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.

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.

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.

Empirical assessment of case-based methods for drug safety alert identification in the French National Healthcare System database (SNDS): Methodology of the ALCAPONE project.

OBJECTIVES: To introduce the methodology of the ALCAPONE project. BACKGROUND: The French National Healthcare System Database (SNDS), covering 99% of the French population, provides a potentially valuable opportunity for drug safety alert generation. ALCAPONE aimed to assess empirically in the SNDS case-based designs for alert generation related to four health outcomes of interest. METHODS: ALCAPONE used a reference set adapted from observational medical outcomes partnership (OMOP) and Exploring and Understanding Adverse Drug Reactions (EU-ADR) project, with four outcomes-acute liver injury (ALI), myocardial infarction (MI), acute kidney injury (AKI), and upper gastrointestinal bleeding (UGIB)-and positive and negative drug controls. ALCAPONE consisted of four main phases: (1) data preparation to fit the OMOP Common Data Model and select the drug controls; (2) detection of the selected controls via three case-based designs: case-population, case-control, and self-controlled case series, including design variants (varying risk window, adjustment strategy, etc.); (3) comparison of design variant performance (area under the ROC curve, mean square error, etc.); and (4) selection of the optimal design variants and their calibration for each outcome. RESULTS: Over 2009-2014, 5225 cases of ALI, 354 109 MI, 12 633 AKI, and 156 057 UGIB were identified using specific definitions. The number of detectable drugs ranged from 61 for MI to 25 for ALI. Design variants generated more than 50 000 points estimates. Results by outcome will be published in forthcoming papers. CONCLUSIONS: ALCAPONE has shown the interest of the empirical assessment of pharmacoepidemiological approaches for drug safety alert generation and may encourage other researchers to do the same in other databases.

Monitoring of drug misuse or potential misuse in a nationwide healthcare insurance database: A cross-sectional study in France.

AIM OF THE STUDY: To provide a tool for drug misuse or potential misuse monitoring by using a healthcare insurance database. METHODS: A cross-sectional study repeated quarterly from 2007 to 2014 was conducted using data from a 1/97th random sample of the French national healthcare reimbursement system. For each drug studied, ad hoc indicators were designed to assess drug misuse, defined as prescriptions that did not comply with the label stipulated in the summary of product characteristics, in terms of the drug (e.g., interactions) or the patient (age, medical history). We focused on specifically identified situations of drug misuse involving non-steroidal anti-inflammatory drugs (NSAIDs), antiemetics in patients with Parkinson's disease and antipsychotics in pediatrics; we also focused on direct anticoagulants, asthma and oral antidiabetic drugs but results for these latter are only shown in supplementary materials. RESULTS: At-risk prescribing of NSAIDs in patients treated by diuretics or renin-angiotensin system inhibitors always remained higher than 14% over the study (maximum: 19%; 2014 quarter 4: 15.4%). Off-label prescribing of contraindicated anti-dopaminergic antiemetics with dopaminergic antiparkinson drugs was marginal (maximum: 2.2%; 2014 quarter 4: 0.5%) but represented at least 5.5% of antiemetic prescriptions. Despite the rise in antipsychotic prescriptions in pediatrics, no dramatic increase in misuse related to age was observed during the study period (2007 quarter 1: 16.1%; 2014 quarter 4: 11.1%). The highest degree of misuse was observed for aripiprazole and for second-generation antipsychotics other than risperidone and aripiprazole. CONCLUSION: This study provides a simple tool to monitor drug misuse or potential misuse using information from a health insurance database. The results highlight the need for the Regulator to rethink risk management information campaigns and to modify the official information on products.

Comparative effectiveness of direct oral anticoagulants versus low-molecular weight heparins for the prevention of venous thromboembolism after total hip or knee replacement: A nationwide database cohort study.

BACKGROUND: Venous thromboembolism (VTE) after total knee or hip replacement (TKR, THR) is usually prevented with low-molecular weight heparin (LMWH), and increasingly by direct oral anticoagulants (DOAC). The aim of the present study was to compare the benefit-risk and medical costs of DOAC vs. LMWH in a real-life setting. METHODS: All patients with THR or TKR in France between Jan-1st 2013 and Sep-30th 2014, discharged to home, were identified and followed-up for 3 months in the French nationwide claims database, SNDS. DOAC users were 1:1 matched with LWMH users on gender, age and propensity score. Relative risks (RR) of hospitalized VTE, hospitalized bleeding and death were estimated using quasi-Poisson models. Medical costs were calculated according to the societal perspective, including total cost for outpatient claims and national DRG costs for hospitalisations. RESULTS: Most DOAC users (≥ 98.8%) were matched to a LMWH patient. For the 63,238 matched THR patients, the 3-month absolute risk of VTE was 0.9‰ with DOAC and 2.5‰ with LMWH (RR = 0.35 [0.23 to 0.54]), of bleeding 1.8‰ and 2.1‰ (0.88 [0.62-1.25]), death 0.7‰ and 1.1‰ (0.68 [0.40-1.15]). For the 31,440 matched TKR patients, risks were 1.6‰ and 2.3‰ (0.69 [0.42-1.16]) for VTE, 2.4‰ and 3.8‰ (0.64 [0.43 to 0.97]) for bleeding, and 0.6‰ and 0.8‰ (0.69 [0.30-1.62]) for all-cause death. Mean medical costs were 28% and 21% lower with DOAC than LMWH for THR and TKR, respectively. This nationwide study found a very low risk of VTE, hospitalized bleeding and death after THR or TKR discharge in patients with VTE prevention in real-life setting, with better benefit-risk profiles of DOAC compared to LMWH, and associated cost savings.

Chronic obstructive pulmonary disease exacerbation and inhaler device handling: real-life assessment of 2935 patients.

Acute exacerbations of chronic obstructive pulmonary disease (COPD) can be prevented by inhaled treatment. Errors in inhaler handling, not taken into account in clinical trials, could impact drug delivery and minimise treatment benefit. We aimed to assess real-life inhaler device handling in COPD patients and its association with COPD exacerbations.To this end, 212 general practitioners and 50 pulmonologists assessed the handling of 3393 devices used for continuous treatment of COPD in 2935 patients. Handling errors were observed in over 50% of handlings, regardless of the device used. Critical errors compromising drug delivery were respectively made in 15.4%, 21.2%, 29.3%, 43.8%, 46.9% and 32.1% of inhalation assessment tests with Breezhaler® (n=876), Diskus® (n=452), Handihaler® (n=598), pressurised metered-dose inhaler (pMDI) (n=422), Respimat® (n=625) and Turbuhaler® (n=420).The proportion of patients requiring hospitalisation or emergency room visits in the past 3 months for severe COPD exacerbation was 3.3% (95% CI 2.0-4.5) in the absence of error and 6.9% (95% CI 5.3-8.5) in the presence of critical error (OR 1.86, 95% CI 1.14-3.04, p<0.05).Handling errors of inhaler devices are underestimated in real life and are associated with an increased rate of severe COPD exacerbation. Training in inhaler use is an integral part of COPD management.

Drug use in French children: a population-based study.

BACKGROUND AND OBJECTIVE: To provide an overview of drug use in outpatient children in France, a population-based study using a national reimbursement claims database representative of 90% of the French population was conducted. DESIGN: Cross-sectional study performed between January and December 2011 using the EGB database (Echantillon Généraliste de Bénéficiaires), a 1/97th sample of the national healthcare insurance system beneficiaries. Drug use in children <18 years old was estimated through reimbursements for prescribed drugs excluding vaccines. Prevalences of use were calculated for different levels of the Anatomical Therapeutic Chemical classification by considering as users children who had at least one reimbursement during the study period. RESULTS: In 2011, 133,800 children were included in the study. The overall prevalence of drug use was 84% and the median number of different drugs per child was 5. Drug use was greatest in children aged <2 years. The most widely used drugs were paracetamol, systemic anti-infectives, nasal corticosteroids and decongestants, and anti-histamines. 21% children <2 years received domperidone. CONCLUSIONS: There is widespread use of medicines that are unlikely to be effective and may have significant toxicity in French children. Irrational use of medicines appears to be greatest in children aged 5 years and under.

Are traditional NSAIDs prescribed appropriately among French elderly with osteoarthritis? Results from the CADEUS cohort.

AIM: To describe the inappropriate use of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) in elderly subjects in the CADEUS cohort using the Beers 2003 criteria modified by recommendations from the French Medicines Agency. METHODS: Of the 23,217 subjects in the CADEUS cohort, 1,851 were ≥65 years old, had bee diagnosed with osteoarthritis (OA), and had been dispensed a tNSAID at least once in the 6 months before the index date. Data were obtained from the French national reimbursement database and from patient and prescriber questionnaires. The Beers criteria for inappropriate use were modified to include all tNSAIDs, and long-term high-dose use was defined as having been dispensed at least five dispensations for tNSAID over a 6-month period with a gap of <45 days between each dispensation and when the gap was >45 days, medicine availability >50% [i.e., defined daily dose (DDD) delivered/theoretical DDD] for the gap. RESULTS: The most frequently dispensed tNSAIDs were piroxicam (25%), diclofenac (24%), ibuprofen (18%), ketoprofen (18%), and naproxen (10%). Of the study population, 1.5% were dispensed indomethacin; 15%, two tNSAIDs; 15%, a tNSAIDs with a platelet aggregation inhibitor; 4.6%, a tNSAID with low-dose aspirin; 0.2%, a tNSAID with vitamin K antagonists. The analysis revealed that 18% of the study population were high-dose and long-term users of tNSAIDs and that 70% of these were dispensed a proton pump inhibitor. CONCLUSIONS: The most common inappropriate tNSAID dispensation was the co-prescription of two different tNSAIDs within 1 month or of a platelet aggregation inhibitor. The real-life consequences of our results need to be ascertained, and it would be interesting to update the Beers criteria.

Concordance between prescriber- and patient-reported previous medical history and NSAID indication in the CADEUS cohort.

PURPOSE: Various data sources may be used in pharmacoepidemiological studies. When they cannot be obtained from valid databases, medical data must be obtained from physicians or patients. In the CADEUS study, both patients and their prescribers reported medical data allowing investigation of the concordance between these sources. METHODS: CADEUS is a French national cohort study of traditional non-steroidal anti-inflammatory drug (NSAID) and coxib users conducted between September 2003 and August 2004 in France that employed self-administered questionnaires to obtain medical data from patients and their prescribers. The Kappa statistic (kappa) was used to measure concordance between patients and prescribers in 18 530 pairs with regard to previous medical history and index NSAID indication. RESULTS: For previous medical history, the proportion of agreement ranged from 70.7 to 99.2% and concordance was: substantial (kappa = 0.61-0.80) for hypertension, myocardial infarction, stroke and diabetes; moderate (kappa = 0.41-0.60) for angina pectoris, peripheral arterial disease and hypercholesterolaemia; fair (kappa = 0.21-0.40) for unstable angina, cardiac insufficiency, dyspepsia, gastroesophageal reflux and gastric ulcer; slight (kappa < 0.21) for upper gastrointestinal haemorrhage. For index NSAID indication, the proportion of agreement ranged from 84.3 to 99.4% and concordance was almost perfect (kappa = 0.81-1.00) for inflammatory rheumatism, flu-like symptoms, dysmenorrhoea and dental pain; substantial for arthritis, back pain and headache; moderate for osteoarticular pain. CONCLUSIONS: Concordance was better for specific or serious conditions both regarding previous medical history and indication. Prescriber or patient perception and understanding may reduce concordance for certain items.

Impact of prescriber nonresponse on patient representativeness.

BACKGROUND: In pharmacoepidemiology studies where patients are selected by prescribers, there is concern that the patients of responding prescribers are not necessarily an unbiased sample of all patients. However, this usually cannot be explored. In the CADEUS study, patients and prescribers were independently contacted so that data are available for patients irrespective of whether their prescriber responded or not. Our objective was to compare the characteristics of patients whose prescriber did or did not respond. METHODS: The CADEUS study included patients treated with COX-2 inhibitors (celecoxib, rofecoxib) or traditional NSAIDs from September 2003 to August 2004. Redeemed prescriptions were randomly sampled on a monthly basis within the database of the French national healthcare insurance system for salaried persons during 1 year. Patients and prescribers were questioned independently. Data from patients and from the database were used to compare patients whose prescriber responded and those whose prescriber did not. RESULTS: Of 45,217 patients, 26,618 had prescriber data. Patients whose prescriber responded were similar to patients whose prescriber did not respond for the main study outcomes: age (56.8 +/- 16.3 years vs. 56.1 +/- 16.3 years), sex (66.0% female vs. 64.8%), cardiovascular disease history (52.2% vs. 52.0%), gastrointestinal disease history (39.5% vs. 39.4%), concomitant prescription of gastroprotective agents (22.4% vs. 23.7%), and NSAID indication, prescription type, use, and duration. CONCLUSIONS: We found no evidence for a difference between patients whose prescriber responded and patients whose prescriber did not participate in the study.