onset and a 12-month follow-up period after. The positive predictive value (PPV) with its 95% confidence interval (95% CI) was calculated as the number of expert-confirmed VTE divided by the number of algorithm-identified VTE. The PPV and its 95% CI were then recomputed among the same patient set initially drawn, once the VTE-identifying algorithm was updated based on expert recommendation. RESULTS: For the 150 patients identified with the first VTE-identifying algorithm, the adjudication committee confirmed 92 cases, resulting in a PPV of 61% (95% CI = [54-69]). The final VTE-identifying algorithm including expert suggestions showed a PPV of 92% (95% CI = [86-98]) with a total of 87 algorithm-identified cases, including 80 retrieved from the 92 confirmed by experts. CONCLUSION: The identification of VTE in the SNDS is possible with a good PPV.

Cardiovascular and renal diseases in type 2 diabetes patients: 5-year cumulative incidence of the first occurred manifestation and hospitalization cost: a cohort within the French SNDS nationwide claims database.

BACKGROUND: Myocardial infarction (MI), stroke, peripheral arterial disease (PAD), heart failure (HF) and chronic kidney disease (CKD) are common cardiovascular renal diseases (CVRD) manifestations for type 2 diabetes. The objective was to estimate the incidence of the first occurring CVRD manifestation and cumulative hospitalization costs of each CVRD manifestation for type 2 diabetes without CVRD history. METHODS: A cohort study of all type 2 diabetes free of CVRD as of January 1st 2014, was identified and followed-up for 5 years within the French SNDS nationwide claims database. The cumulative incidence of the first occurring CVRD manifestation was estimated using the cumulative incidence function, with death as a competing risk. Cumulative hospitalization costs of each CVRD manifestations were estimated from the perspective of all payers. RESULTS: From 2,079,089 type 2 diabetes without cancer or transplantation, 76.5% were free of CVRD at baseline with a mean age of 65 years, 52% of women and 7% with microvascular complications history. The cumulative incidence of a first CVRD manifestation was 15.3% after 5 years of follow-up with a constant linear increase over time for all CVRD manifestations: The most frequent was CKD representing 40.6% of first occurred CVRD manifestation, followed by HF (23.0%), then PAD (13.5%), stroke (13.2%) and MI (9.7%). HF and CKD together reached about one patient out of ten after 5 years and represented 63.6% of first CVRD manifestations. The 5-year global cost of all CVRD hospitalizations was 3.9 billion euros (B€), i.e. 2,450€ per patient of the whole cohort, with an exponential increase over time for each specific CVRD manifestation. The costliest was CKD (2.0 B€), followed by HF (1.2 B€), then PAD (0.7 B€), stroke (0.6 B€) and MI (0.3 B€). CONCLUSIONS/INTERPRETATION: While MI, stroke and PAD remain classic major risks of complications for CVRD-free type 2 diabetes, HF and CKD nowadays represent individually a higher risk and cost than each of these classic manifestations, and jointly represents a risk and a cost twice as high as these three classic manifestations all together. This should encourage the development of specific HF and CKD preventive strategies.

Clustering of prostate cancer healthcare pathways in the French National Healthcare database.

Background: Healthcare pathways of patients with prostate cancer are heterogeneous and complex to apprehend using traditional descriptive statistics. Clustering and visualization methods can enhance their characterization. Methods: Patients with prostate cancer in 2014 were identified in the French National Healthcare database (Système National des Données de Santé-SNDS) and their data were extracted with up to 5 years of history and 4 years of follow-up. Fifty-one-specific encounters constitutive of prostate cancer management were synthesized into four macro-variables using a clustering approach. Their values over patient follow-ups constituted healthcare pathways. Optimal matching was applied to calculate distances between pathways. Partitioning around medoids was then used to define consistent groups across four exclusive cohorts of incident prostate cancer patients: Hormone-sensitive (HSPC), metastatic hormone-sensitive (mHSPC), castration-resistant (CRPC), and metastatic castration-resistant (mCRPC). Index plots were used to represent pathways clusters. Results: The repartition of macro-variables values-surveillance, local treatment, androgenic deprivation, and advanced treatment-appeared to be consistent with prostate cancer status. Two to five clusters of healthcare pathways were observed in each of the different cohorts, corresponding for most of them to relevant clinical patterns, although some heterogeneity remained. For instance, clustering allowed to distinguish patients undergoing active surveillance, or treated according to cancer progression risk in HSPC, and patients receiving treatment for potentially curative or palliative purposes in mHSPC and mCRPC. Conclusion: Visualization methods combined with a clustering approach enabled the identification of clinically relevant patterns of prostate cancer management. Characterization of these care pathways is an essential element for the comprehension and the robust assessment of healthcare technology effectiveness.

Real-World Effectiveness of Osteoporosis Medications in France: A Nationwide Cohort Study.

Although drugs for osteoporosis have been demonstrated to be effective in reducing fracture risk in placebo-controlled clinical trials, data on effectiveness in real-world practice is limited. Data from the French national health insurance claims database (SNDS) were used to follow five cohorts of women aged ≥55 years after initiating treatment for ≥6 months with either denosumab, zoledronic acid, oral bisphosphonates, raloxifene, or teriparatide in 2014-2016. Fracture incidence was compared within each cohort between the 3 months following initiation (baseline fracture risk) and the 12month, 18month, and 24 month postinitiation periods. Data are presented as incidence rate ratios (IRRs) with their 95% confidence intervals (CIs)s. Overall, 67,046 women were included in the denosumab cohort, 52,914 in the oral bisphosphonate cohort, 41,700 in the zoledronic acid cohort, 11,600 in the raloxifene cohort, and 7510 in the teriparatide cohort. The baseline vertebral fracture rate ranged from 1.74 per 1000 person years (‰PY) in the raloxifene cohort to 34.75‰PY in the teriparatide cohort, and the baseline hip fracture rate from 0.70‰PY in the raloxifene cohort to 10.52‰PY in the zoledronic acid cohort. Compared with the baseline fracture rate, vertebral fractures involving hospitalization were significantly reduced in the 3-24-month postinitiation period with denosumab (IRR 0.6; 95% CI, 0.5-0.7), zoledronic acid (IRR 0.4; 95% CI, 0.3-0.4), teriparatide (IRR 0.3; 95% CI, 0.2-0.5), and oral bisphosphonates (IRR 0.6; 95% CI, 0.4-0.8). Hip fracture incidence was reduced with denosumab (IRR 0.8; 95% CI, 0.6-0.9), but higher for oral bisphosphonates (IRR 1.7; 95% CI, 1.2-2.3); no significant change in hip fracture rate was observed for zoledronic acid, teriparatide, or raloxifene. A reduction in nonvertebral, non-hip fracture incidence was observed only in the denosumab cohort (IRR 0.8; 95% CI, 0.7-0.9). These findings indicate that treatment with osteoporosis drugs is effective in the real-world setting. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post-Fracture Treatment, and All-Cause Mortality.

In this international study, we examined the incidence of hip fractures, postfracture treatment, and all-cause mortality following hip fractures, based on demographics, geography, and calendar year. We used patient-level healthcare data from 19 countries and regions to identify patients aged 50 years and older hospitalized with a hip fracture from 2005 to 2018. The age- and sex-standardized incidence rates of hip fractures, post-hip fracture treatment (defined as the proportion of patients receiving anti-osteoporosis medication with various mechanisms of action [bisphosphonates, denosumab, raloxifene, strontium ranelate, or teriparatide] following a hip fracture), and the all-cause mortality rates after hip fractures were estimated using a standardized protocol and common data model. The number of hip fractures in 2050 was projected based on trends in the incidence and estimated future population demographics. In total, 4,115,046 hip fractures were identified from 20 databases. The reported age- and sex-standardized incidence rates of hip fractures ranged from 95.1 (95% confidence interval [CI] 94.8-95.4) in Brazil to 315.9 (95% CI 314.0-317.7) in Denmark per 100,000 population. Incidence rates decreased over the study period in most countries; however, the estimated total annual number of hip fractures nearly doubled from 2018 to 2050. Within 1 year following a hip fracture, post-hip fracture treatment ranged from 11.5% (95% CI 11.1% to 11.9%) in Germany to 50.3% (95% CI 50.0% to 50.7%) in the United Kingdom, and all-cause mortality rates ranged from 14.4% (95% CI 14.0% to 14.8%) in Singapore to 28.3% (95% CI 28.0% to 28.6%) in the United Kingdom. Males had lower use of anti-osteoporosis medication than females, higher rates of all-cause mortality, and a larger increase in the projected number of hip fractures by 2050. Substantial variations exist in the global epidemiology of hip fractures and postfracture outcomes. Our findings inform possible actions to reduce the projected public health burden of osteoporotic fractures among the aging population. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Strong instrumental variables biased propensity scores in comparative effectiveness research: A case study in oncology.

BACKGROUND AND OBJECTIVES: Some medications require specific medical procedures in the weeks before their start. Such procedures may meet the definition of instrumental variables (IVs). We examined how they may influence treatment effect estimation in propensity score (PS)-adjusted comparative studies, and how to remedy. STUDY DESIGN AND SETTING: Different covariate assessment periods (CAPs) did and did not include the month preceding treatment start were used to compute PS in the French claims database (Sytème National des Données de Santé-SNDS), and 1:1 match patients with metastatic castration resistant prostate cancer initiating abiraterone acetate or docetaxel. The 36-month survival was assessed. RESULTS: Among 1, 213 docetaxel and 2, 442 abiraterone initiators, the PS distribution resulting from the CAP [-12; 0 months] distinctly separated populations (c = 0.93; 273 matched pairs). The CAPs [-12;-1 months] identified 765 pairs (c = 0.81). Strong docetaxel treatment predictors during the month before treatment start were implantable delivery systems (1% vs. 59%), which fulfilled IV conditions. The 36-month survival was not meaningfully different under the [-12; 0 months] CAP but differed by 10% points (38% vs. 28%) after excluding month -1. CONCLUSION: In the setting of highly predictive pretreatment procedures, excluding the immediate pre-exposure time from the CAP will reduce the risk of including potential IVs in PS models and may reduce bias.

Abiraterone acetate versus docetaxel for metastatic castration-resistant prostate cancer: a cohort study within the French nationwide claims database.

OBJECTIVES: To conduct the direct comparison of abiraterone acetate and docetaxel for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) in real-life settings. METHODS: Data were extracted from the French nationwide claims database (SNDS) on all men aged ≥40 years starting first-line treatment with abiraterone acetate or docetaxel for mCRPC in 2014. A high-dimensional propensity score including 100 baseline characteristics was used to match patients of both groups and form two comparative cohorts. Three-year overall survival and treatment discontinuation-free survival were determined using Kaplan-Meier analysis. RESULTS: In 2014, 2,444 patients started abiraterone for treatment of mCRPC and 1,214 started docetaxel. After trimming and matching, 716 patients were available in each group. Median overall survival tended to be longer in the abiraterone acetate cohort (23.8 months, 95% confidence interval = [21.5; 26.0]) than in the docetaxel cohort (20.3 [18.4; 21.6] months). Survival at 36 months was 34.6% for abiraterone acetate and 27.9% for docetaxel (p = 0.0027). Treatment discontinuation-free median was longer in the abiraterone acetate cohort compared to the docetaxel cohort (10.8 [10.1; 11.7] versus 7.4 [7.0; 8.0] months). CONCLUSION: The findings underline the interest of oral abiraterone acetate over intravenous docetaxel as the first-line treatment option in mCRPC.

Comparative effectiveness of dimethyl fumarate in multiple sclerosis.

AIMS: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse subject to treatment (ARRt) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real-life setting. METHODS: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between 1 July 2015 and 12 December 2017, with 4.5 years of database history and 1-3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional propensity score. Negative binomial regression and a logistic regression model were used to estimate the relative risk (RR ± [95% CI]) of ARRt and the odds ratio (OR ± [95% CI]) of disability progression, respectively. RESULTS: Overall, 9304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF-IMM patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARRt compared to IMM (RR 0.72 [0.61-0.86]) and TERI (0.81 [0.68-0.96]) and did not show any significant difference when compared with FTY. The risk of the progression of MS-specific disability was not significantly different for any matched cohorts. CONCLUSION: DMF is associated with lower risk of treated relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding.

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population.

Patients with stable coronary artery disease and type 2 diabetes but without prior myocardial infarction or stroke and THEMIS-like patients: real-world prevalence and risk of major outcomes from the SNDS French nationwide claims database.

AIM AND HYPOTHESES: The THEMIS randomized trial compared ticagrelor plus aspirin versus placebo plus aspirin for patients with stable coronary artery disease and type 2 diabetes mellitus (CAD-T2DM), and without prior myocardial infarction (MI) or stroke. The aim of the study was to quantify the size of the CAD-T2DM population without prior MI or stroke population in a real-world setting, and more specifically populations with similar THEMIS selection criteria (THEMIS-like and THEMIS-PCI-like populations), as well as their risk of major outcomes in current practice. METHODS: A 2-year follow-up cohort study included all CAD-T2DM without MI/stroke prevalent patients on January 1st, 2014 in the SNDS French nationwide claims database. The THEMIS-like population concerned those ≥ 50 years of age with similar THEMIS inclusion and exclusion criteria. Prevalence was standardized to the European population. The cumulative incidence function was used to estimate the incidence of clinical outcomes (MI, ischemic stroke, and major bleeding according to the TIMI classification) with death as competing risk, and the Kaplan-Meier estimate for all-cause death and a composite outcome of MI, stroke and all-cause death. RESULTS: From a population of about 50 million adults, the prevalence of CAD-T2DM without MI/stroke, THEMIS-like and THEMIS-PCI-like populations was respectively at 6.04, 1.50 and 0.27 per 1000 adults, with a mean age of 72.7, 72.3 and 70.9 years and less comorbidities and diabetic complications for the THEMIS-like and THEMIS-PCI-like population. The 2-year cumulative incidence was respectively 1.7%, 1.3% and 1.6% for MI, 1.7%, 1.5% and 1.4% for stroke, 4.8%, 3.1% and 2.9% for major bleeding, 13.6%, 9.7% and 6.8% for all-cause death, and 16.2%, 12.0% and 9.5% for the composite outcome. CONCLUSION: THEMIS-like prevalence was estimated at 1.50 per 1,000 adults, representing about a quarter of CAD-T2DM without MI/stroke patients, and 0.27 per 1000 adults for the THEMIS-PCI-like populations. In current French practice, the median age of both these populations was about 5-6 years older than in the THEMIS trial, with a 2-year incidence of major outcomes between two or four time above the ones of the placebo arm of the THEMIS trial using very close definitions. Registration No. EUPAS27402 ( http://www.ENCEPP.eu ).

NSAIDs and COVID-19: A Systematic Review and Meta-analysis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been discouraged for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, fearing that they could increase the risk of infection or the severity of SARS-CoV-2. METHODS: Original studies providing information on exposure to NSAIDs and coronavirus disease 2019 (COVID-19) outcomes were retrieved and were included in a descriptive analysis and a meta-analysis with Cochrane Revue Manager (REVMAN 5.4), using inverse variance odds ratio (OR) with random- or fixed-effects models. RESULTS: Of 92,853 papers mentioning COVID-19, 266 mentioned NSAIDs and 61 mentioned ibuprofen; 19 papers had analysable data. Three papers described NSAID exposure and the risk of SARS-CoV-2 positivity, five papers described the risk of hospital admission in positive patients, 10 papers described death, and six papers described severe composite outcomes. Five papers studied exposure to ibuprofen and death. Using random-effects models, there was no excess risk of SARS-CoV-2 positivity (OR 0.86, 95% confidence interval [CI] 0.71-1.05). In SARS-CoV-2-positive patients, exposure to NSAIDs was not associated with excess risk of hospital admission (OR 0.90, 95% CI 0.80-1.17), death (OR 0.88, 95% CI 0.80-0.98), or severe outcomes (OR 1.14, 95% CI 0.90-1.44). With ibuprofen, there was no increased risk of death (OR 0.94, 95% CI 0.78-1.13). Using a fixed-effect model did not modify the results, nor did the sensitivity analyses. CONCLUSION: The theoretical risks of NSAIDs or ibuprofen in SARS-CoV-2 infection are not confirmed by observational data.

Global epidemiology of hip fractures: a study protocol using a common analytical platform among multiple countries.

INTRODUCTION: Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records. METHODS AND ANALYSIS: This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported. ETHICS AND DISSEMINATION: Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

Intra-database validation of case-identifying algorithms using reconstituted electronic health records from healthcare claims data.

BACKGROUND: Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative. OBJECTIVES: To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs). METHODS: Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm. RESULTS: Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV. CONCLUSION: The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Effectiveness of first-line cetuximab in wild-type RAS metastatic colorectal cancer according to tumour BRAF mutation status from the EREBUS cohort.

AIMS: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). METHODS: EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. RESULTS: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. CONCLUSIONS: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.

Treatment resistant depression incidence and prevalence using the French nationwide claims database.

PURPOSE: To estimate annual incidence and prevalence of Treatment-Resistant Depression (TRD) in France. METHODS: We identified all adult patients (≥ 18 years) with a TRD episode between 1 January 2012 and 31 December 2014 in the EGB (Échantillon généraliste des bénéficiaires), a permanent random sample of the French nationwide claims database. After a 6-month washout period without hospitalization for depression or any antidepressants (AD), and after exclusion of psychotic or bipolar affective disorders, Parkinson's disease and dementia, a TRD episode was defined by three successive sequences of different AD over a 3-month treatment period (6 months for a sensitive analysis), with at least 3 weeks before each sequence change and a Medication Possession Ratio ≥ 80%; or by the dispensing of >two different AD together; or of an AD with a potentiator (lithium, antiepileptic drugs, antipsychotic drugs, thyroid hormones) over the same treatment period. The annual incidence rate was estimated from 2012 to 2014 and the prevalence using a Gamma parametric function based on treatment duration and a 30-year prediction. RESULTS: Between 2012 and 2014, 700 patients were identified in EGB with a TRD episode. The mean age was 47.4 years (±15.3); 52.7% were women. Annual incidence and prevalence of TRD were estimated at 5.8 and 25.8 per 10 000 patients, respectively and at 7.8 and 37.6 per 10 000 patients, respectively in the sensitivity analysis. CONCLUSION: This study provides the first population-based estimates for incidence and prevalence of TRD in France.

Empirical assessment of case-based methods for identification of drugs associated with acute liver injury in the French National Healthcare System database (SNDS).

PURPOSES: Drug induced acute liver injury (ALI) is a frequent cause of liver failure. Case-based designs were empirically assessed and calibrated in the French National claims database (SNDS), aiming to identify the optimum design for drug safety alert generation associated with ALI. METHODS: All cases of ALI were extracted from SNDS (2009-2014) using specific and sensitive definitions. Positive and negative drug controls were used to compare 196 self-controlled case series (SCCS), case-control (CC), and case-population (CP) design variants, using area under the receiver operating curve (AUC), mean square error (MSE) and coverage probability. Parameters that had major impacts on results were identified through logistic regression. RESULTS: Using a specific ALI definition, AUCs ranged from 0.78 to 0.94, 0.64 to 0.92 and 0.48 to 0.85, for SCCS, CC and CP, respectively. MSE ranged from 0.12 to 0.40, 0.22 to 0.39 and 1.03 to 5.29, respectively. Variants adjusting for multiple drug use had higher coverage probabilities. Univariate regressions showed that high AUCs were achieved with SCCS using exposed time as the risk window. The top SCCS variant yielded an AUC = 0.93 and MSE = 0.22 and coverage = 86%, with 1/7 negative and 13/18 positive controls presenting significant estimates. CONCLUSIONS: SCCS adjusting for multiple drugs and using exposed time as the risk window performed best in generating ALI-related drug safety alert and providing estimates of the magnitude of the risk. This approach may be useful for ad-hoc pharmacoepidemiology studies to support regulatory actions.

Patterns of quadruple therapy use including bismuth for Helicobacter pylori eradication: A cohort study in the French national claims database.

BACKGROUND: Quadruple therapy using a single capsule formulation of bismuth, metronidazole and tetracycline (BMT; Pylera®), associated with omeprazole for the eradication of Helicobacter pylori, represents the reintroduction of bismuth in France after 40 years. OBJECTIVE: To describe the real-life patterns of use of BMT following a request from the French health authorities. METHODS: Patients with a first BMT dispensing (index date, ID), with one year of data before and after ID, were identified in the French nationwide claims database 1/97 sample. Misuse of BMT was defined as dispensing>1 pack of BMT at ID or absence of a diagnostic test in the preceding year. RESULTS: In total, 540 patients were included. Prescribers were gastroenterologists (n=243; 45%) and general practitioners (n=160; 30%). A proton pump inhibitor was co-dispensed to 504 patients (96%). Ten patients (2%) had contraindications to BMT. Fifty-nine patients (11%) met the misuse criteria: ten (2%) were dispensed>1 pack of BMT and 49 (9%) had not had a diagnostic test for H. pylori in the previous year. During follow-up, 27 patients (5%) required retreatment (treatment failure). CONCLUSION: In this real-life study, most patients were dispensed only one pack of BMT, consistent with recommendations. Misuse related principally to the absence of prior diagnostic test for H. pylori.

Epidemiology of metastatic castration-resistant prostate cancer: A first estimate of incidence and prevalence using the French nationwide healthcare database.

BACKGROUND: There is a lack of information about the burden of metastatic castration-resistant prostate cancer (mCRPC). The present work aims to estimate the incidence and prevalence of mCRPC in 2014 using the French nationwide healthcare database (SNDS). METHODS: Prevalence and incidence were estimated based on an SNDS extraction of men covered by the general healthcare insurance (86 % of the French population), and aged ≥40. Patients with mCRPC were identified amongst prostate cancer cases using an algorithm estimating a date of first metastasis management and a date of castration resistance. This algorithm was validated by clinical experts through a blind review of 200 anonymized medical charts from SNDS data. Prevalence and incidence were standardized on the European Standard Population (2013 edition). RESULTS: Prevalence and incidence of mCRPC were estimated as, respectively, 62 and 21 cases per 100 000 men in 2014. Less than one mCRPC case per 100 000 was observed in men aged 40-49. Maximum mCRPC incidence was in men aged 80-89 (175 per 100 000). The algorithm used for mCRPC identification had 97 % positive and 99 % negative predictive values. CONCLUSION: The good performances of the algorithm for mCRPC identification and the consistency of the generated results with the existing data highlight the robustness of these first estimates of mCRPC prevalence and incidence. Future updates will call for algorithm adjustment as practices evolve over time. These first real-life data will serve for future follow-up of the impact of changes in the management of prostate cancer.

Empirical assessment of case-based methods for identification of drugs associated with upper gastrointestinal bleeding in the French National Healthcare System database (SNDS).

PURPOSE: Upper gastrointestinal bleeding (UGIB) is a severe and frequent drug-related event. In order to enable efficient drug safety alert generation in the French National Healthcare System database (SNDS), we assessed and calibrated empirically case-based designs to identify drug associated with UGIB risk. METHODS: All cases of UGIB were extracted from SNDS (2009-2014) using two definitions. Positive and negative drug controls were used to compare 196 self-controlled case series (SCCS), case-control (CC) and case-population (CP) design variants. Each variant was evaluated in a 1/10th population sample using area under the receiver operating curve (AUC) and mean square error (MSE). Parameters that had major impacts on results were identified through logistic regression. Optimal designs were replicated in the unsampled population. RESULTS: Using a specific UGIB definition, AUCs ranged from 0.64 to 0.80, 0.44 to 0.61 and 0.50 to 0.67, for SCCS, CC and CP, respectively. MSE ranged from 0.07 to 0.39, 0.83 to 1.33 and 1.96 to 4.6, respectively. Univariate regressions showed that high AUCs were achieved with SCCS with multiple drug adjustment and a 30-day risk window starting at exposure. The top-performing SCCS variant in the unsampled population yielded an AUC = 0.84 and MSE = 0.14, with 10/36 negative controls presenting significant estimates. CONCLUSIONS: SCCS adjusting for multiple drugs and using a 30-day risk window has the potential to generate UGIB-related alerts in the SNDS and hypotheses on its potential population impact. Negative control implementation highlighted that low systematic error was generated but that protopathic bias and confounding by indication remained unaddressed issues.