Prevalence and associated factors of antibiotic exposure during pregnancy in a large French population-based study during the 2010-19 period.

BACKGROUND: Although bacterial infections are frequent during pregnancy, the prescription of antibiotics to pregnant women represents a challenge for physicians, driven by the benefit-risk balance. OBJECTIVES: To assess the extent of prenatal antibiotic exposure and its associated factors. METHODS: This study included pregnancies in the National Mother-Child EPI-MERES Register 2010-19 (built from the French Healthcare Data System) regardless of outcome. Antibiotic exposure was defined as having at least one antibiotic prescription filled during pregnancy. The prevalence of pregnancies exposed to antibiotics was estimated. Univariable Poisson regression with generalized estimating equations was used to compare the number of antibiotic prescriptions filled during pregnancy and the period after pregnancy with the period 1 year before pregnancy. Multivariable Poisson regression was used to investigate factors associated with antibiotic exposure during pregnancy. RESULTS: Among 9 769 764 pregnancies, 3 501 294 (35.8%) were exposed to antibiotics and amoxicillin was the most common. Compared with a similar period 1 year before pregnancy, the number of filled antibiotic prescriptions was lower during pregnancy [incidence rate ratio (IRR) 0.903 (95% CI 0.902-0.905)] and during the period 1 year after pregnancy [IRR 0.880 (95% CI 0.879-0.881)]. Region of residence, deprivation index, smoking-related conditions and chronic diseases (especially chronic respiratory diseases) were associated with antibiotic exposure during pregnancy. CONCLUSIONS: Antibiotic prescriptions are filled less frequently during pregnancy than during the preceding year. This may be due to a more relevant benefit-risk assessment. Pregnant women living with social deprivation, those with smoking-related conditions and those with chronic diseases are more likely to fill antibiotic prescriptions.

Risk of major adverse cardiovascular and venous thromboembolism events in patients with rheumatoid arthritis exposed to JAK inhibitors versus adalimumab: a nationwide cohort study.

OBJECTIVES: To assess the risk of major adverse cardiovascular events (MACEs) and venous thromboembolism events (VTEs) among patients initiating a Janus kinase inhibitor (JAKi) (tofacitinib and baricitinib) versus adalimumab in a large real-world population of patients with rheumatoid arthritis. METHODS: We conducted a nationwide population-based cohort study of the French national health data system, the exposed group initiating a JAKi and non-exposed group initiating adalimumab. We included all individuals who had their first dispensation of a JAKi or adalimumab between 1 July 2017 and 31 May 2021 and had rheumatoid arthritis. The primary endpoints were the occurrence of a MACE or VTE. Weighted hazard ratio (HRw) values were estimated with the inverse probability of treatment weighting method to account for confounding factors with concomitant administration of methotrexate as a time-varying variable. RESULTS: The cohort included 15 835 patients: 8481 and 7354 in the exposed and non-exposed groups (mean age 59.3 and 55.3 years, female 78.3% and 71.2%, respectively). During follow-up, 54 and 35 MACEs and 75 and 32 VTEs occurred in the exposed and non-exposed groups, respectively. Risk of MACEs for the exposed versus non-exposed group was not significant: HRw 1.0 (95% CI 0.7 to 1.5) (p=0.99), nor was risk of VTEs significant: HRw 1.1 (0.7 to 1.6) (p=0.63). Despite a lack of power, results were consistent among patients aged 65 years or older with at least one cardiovascular risk factor. CONCLUSIONS: This study provides reassuring data regarding the risks of MACEs and VTEs in patients initiating a JAKi versus adalimumab, including patients at high risk of cardiovascular diseases.

Persistence of second-line biologics in psoriasis after first-line biologic failure: a nationwide cohort study from the French health insurance database (SNDS).

BACKGROUND: Many biologics are available for psoriasis and have been compared in real-life studies based on their persistence (i.e. time between initiation and discontinuation). However, after first-line biologic failure, data are lacking on the choice of second-line biologic among the four available classes [tumour necrosis factor inhibitors (TNFi); interleukin (IL)-12/IL-23 inhibitor (IL-12/IL-23i); IL-17 inhibitors (IL-17i); and IL-23 inhibitors (IL-23i)]. OBJECTIVES: To compare the long-term persistence of available second-line biologics in psoriasis according to prior exposure. METHODS: This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to a hospital discharge database. Participants were adults with psoriasis, defined as having at least two prescriptions of a topical vitamin D derivative within a 2-year period, with initiation of a second-line biologic between 1 January 2015 and 31 December 2021. We included patients who initiated a second-line biologic directly after first-line discontinuation (i.e. without a 'washout' period). The end of follow-up was 30 June 2022. Discontinuation was defined as > 90 days without filling a prescription for the same treatment after the period covered by the previous prescription. Comparison of persistence by biologic class involved using propensity score-weighted Cox models (inverse probability treatment weighting) and adjustment of specific systemic nonbiologics (time-dependent variables). RESULTS: We included 8693 patients [mean (SD) age 50 (14) years; 50.5% male]; 2824 (32.5%) started TNFi, 1561 (18.0%) IL-12/IL-23i, 2707 (31.1%) IL-17i and 1601 (18.4%) IL-23i. Overall, 1- and 3-year persistence rates were 60% and 30%, respectively. After weighting and adjustment, persistence was longer with IL-12/IL-23i [weighted hazard ratio (HRw) 0.68, 95% confidence interval (CI) 0.62-0.76)], IL-17i (HRw 0.70, 95% CI 0.64-0.78) and IL-23i (HRw 0.36, 95% CI 0.31-0.42) than TNFi, except after first-line IL-17i treatment, with no difference between IL-12/IL-23i, IL-17i and TNFi second-line persistence. Persistence was longer with IL-23i as a second-line treatment than IL-12/IL-23i (HRw 0.53, 95% CI 0.44-0.63) and IL-17i (HRw 0.51, 95% CI 0.44-0.60), regardless of first-line treatment, with no difference seen between IL-12/IL-23i and IL-17i (HRw 0.97, 95% CI 0.87-1.09). CONCLUSIONS: This real-life study suggests the longer persistence of IL-23i than TNFi, IL-17i and IL-12/IL-23i as second-line treatment for psoriasis. Persistence rates for all biologics remained low at 3 years.

Trends in anti-infective use during pregnancy in France between 2010 and 2019: a nationwide population-based study.

AIMS: To describe the trends in anti-infective use during pregnancy between 2010 and 2019 and determine whether they were prescribed according to drug foetal safety international classification systems. METHODS: We conducted a population-based, nationwide study using the French national health data system including all pregnancies ended between 2010 and 2019. Anti-infective agents were considered according to their pharmacological group and potential harmful risk using the Australian and Swedish classification systems. Prevalence rate was estimated annually and by trimester. Average annual percent change (AAPC) and 95% confidence intervals (CIs) were calculated using Joinpoint regression. RESULTS: Among 7 571 035 pregnancies, 3 027 031 (40.0%) received ≥1 antibacterial. This proportion decreased significantly from 41.5% in 2010 to 36.1% in 2019 (AAPC = -1.7%, [95%CI, -2.5 to -1.0%]). Conversely, use of antiviral agents increased during the 10-year study period for anti-herpes simplex virus agents (AAPC = 4.4%, [3.7-5.2%]), influenza agents (AAPC = 25.4%, [6.2-48.1%]) and for HIV-antiretroviral agents (AAPC = 1.3%, [0.6-2.0%]). Use of influenza vaccine increased from 0.2% in 2010 to 4.2% in 2019 (AAPC = 49.7%, [39.3-60.9%]). Among all pregnancies, 0.9% had been exposed to a potentially harmful anti-infective agent increasing from 0.7% in 2010 to 1.2% in 2019 (AAPC = 6.4%, [4.4-8.5%]). CONCLUSION: Based on >7 million pregnancies identified from French nationwide data, this study showed that antibacterials are frequently prescribed during pregnancy although their use has decreased over the past 10 years. Our results suggest that anti-infective agents are generally prescribed in accordance with recommendations, although with a potential for improvement in influenza vaccination.

Potentially inappropriate medications in nursing homes and the community older adults using the French health insurance databases.

PURPOSE: Potentially inappropriate medications (PIMs) have become a major issue in improving prescribing practices and reducing the risk of adverse drug events in older people. However, very few studies have compared exposition to PIMs controlling for differences in demographic and health between nursing home residents (NHRs) and community-dwelling older adults (CDOAs). This study aimed to assess the prescribing pattern of PIMs between NHRs and CDOAs. METHODS: We conducted a cross-sectional study over three months in 2019 using the French Health Insurance databases. The study population included 274 971 NHRs and 4 893 721 CDOAs aged 75 years or over. The prevalence ratio (PR) between NHRs and CDOAs of 17 PIM indicators, based on the Beers and STOPP criteria lists, was assessed using multivariable robust Poisson regression adjusted for age, sex, diseases, and polypharmacy. RESULTS: During the study period, 54% of NHRs and 29% of CDOAs received at least one PIM. After adjustment, the prevalence of PIMs was 33% higher among NHRs compared to CDOAs (aPR = 1.33; 95% CI [1.33-1.34]). NHRs received PIMs related to benzodiazepines (aPR = 1.43; 95% CI [1.42-1.43]), anticholinergic drugs (aPR = 1.29; 95% CI [1.27-1.31]), and at least three central nervous system-active drugs (aPR = 1.94; 95% CI [1.92-1.96]) more frequently. Prevalence of PIMs related to non-steroidal anti-inflammatory drugs (aPR = 0.50; 95% CI [0.48-0.52]) and long-acting benzodiazepines (aPR = 0.84; 95% CI [0.82-0.85]) was lower among NHRs. CONCLUSION: The NHRs were at greater risk for PIM than CDOAs, although differences exist according to the category of PIMs. As the population is aging, it is essential to promote and evaluate interventions in NHs and the community to enhance medication optimization.

Risk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in France.

BACKGROUND: The BNT162b2 (Pfizer-BioNTech) vaccine has been shown to be safe with regard to risk for severe cardiovascular events (such as myocardial infarction [MI], pulmonary embolism [PE], and stroke) in persons aged 75 years or older. Less is known about the safety of other COVID-19 vaccines or outcomes in younger populations. OBJECTIVE: To assess short-term risk for severe cardiovascular events (excluding myocarditis and pericarditis) after COVID-19 vaccination in France's 46.5 million adults younger than 75 years. DESIGN: Self-controlled case series method adapted to event-dependent exposure and high event-related mortality. SETTING: France, 27 December 2020 to 20 July 2021. PATIENTS: All adults younger than 75 years hospitalized for PE, acute MI, hemorrhagic stroke, or ischemic stroke (n = 73 325 total events). MEASUREMENTS: Linkage between the French National Health Data System and COVID-19 vaccine databases enabled identification of hospitalizations for cardiovascular events (MI, PE, or stroke) and receipt of a first or second dose of the Pfizer-BioNTech, mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine. The relative incidence (RI) of each cardiovascular event was estimated in the 3 weeks after vaccination compared with other periods, with adjustment for temporality (7-day periods). RESULTS: No association was found between the Pfizer-BioNTech or Moderna vaccine and severe cardiovascular events. The first dose of the Oxford-AstraZeneca vaccine was associated with acute MI and PE in the second week after vaccination (RI, 1.29 [95% CI, 1.11 to 1.51] and 1.41 [CI, 1.13 to 1.75], respectively). An association with MI in the second week after a single dose of the Janssen vaccine could not be ruled out (RI, 1.75 [CI, 1.16 to 2.62]). LIMITATIONS: It was not possible to ascertain the relative timing of injection and cardiovascular events on the day of vaccination. Outpatient deaths related to cardiovascular events were not included. CONCLUSION: In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with increased incidence of MI and PE. No association between mRNA-based vaccines and the cardiovascular events studied was observed. PRIMARY FUNDING SOURCE: None.

A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.

We propose a modified self-controlled case series (SCCS) method to handle both event-dependent exposures and high event-related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID-19 vaccines. Event-dependence of vaccinations, and high event-related mortality, are likely to arise in other SCCS studies of COVID-19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death.

Risk of intracranial meningioma with three potent progestogens: A population-based case-control study.

BACKGROUND AND PURPOSE: A dose-dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75-5 mg/day) and chlormadinone acetate (CMA) (2-10 mg/day). METHODS: In this nationwide population-based case-control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls. RESULTS: In total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3-7.1). The OR was 1.2 (1.0-1.4) for short-term use (<1 year) and 9.5 (8.8-10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5-26.4), NOMAC (OR = 6.5, 95% CI 5.8-7.2) and CMA (OR = 4.7, 95% CI 4.5-5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5-48.2) and 23.9 (95% CI 17.8-32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028-2220) (212/year). CONCLUSION: A strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk.

Risk of secondary hematologic malignancies associated with breast cancer chemotherapy and G-CSF support: A nationwide population-based cohort.

Our study aimed to analyze the risk of hematologic malignancies (HM) associated with the use of G-CSF with chemotherapy for BC. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident breast cancer between 2007 and 2015, who received chemotherapy for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL) and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Among a total of 122 373 BC survivors, 38.9% received chemotherapy only and 61.1% received chemotherapy + G-CSF. Overall, 781 cases of hematologic malignancies occurred. We observed a nonsignificant increase in the risk of AML (aHR, 1.3; 95% CI, 1.0-1.7), of MDS (aHR, 1.3; 95% CI, 0.9-1.8) and of ALL/LL (aHR, 2.0; 95% CI, 1.0-4.4) among patients treated by chemotherapy + G-CSF compared to chemotherapy only. In analyses by dose, we observed a slight increase in the risk of AML (1-3 doses: aHR, 1.2; 95% CI, 0.8-1.7/4+ doses: aHR, 1.3; 95% CI, 1.0-1.8) and of MDS (1-3 doses: aHR, 1.1; 95% CI, 0.7-1.7/4+ doses: aHR, 1.4; 95% CI, 1.0-1.9), a significant increase in risk of ALL (1-3 doses: aHR, 1.5; 95% CI, 0.5-3.9 / 4+ doses: aHR, 2.3; 95% CI, 1.0-5.1) with increasing cycles of G-CSF. Our population-based study showed that the ALL/LL was the only HM at increased risk with the use of growth factors with a possible dose-effect relationship. Our data regarding the risk of all the other HM are reassuring.

Colonoscopy in France during the COVID-19 pandemic.

PURPOSE: We hypothesized that the COVID-19 pandemic may have modified dispensing of colonoscopy preparations, a proxy for the number of colonoscopies performed. We therefore studied changes in dispensing of colonoscopy preparations during the pandemic in France. METHODS: Using the French national health data system, we identified colonoscopy preparations dispensed from 2018 to 2020. The expected 2020 dispensations were estimated from 2018 to 2019 dispensations. RESULTS: Dispensing of colonoscopy preparations decreased markedly during the eight weeks of national lockdown: 83,045 colonoscopy preparations were dispensed, i.e., 181,826 (68.6%) fewer than expected. After lockdown, dispensing of colonoscopy preparations gradually returned to expected numbers. Overall, this represents an estimated decrease of roughly 250,000 colonoscopy preparations during the six-month period following onset of the pandemic. This shortfall in the dispensing of colonoscopy preparations was of the same order of magnitude in people under or over 50 years of age, in men and women, and in those in the highest and the lowest quintiles of the deprivation index. CONCLUSION: In conclusion, roughly 250,000 fewer colonoscopy preparations were dispensed during the first six months of the COVID-19 pandemic in France. Deleterious consequences on morbidity and mortality related to gastroenterological diseases, such as colorectal cancer, are to be feared.

Decreasing trends in potentially inappropriate medications in older people: a nationwide repeated cross-sectional study.

BACKGROUND: Potentially Inappropriate Medications (PIMs) and polypharmacy are widely used indicators of suboptimal prescribing for older people. The aim of this study was to describe the changes in the prevalence of PIMs and polypharmacy among people aged 75 years and over between 2011 and 2019 in France. METHODS: PIMs and polypharmacy were assessed among people aged 75 years and over every two years between 2011 and 2019 using the French health insurance data system. Sixteen PIM criteria from the 2015 Beers and STOPP lists were assessed. Polypharmacy (5 to 9 drugs) and hyper-polypharmacy (≥10 drugs) were defined based on the average number of drugs dispensed per quarter. The Annual Percent Change (APC) and 95%CI were assessed using linear regression models after standardization of the prevalence on age and sex. RESULTS: The study population included 5,777,645 individuals over 75 years old in 2011 and 6,328,155 in 2019. The prevalence of PIMs decreased from 49.6 to 39.6% over the study period (APC: - 1.19% [- 1.35;-1.04]). Of the sixteen indicators assessed, the prevalence of thirteen decreased between 2011 and 2019. Benzodiazepines were the most frequent PIMs (34.7% in 2011 to 26.9% in 2019), followed by anticholinergic drugs (12.1% in 2011 to 8.3% in 2019), oral non-steroidal anti-inflammatory drugs (11.4 to 7.8%), and PIMs related to antihypertensive drugs (7.4 to 6.0%). Overall, women and individuals aged 85 years and older were more likely to receive PIMs. The prevalence of hyper-polypharmacy decreased from 30.5 to 25.9% over the study period. CONCLUSION: This study, which is the first to assess the change in prevalence of PIMs and polypharmacy over time from comprehensive health data in France, highlights that PIMs and hyper-polypharmacy declined between 2011 and 2019. However, PIMs remains frequent for older people and often involves benzodiazepines.

Use of proton pump inhibitors in adults in France: a nationwide drug utilization study.

PURPOSE: Proton pump inhibitor (PPI) drugs are approved for the management of gastric acid-related diseases, mainly treatment of gastroesophageal reflux disease, treatment of nonsteroidal anti-inflammatory drugs (NSAID)-related gastrointestinal complications and prevention in at-risk patients, Helicobacter pylori eradication, and treatment of ulcers. PPIs are one of the most commonly prescribed drug class worldwide, and off-label use is widespread. The aim of this study was to describe outpatient PPI use of the whole adult population in France, based on the French National Health Data System (SNDS). METHODS: All individuals aged 18 years or older, with at least one dispensing for PPI between January 1, 2015 and December 31, 2015, were identified as PPI users. PPI users were considered as new users if they received no dispensing for PPI in the prior year. New users were followed until treatment discontinuation or up to 1 year, whichever occurred first. Characteristics of new users and of their PPI treatment were described, overall and separately by treatment indication. RESULTS: In total, 15,388,419 PPI users were identified in 2015 (57.0% women; mean age 57.0 years), accounting for 29.8% of the French adult population. Of them, 7,399,303 were new PPI users; mean treatment duration was 40.9 days, and 4.1% received a continuous PPI therapy lasting more than 6 months (10.2% among new users > 65 years versus 2.4% among those 18-65 years). For 53.5% of new users, indication for PPI therapy was a co-prescription with NSAID; in this indication, the large majority of patients (79.7%) had no measurable risk factor supporting a systematic prophylactic co-prescription of PPI. A proportion of 32.4% of new users did not have any identified comedication or inpatient diagnosis supporting an indication for PPI therapy; among them, only a small proportion (7.3% overall, and 8.4% of patients aged > 65 years) underwent a procedure investigating the digestive tract at the time of PPI initiation. CONCLUSION: The results of this study suggest PPI overuse in France, not always in line with the French guidelines. In particular, inappropriate co-prescription with NSAID was frequent. Efforts should be made to limit PPI treatment to appropriate indications and durations.

Risk of Serious and Opportunistic Infections Associated With Treatment of Inflammatory Bowel Diseases.

BACKGROUND & AIMS: The risk of infection associated with tumor necrosis factor antagonists (anti-TNF) and thiopurines (combination therapy) is uncertain. We assessed the risk of serious and opportunistic infections in patients with inflammatory bowel disease (IBD) treated with thiopurine monotherapy, anti-TNF monotherapy, or combination therapy in a large cohort of patients in France. METHODS: We performed a nationwide population-based study of patients (18 years or older) with a diagnosis of IBD in the French national health insurance database; we collected data from January 1, 2009 until December 31, 2014. The risks of serious and opportunistic infections associated with exposure to combination therapy, anti-TNF, and thiopurine monotherapies were compared using marginal structural Cox proportional hazard models adjusted for baseline and time-varying sociodemographic characteristics, medications, and comorbidities. RESULTS: Among the 190,694 patients with IBD included in our analysis, 8561 serious infections and 674 opportunistic infections occurred. Compared with anti-TNF monotherapy, combination therapy was associated with increased risks of serious infection (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.05-1.45) and opportunistic infection (HR, 1.96; 95% CI, 1.32-2.91). Compared with thiopurine monotherapy, anti-TNF monotherapy was associated with increased risks of serious infection (HR, 1.71; 95% CI, 1.56-1.88), mycobacterial infection (HR, 1.98; 95% CI, 1.15-3.40), and bacterial infection (HR, 2.38; 95% CI, 1.23-4.58, respectively). Conversely, anti-TNF monotherapy was associated with decreased risk of opportunistic viral infection compared with thiopurine monotherapy (HR, 0.57; 95% CI, 0.38-0.87). CONCLUSIONS: In a nationwide cohort study of patients with IBD in France, we found heterogeneity in risks of serious and opportunistic infections in patients treated with immune-suppressive regimens. These should be carefully considered and weighed against potential benefits for IBD treatment in patient management.

Statins for primary prevention of cardiovascular disease and the risk of acute kidney injury.

PURPOSE: To investigate the risk of acute kidney injury (AKI) in subjects initiating statin therapy for primary prevention of cardiovascular disease (CVD). METHODS: A nationwide cohort study using French hospital discharge and claims databases was performed, studying subjects from the general population aged 40 to 75 years in 2009, with no history of CVD and no lipid-lowering drugs during the preceding 3-year period, followed for up to 7 years. Exposure to statins (type, dose, and time since first use) and to other drugs for CVD risk was assessed. The primary outcome was hospital admission for AKI. RESULTS: The cohort included 8 236 279 subjects, 818 432 of whom initiated a statin for primary prevention. During 598 487 785 person-months exposed to statins, 700 events were observed, corresponding to an incidence of AKI of 4.59 per 10 000 person-years (7.01 in men, 3.01 in women). AKI mainly occurred in the context of organ failure, sepsis, and genitourinary disease. A 19% increased rate of AKI (hazard ratio = 1.19, 95%CI: 1.08-1.31) was observed in men exposed to statins, whereas no increase in the overall risk of AKI was observed in women. However, exposure to high-potency statins was associated with a 72% to 116% increased risk in both genders and a dose-effect relationship observed for rosuvastatin and atorvastatin. No temporal pattern of occurrence nor interaction with drugs for CVD risk was observed. CONCLUSIONS: Although the overall risk of AKI appears moderately increased, more attention should be paid to renal function in subjects taking statins for primary prevention both in clinical practice and from a research viewpoint.

Risk of hospitalisation and death related to baclofen for alcohol use disorders: Comparison with nalmefene, acamprosate, and naltrexone in a cohort study of 165 334 patients between 2009 and 2015 in France.

PURPOSE: Baclofen is widely used off-label for alcohol use disorders (AUD) in France, despite its uncertain efficacy and safety, particularly at high doses. This study was designed to evaluate the safety of this off-label use compared to the main approved drugs for AUD (acamprosate, naltrexone, nalmefene). METHODS: This cohort study from the French Health Insurance claims database included patients, aged 18 to 70 years, with no serious comorbidity (assessed by the Charlson score) initiating baclofen or approved drugs for AUD between 2009 and 2015. The risk of hospitalisation or death associated with baclofen, at variable doses over time (from low doses <30 mg/day to high doses ≥180 mg/day), compared to approved drugs, was evaluated by a Cox model adjusted to sociodemographic and medical characteristics. RESULTS: The cohort included 165 334 patients, 47 614 of whom were exposed to baclofen. Patients exposed to baclofen differed from those treated with approved drugs in terms of sociodemographic and medical characteristics (more females, higher socioeconomic status, fewer hospitalisations for alcohol-related problems), but these differences tended to fade at higher doses of baclofen. Baclofen exposure was significantly associated with hospitalisation (hazard ratio [HR] = 1.13 [95%CI: 1.09-1.17]) and death (HR = 1.31 [95%CI: 1.08-1.60]). The risk increased with dose, reaching 1.46 [1.28-1.65] for hospitalisation and 2.27 [1.27-4.07] for death at high doses. Similar results were in patients with a history of hospitalisation for alcohol-related problems. CONCLUSIONS: This study raises concerns about the safety of baclofen for AUD, particularly at high doses, with higher risks of hospitalisation and mortality than approved drugs.

Development of an algorithm to identify pregnancy episodes and related outcomes in health care claims databases: An application to antiepileptic drug use in 4.9 million pregnant women in France.

PURPOSE: Access to claims databases provides an opportunity to study medication use and safety during pregnancy. We developed an algorithm to identify pregnancy episodes in the French health care databases and applied it to study antiepileptic drug (AED) use during pregnancy between 2007 and 2014. METHODS: The algorithm searched the French health care databases for discharge diagnoses and medical procedures indicative of completion of a pregnancy. To differentiate claims associated with separate pregnancies, an interval of at least 28 weeks was required between 2 consecutive pregnancies resulting in a birth and 6 weeks for terminations of pregnancy. Pregnancy outcomes were categorized into live births, stillbirths, elective abortions, therapeutic abortions, spontaneous abortions, and ectopic pregnancies. Outcome dates and gestational ages were used to calculate pregnancy start dates. RESULTS: According to our algorithm, live birth was the most common pregnancy outcome (73.9%), followed by elective abortion (17.2%), spontaneous abortion (4.2%), ectopic pregnancy (1.1%), therapeutic abortion (1.0%), and stillbirth (0.4%). These results were globally consistent with French official data. Among 7 559 701 pregnancies starting between 2007 and 2014, corresponding to 4 900 139 women, 6.7 per 1000 pregnancies were exposed to an AED. The number of pregnancies exposed to older AEDs, comprising the most teratogenic AEDs, decreased throughout the study period (-69.4%), while the use of newer AEDs increased (+73.4%). CONCLUSIONS: We have developed an algorithm that allows identification of a large number of pregnancies and all types of pregnancy outcomes. Pregnancy outcome and start dates were accurately identified, and maternal data could be linked to neonatal data.

Is There a Cardiotoxicity Associated With Metallic Head Hip Prostheses? A Cohort Study in the French National Health Insurance Databases.

BACKGROUND: There are four distinguishable types of THA devices in wide use, as defined by the femoral and acetabular bearing surfaces: metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), metal-on-metal (MoM), and ceramic-on-ceramic (CoC). Metallic head THAs (MoP and MoM) can potentially induce cardiac toxicity because cobalt species, generated at the head-neck trunnion, and in the case of MoM devices, at the articular surface as well, can be absorbed systemically. However, studies have provided inconsistent results. QUESTIONS/PURPOSES: The purpose of this study was to assess the risk of dilated cardiomyopathy (DCM) or heart failure (HF) associated with metallic head THAs using data from the French national health insurance databases. METHODS: Between 2008 and 2011 in France, 399,968 patients ≥ 55 years had a first THA. A total of 127,481 were excluded after we applied the exclusion criteria regarding arthroplasty and 17,137 as a result of a history of DCM/HF, recorded in the French national health insurance reimbursement databases, between January 1, 2006, and the date of inclusion. The final cohort included 255,350 individuals (43% men; mean age 72 ± 9 years). Of them, 93,581 (37%) had been implanted with MoP, 58,095 (23%) with CoP, 11,298 (4%) with MoM, and 92,376 (36%) with CoC THAs. Patients were followed until December 2015. Patients with incident DCM/HF were identified by a new entitlement to the long-term disease scheme or a first hospitalization with a diagnosis of DCM or HF. MoP and CoP THAs are generally implanted in old patients, whereas MoM and CoC are mostly indicated in young, active male patients. Thus, to consider the specific indications of the bearing couples, analyses were separately performed in two distinct subcohorts, one comprising patients with MoP or CoP and one comprising patients with MoM or CoC THA. In each subcohort, the DCM/HF risk was compared between patients with metallic head versus nonmetallic head THAs (MoP versus CoP, MoM versus CoC). Hazard ratios (adjusted HRs) of incident DCM/HF were estimated using Cox models adjusted for baseline sex, age, THA characteristics (fixation technique with cement, use of a modular femoral neck), and comorbidities at baseline. Cox models were stratified by sex and age. RESULTS: The crude incidence of DCM/HF per 100 person-years was 2.4 in patients with MoP, 1.8 with CoP, 1.2 with MoM, and 1.1 with CoC THAs. Overall, metallic head THAs were associated with a slight increase in DCM/HF risk (MoP versus CoP: adjusted HR, 1.08; 95% confidence interval [CI], 1.05-1.12; p < 0.001; MoM versus CoC: adjusted HR, 1.11; 95% CI, 1.03-1.19; p = 0.007). In the MoM-CoC subcohort, the risk tended to be more pronounced with MoM versus CoC THAs in women (MoM versus CoC: adjusted HR, 1.20; 95% CI, 1.07-1.35; p = 0.002) and patients aged ≥ 75 years (MoM versus CoC: adjusted HR, 1.16; 95% CI, 1.04-1.29; p = 0.009). CONCLUSIONS: Metallic head THAs were associated with a slightly increased DCM/HF risk, especially with MoM in women and older patients. Some caveats should be mentioned: severity of DCM or HF was not available and residual confounding cannot be ruled out despite considering many covariates. Our findings suggest that cardiac function should be regularly monitored in patients with metallic head THAs. Further investigations should be planned on large international cohorts. LEVEL OF EVIDENCE: Level III, therapeutic study.