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.
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.
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.
The theoretical risks of NSAIDs or ibuprofen in SARS-CoV-2 infection are not confirmed by observational data.
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.
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).
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.
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.
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.
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.
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.
The French health care system is based on universal coverage by one of several health care insurance plans. The SNIIRAM database merges anonymous information of reimbursed claims from all these ...plans, linked to the national hospital‐discharge summaries database system (PMSI) and the national death registry. It now covers 98.8% of the French population, over 66 million persons, from birth (or immigration) to death (or emigration), making it possibly the world's largest continuous homogeneous claims database. The database includes demographic data; health care encounters such as physician or paramedical visits, medicines, medical devices, and lab tests (without results); chronic medical conditions (ICD10 codes); hospitalisations with ICD10 codes for primary, linked and associated diagnoses, date and duration, procedures, diagnostic‐related groups, and cost coding; date but currently not cause of death. The power of the database is correlatively great, and its representativeness is near perfect, since it essentially includes the whole country's population. The main difficulty in using the database, beyond its sheer size and complexity, is the administrative process necessary to access it. Recent legislative advances are making this easier.
EGB (Echantillon Généraliste de Bénéficiaires) is the 1/97th random permanent representative sample of SNIIRAM, with planned 20‐year longitudinal data (10 years at this time). Access time is 1 to 3 months, but its power is less (780 000 subjects). This is enough to study common issues with older drugs but may be limited for new products or rare events.
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.
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.
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€).
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.
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