Major adverse cardiovascular events in patients with atopic dermatitis treated with oral Janus kinase inhibitors: a systematic review and meta-analysis.

BACKGROUND: On the basis of safety data for patients with inflammatory rheumatism or inflammatory bowel disease, treatment with Janus kinase (JAK) inhibitors (JAKi) has been linked to the occurrence of major adverse cardiovascular events (MACE). However, these inflammatory diseases are proatherogenic; in contrast, patients with atopic dermatitis (AD) do not usually have a high cardiovascular (CV) comorbidity burden. OBJECTIVES: To perform a systematic review and meta-analysis of MACE in patients with AD treated with JAKi. METHODS: We systematically searched PubMed, Embase, Cochrane Library and Google Scholar from their inception to 2 September 2022. Cohort studies, randomized controlled trials and pooled safety analyses providing CV safety data on patients taking JAKi for AD were selected. We included patients aged ≥ 12 years. We built a 'controlled-period' cohort (n = 9309; 6000 exposed to JAKi and 3309 exposed to comparators) and an 'all-JAKi' cohort (n = 9118 patients exposed to a JAKi in any of the included studies). The primary outcome was a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death. The broader secondary MACE outcome encompassed ACS, stroke (whether ischaemic or haemorrhagic), transient ischaemic attack and CV death. The frequency of primary and secondary MACE was assessed in both cohorts. A fixed-effects meta-analysis using the Peto method was used to calculate the odds ratio (OR) for MACE in the 'controlled-period' cohort. Evaluation of the risk of bias was done using the Cochrane risk-of-bias tool (version 2). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Eight per cent of the records identified initially met the selection criteria, corresponding to 23 records included in the 'all-JAKi' cohort. Patients had been exposed to baricitinib, upadacitinib, abrocitinib, ivarmacitinib, placebo or dupilumab. Four primary events (three with JAKi and one with placebo) and five secondary events (four with JAKi and one with placebo) occurred among 9309 patients in the 'controlled-period' cohort (MACE frequency 0.04% and 0.05%, respectively). Eight primary events and 13 secondary events occurred among 9118 patients in the 'all-JAKi' cohort (MACE frequency 0.08% and 0.14%, respectively). The OR for primary MACE in patients with AD treated with JAKi vs. placebo or dupilumab was 1.35 (95% confidence interval 0.15-12.21; I2 = 12%, very low certainty of evidence). CONCLUSIONS: Our review highlights rare cases of MACE among JAKi users for AD. JAKi may have little-to-no effect on the occurrence of MACE in patients with AD vs. comparators, but the evidence is uncertain. Real-life long-term population-level safety studies are needed.

Real-World Treatment Patterns Among French Patients With Metastatic Castration-Resistant Prostate Cancer Under Abiraterone or Enzalutamide.

PURPOSE: Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation. METHOD: Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up. RESULTS: Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients. CONCLUSION: Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

Pharmacokinetic Interactions Between Abiraterone, Apalutamide, Darolutamide or Enzalutamide and Antithrombotic Drugs: Prediction of Clinical Events and Review of Pharmacological Information.

PURPOSE: Abiraterone, apalutamide, darolutamide and enzalutamide are second-generation hormone therapies used for advanced prostate cancer; the majority of patients receiving these treatments are elderly, poly-medicated patients. Since their first market authorizations, their pharmacokinetic (PK) characteristics are increasingly well known. A potential risk of drug-drug interaction (DDI), especially with cardiovascular drugs, needs to be considered. In the case of antithrombotics, treatment imbalance can lead to severe consequences. OBJECTIVES: To describe PK profiles of hormone therapies and antithrombotics and to predict DDIs and potentially related clinical events. METHODS: PK profiles (CYP450 and P-gp substrate, inducer or inhibitor) are described by cross-referencing data sources (summary of product characteristics, European public assessment reports, PubMed database, Micromedex®, etc.); a description of the potential interactions with anti-cancer drugs for each DDI and related clinical events is provided. We discuss management recommendations, including those set out in international guidelines. RESULTS: Antithrombotics are mainly metabolized by CYP 2C9, 2C19 or 3A4. For abiraterone (CYP 2C8, 2D6 inhibitor) and darolutamide (CYP 3A4 inducer), no interaction was identified with antithrombotics. For apalutamide (CYP 2C9, 2C19, 3A4 and P-gp inducer) and enzalutamide (CYP 2C9, 2C19, 3A4 inducer and P-gp inhibitor), several PK interactions were identified with antithrombotics, which could lead to various clinical events (haemorrhage or thromboembolism). CONCLUSION: Numerous interactions are expected between enzalutamide or apalutamide and antithrombotics, for which management should be deployed on a case-by-case basis. PK and pharmaco-epidemiological studies could shed light on whether or not there are clinically significant events related to DDIs with antithrombotics.

Osteonecrosis of the jaw under palbociclib: A case series description.

INTRODUCTION: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. MATERIALS AND METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. CONCLUSION: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

Contribution of voriconazole N-oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection.

BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient's drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyse risk factors for the patient's concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 µg/ml (1.2; 4.2), 2.1 µg/ml (1.5; 3.0) and 1.0 (0.6; 1.9) for VRC, NOX and the MR, respectively. VRC Cmin <2 µg/ml were associated with a higher MR during the previous visit. MR values >1.15 and <0.48 were determined to be the best predictors for having a VRC Cmin lower than 2 µg/ml and above 5.5 µg/ml, respectively, at the next visit. CONCLUSIONS: Measurement of NOX resulted useful for TDM of patients treated with VRC. The MR using NOX informed interpretation and clinical decision-making and is very interesting for complex patients. VRC phenotyping based on the MR is now performed routinely in our institution. A dosing algorithm has been suggested from these results.

Oral Janus kinase inhibitors and venous thromboembolic events in atopic dermatitis: protocols for a case-time control study and a nested case-control study based on the French national health insurance (SNDS) cohort.

INTRODUCTION: Atopic dermatitis (AD) is a highly prevalent, chronic, inflammatory skin disease. Several orally administered Janus kinase inhibitors (JAKis, including baricitinib, upadacitinib and abrocitinib) have received a marketing authorisation for AD.Clinical trials in rheumatoid arthritis (RA) have flagged up a potential risk of JAKi-induced venous thromboembolic events (VTEs). Accordingly, the summary of product characteristics for a JAKi must mention VTEs as potential adverse drug reactions. In contrast to RA, AD per se is not associated with an elevated risk of VTEs. Assessing this potential risk among patients with AD would shed further light on the putative underlying relationship between JAKis and VTEs.Our research question is to investigate whether JAKi administration increases the risk of VTEs in adults with AD. Our primary objective is to assess the risk of VTEs in adults with AD exposed to JAKis compared to AD adults not exposed to JAKis, and our secondary objective is to evaluate whether JAKi initiation acts as a trigger of VTEs in adults with AD within 3 months. METHODS AND ANALYSIS: Hence, we have designed (1) a nested case-control study and (2) a case-time control study in a cohort of adults with AD with data from the French national health insurance system (2017-2025).Here, we describe the study protocol, our methodological choices and certain novel aspects, including the combined value of the two assumptions and the use of an exhaustive national health insurance database with potentially greater statistical power for studying rare events in the population of patients with AD at a low risk of VTEs (thus limiting the influence of confounding factors). ETHICS AND DISSEMINATION: The protocol has been approved by an independent ethics committee and registered with the French National Data Protection Commission. The study's findings will be published in peer-reviewed scientific journals and presented at international conferences.

Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients.

INTRODUCTION: While pirfenidone and nintedanib have greatly influenced the treatment of idiopathic pulmonary fibrosis (IPF), both drugs have significant early adverse drug reactions (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals. METHODS: We analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January 2011 and January 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems. RESULTS: The 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients. DISCUSSION: Most ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.

Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: A French population-based study on prostate cancer patients.

AIMS: Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. METHOD: Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. RESULTS: Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. CONCLUSION: Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.

The Trigger Tool Method for Routine Pharmacovigilance: A Retrospective Cohort Study of the Medical Records of Hospitalized Geriatric Patients.

OBJECTIVE: The main objective was to assess the feasibility of the trigger tool method for the retrospective detection of adverse drug reactions (ADRs) in the Rennes University Hospital. The secondary objective was to describe the performance of the method in terms of positive predictive values (PPVs) and severity or preventability of ADRs. METHODS: Using the Rennes University Hospital clinical data warehouse, pharmacovigilance experts performed a retrospective review of a random sample of 30 inpatient hospital medical records per month using the triggers "fall" and "delirium" to identify related ADRs among patients 65 years and older in 2018 in the geriatrics department. Using the Z test, we compared the proportion of medical records with a positive (identified) trigger related to an ADR, which were reviewed within 20 minutes using the reference of 50% reviewed within 20 minutes. RESULTS: Among the 355 medical records reviewed, 222 had at least 1 trigger and 98 at least 1 related ADR. Among the 222 positive trigger medical records, 99.6% were reviewed in under 20 minutes (P < 0.001). The pharmacovigilance assessment took 3 months. The PPVs reached 53.9% (46.0%-61.7%) for falls and 21.0% (14.3%-27.5%) for delirium. Among the ADRs, 80% were serious and 53% were preventable. CONCLUSIONS: Given the low PPV of the triggers used and the considerable need for technical and human resources, the trigger tool method cannot be used as a routine tool at the pharmacovigilance center. However, it could be implemented occasionally for specific purposes such as monitoring the impact of risk minimization measures to prevent ADRs.

Changes in prostate cancer screening practice by blood PSA testing between 2011 and 2017, a French population-based study.

OBJECTIVE: The aim of the study was to determine the trend of first blood prostate-specific antigen (PSA) test prescription in France between 2011 and 2017, based on the assumption that prostate cancer (PCa) screening is expected to decline over the years. METHOD: Using a representative sample of the French population from the French Health Insurance database, we identified 50-52-year-old men without PCa and without any blood PSA test in the five years before 2011, 2014 and 2017 (January 1-December 31 of each year). For each of these three years, the primary outcome was the first reimbursement of a blood PSA test. We used a logistic regression model with first blood PSA test as the outcome and year as the main explanatory variable. As secondary objectives, we also identified the prescriber's specialty, the urological consultation frequency, and the number of prostate biopsies in the year after the first blood PSA test reimbursement (only for 2011 and 2014). RESULTS: In 2011, 2014 and 2017, 5 275, 5 792 and 5 887 50-52-year-old men, respectively, were included. The percentage of patients with a first blood PSA test prescription decreased linearly from 2011 to 2017: 15.7% in 2011, 13.2% in 2014, and 12.4% in 2017 (p < .001). Blood PSA testing was mainly prescribed by general practitioners (>95%). The median interval between PSA tests was 13 months in 2011 and 14 months in 2014. Fewer than 10% of men had ≥1 consultation with an urologist during the year after the first blood PSA test. After the first blood PSA test, eight prostate biopsies were performed in 2011 and two in 2014. CONCLUSION: Our results suggest that in France, PCa screening is a primary care issue. Although PCa screening remains controversial and confusion exists about the best practice, our study showed a linear decrease of blood PSA test prescriptions for 50-52-year-old men between 2011 and 2017, although the reason for screening was unknown. As clinical information was not available, additional evidence is needed to determine the real impact of this decrease on the cancer-specific and overall mortality.

Androgen deprivation therapy prescription, blood and bone-density testing in a French population-based study exploring adherence to the French prostate cancer guidelines.

The safety profile of androgen deprivation therapy (ADT) is well known, and cardiovascular and osteoporosis risk factors should be assessed before ADT initiation. In order to examine whether the French Committee of Urologic Oncology Prostate Cancer (PCa) Guidelines were properly followed by clinicians, including urologists, oncologists and radiotherapists, we used a nationwide comprehensive cohort of prostate cancer patients, who were new ADT users in 2011 and were followed-up to 2013. Reimbursements for biological examinations and prescribers were identified, as well as PCa specialist consultations at drug initiation. Our results in this French cohort showed that the proportions of patients resorting to specialized care between one year and 3 months before ADT initiation and in the 6 months following was around 40% for fasting glucose and 30% for lipid assessments. Bone densitometry was performed in approximately 1% of patients. In the 12 months after ADT initiation, 75% of the patients were seen by a urologist and about 47% by an oncologist or a radiotherapist. Overall, there is still room for improvement in terms of ADT monitoring by clinicians and in the information provided to general practitioners and patients regarding the expected adverse effects of this treatment.

Overall Survival Among Chemotherapy-Naive Patients With Castration-Resistant Prostate Cancer Under Abiraterone Versus Enzalutamide: A Direct Comparison Based on a 2014-2018 French Population Study (the SPEAR Cohort).

Abiraterone acetate (ABI) and enzalutamide (ENZ) are considered to be clinically relevant comparators among chemotherapy-naive patients with castration-resistant prostate cancer. No clinical trials comparing overall survival with ABI versus ENZ in a head-to-head approach have been published so far. A few observational studies with low power suggested a potential benefit of ENZ. We used the French National Health Data System to compare overall survival of new users of ABI and ENZ among chemotherapy-naive patients with castration-resistant prostate cancer in 2014-2017, followed through 2018 (the SPEAR cohort, a 2014-2018 cohort study). With an intent-to-treat approach, a survival analysis was performed, estimating hazard ratios for overall survival with the inverse probability weighted Cox model method. Among 10,308 new users, 64% were treated with ABI and 36% with ENZ. The crude mortality rate was 25.2 per 100 person-years (95% confidence interval (CI): 24.4, 26.0) for ABI and 23.7 per 100 person-years (95% CI: 22.6, 24.9) for ENZ. In the weighted analysis, ENZ was associated with better overall survival compared with ABI (hazard ratio = 0.90 (95% CI: 0.85, 0.96) with a median overall survival of 31.7 months for ABI and 34.2 months for ENZ). When restricting to 2015-2017 new users, the effect estimate shifted up to a hazard ratio of 0.93 (95% CI: 0.86, 1.01).

Risk of cardiovascular disease following gonadotropin-releasing hormone agonists vs antagonists in prostate cancer: Real-world evidence from five databases.

Observational studies in prostate cancer (PCa) have shown an increased risk of cardiovascular disease (CVD) following gonadotropin-releasing hormone (GnRH) agonists, whereas randomised-controlled trials have shown no associations. Compared to GnRH agonists, GnRH antagonists have shown less atherosclerotic effects in preclinical models. We used real-world data from five countries to investigate CVD risk following GnRH agonists and antagonists in PCa men. Data sources included cancer registries, primary and secondary healthcare databases. CVD event was defined as an incident or fatal CVD. Multivariable Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using random-effects meta-analysis. Stratified analyses were conducted by history of CVD and age (75 years). A total of 48 757 men were on GnRH agonists and 2144 on GnRH antagonists. There was no difference in risk of any CVD for men on GnRH antagonists and agonists (HR: 1.25; 95% CI: 0.96-1.61; I2 : 64%). Men on GnRH antagonists showed increased risk of acute myocardial infarction (HR: 1.62; 95% CI: 1.11-2.35; I2 : 0%) and arrhythmia (HR: 1.55; 95% CI: 1.11-2.15, I2 : 17%) compared to GnRH agonists. Having a history of CVD was found to be an effect modifier for the associations with some CVD subtypes. Overall, we did not observe a difference in risk of overall CVD when comparing GnRH antagonists with agonists-though for some subtypes of CVD we noted an increased risk with antagonists. Further studies are required to address potential confounding caused by unadjusted variables such as severity of CVD history and PCa stage.

[Adverse drug reactions profiles for abiraterone and enzalutamide: A pharmacovigilance descriptive analysis]. / Profils d'effets indésirables sous abiratérone et enzalutamide : analyse descriptive des données de la base nationale de pharmacovigilance.

OBJECTIVE: The aim of this study was to describe the profile of adverse drug reactions (ADRs) observed with abiraterone and enzalutamide, based on cases registered in the French regional pharmacovigilance centres to identify potential pharmacovigilance signals. METHODS: We extracted from the French pharmacovigilance database all cases of ADRs or drug interactions involving abiraterone or enzalutamide from the time they market authorization date until December 31st, 2017. Signal detection results have been transmitted by the French Agency for Health Products (ANSM). The data were compared with those of the risk management plans for each drug and the literature. RESULTS: Among the 233 observations analyzed, nearly 62% involved abiraterone as a suspect drug and 38% involved enzalutamide; only 1 case involved both drugs. The ADRs profile is different between the drugs. Abiraterone is mostly associated with expected cardiac diseases (heart failure, and QT prolongation), expected with the drug. Also described, several cases of hepatotoxicity have been reported, however some cases with fatal outcome suggest that despite a follow-up of the liver function tests, it is difficult to anticipate this risk. Signals concerning acute renal failure and ischemic stroke have arisen. Enzalutamide is more particularly associated with various neurological disorders (convulsions, hallucinations, fatigue, and memory impairment) expected with the drug. While ischemic heart disease is also expected, signals of heart failure and atrial fibrillation have arisen. A potential hepatotoxicity of the molecule is discussed because of cases of cholestatic hepatitis. CONCLUSION: The analysis of the French pharmacovigilance database cases allows to confirm an expected and monitored risk profile in the risk management plan for both drugs. Several signals have arisen, some of which will be investigated through a pharmacoepidemiology study.

[Drug interactions with colchicine, are the contraindications well respected? A descriptive study of prescriptions in Brittany based on data from the French National Health Data System]. / Interactions médicamenteuses avec la colchicine, les contre-indications sont-elles bien respectées ? Étude descriptive des prescriptions en Bretagne à partir des données de l'Assurance maladie.

Although the French Health Authority "ANSM" widely informed healthcare professionals about the risk factors for colchicine overdose, its impact and suitable dosages, cases of potentially fatal preventable overdose continue to be reported in France. Using the French National Health Insurance of the Brittany area, we quantified the proportion of prescriptions presenting an absolute drug contraindication (CI) to colchicine (according to the ANSM Drug Interactions "Thesaurus") and its impact in terms of hospitalisation. Between 2013 and 2016, nearly 77,000 patients (mean age, 66±15 years) were reimbursed for at least one colchicine-based drug (Colchimax®, Colchicine Opocalcium®), representing nearly 205,000 prescriptions. General practitioners were the main prescribers (93%). Among the prescriptions, 0.5% had absolute IC with colchicine: in 51% of cases with pristinamycin, followed by azithromycin (15.6%), clarithromycin (15.2%) and roxithromycin (11.9%). In the 15 days following the simultaneous prescription of colchicine and a contraindicated drug, 53 hospital stays were recorded. However, using only the primary diagnosis of hospitalization was not sufficiently relevant to conclude that there was no potential overdose of colchicine. Over the study period, the Thesaurus contained inconsistencies that confused clinicians: mention of absolute IC with colchicine in the "macrolide" and "pristinamycin" sections but not in the sections of 'potent CYP inhibitors' or macrolide class molecules. Overall, very few prescriptions included absolute IC with colchicine. Regular training and information of healthcare professionals remains essential to limit the risk of colchicine overdose and to remind them of the potentially fatal consequences.

Major bleeding risk associated with oral anticoagulant in real clinical practice. A multicentre 3-year period population-based prospective cohort study.

AIMS: The objective was to compare major bleeding risk of direct oral anticoagulants (DOACs; per type and dose) with vitamin K antagonists (VKAs), irrespective of indication, using real-world data. METHODS: A population-based prospective cohort study, using the French national health data system (SNIIRAM), identified 47 469 adults living within 5 well-defined geographical areas, who were new users of oral anticoagulants in the period 2013-2015: 20 205 VKA users, 19 579 rivaroxaban users, 4225 dabigatran users and 3460 apixaban users. From all emergency departments within these areas, clinical data for all adults referred for bleeding was collected and medically validated. The databases were linked for common key variables. The main outcome measure was major bleeding: intracranial haemorrhage, major gastrointestinal bleeding and other major bleeding events. Hazard ratios were derived from adjusted Cox proportional hazard models. We used propensity score weighting as a sensitivity analysis, with separate analyses according to indications (atrial fibrillation or venous thromboembolism). RESULTS: Compared to VKAs, high and low-dose DOACs were associated with a reduced risk of intracranial haemorrhage (adjusted hazard ratio 0.55, 95% confidence interval 0.37-0.82 and 0.54, 0.26-1.12 respectively), and a reduced risk of other major bleeding events (0.41, 0.29-0.58 and 0.41, 0.22-0.79 respectively), irrespective of duration and indication. Neither DOAC dose evidenced any significant difference from VKAs in terms of risk of major gastrointestinal bleeding. CONCLUSION: There is a clear benefit of using DOACs with regard to intracranial haemorrhage. The study provides new insight into major gastrointestinal and other major bleeding events.

[Pitch perception modification due to antiepileptics: A literature and pharmacovigilance databases review]. / Modification de la perception des sons sous antiépileptiques : une revue de la littérature et des bases de pharmacovigilance.

Pitch perception modifications are among the little-known adverse effects observed with antiepileptics, mainly affecting patients treated with carbamazepine (CBZ). Here, we describe an original French case of pitch perception modification due to CBZ resulting in perfect pitch loss. We also reviewed the literature as well as French and world health organisation global pharmacovigilance database. The case report concerns a 22-year-old patient with perfect pitch with untreated left temporal partial epilepsy. Following a generalized seizure, the introduction of CBZ prolonged release (200mg twice a day) is decided. As soon as CBZ is introduced, the patient notices a change in pitch perception, about a semitone lower. This adverse effect persisted despite a gradual decrease in doses. The patient reported a total recovery of his perfect pitch when CBZ stopped completely 11 years later. In the French pharmacovigilance database, only one other case of pitch perception modification under CBZ was recorded (no cases were found with oxcarbazepine, lacosamide, sodium valproate, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, ethosuximide, vigabatrine, felbamate, gabapentin, tiagabine and topiramate). In the literature, 27 cases of pitch perception modification have been published with CBZ, 1 case with oxcarbazepine and 1 case with lacosamide. Pitch perception modification is a very rare adverse effect of CBZ, oxcarbazepine and lacosamide, identified in the literature mainly in the Japanese population, in experienced musicians. A rapid onset after the introduction of treatment, a complete resolution of symptoms, in most cases upon discontinuation of treatment, is observed, with no sequelae reported. Due to the impact on quality of life, especially in patients whose profession is related to music, knowledge of this adverse event seems important to evoke this diagnosis.

Prescription patterns of first- and second-generation antipsychotic drugs in the French population.

This study assessed in depth the use of first- and second-generation antipsychotic (FGAP/SGAP) drugs in France. A 1/97th random sample of beneficiaries affiliated to the French Health Insurance system-Echantillon Généraliste des Bénéficiaires (EGB)-was used: (i) 621 662 persons in 2015 among which 11 319 had an antipsychotic (AP) prescription; (ii) a sample of first AP prescriptions concerning 5 935 patients in 2013 and 2014 (no AP in the last 6 months of 2012) for whom diagnosis was available in 40% of cases. In 2015, AP prevalence was 21.9/1 000. SGAP/FGAP ratio was 1.02. Long-lasting prescriptions were rare: 1.79/1 000 for FGAP and 1.38/1 000 for SGAP. FGAP first prescriptions were higher than SGAP for each age class, except for <18 aged patients; 2.85% had both generations; 50.7% of the patients had another psychotropic. GPs prescribed more FGAPs than SGAPs, psychiatrists prescribed more SGAPs and hospital-based practitioners prescribed both generations equally, and these patterns changed across age ranges: For the elderly, GPs are the more frequent prescribers. SGAP/FGAP ratio is different by diagnostic categories. In France, FGAPs are largely prescribed by GPs mainly for the elderly, but young and adult patients are concerned as well. Inappropriate antipsychotic consumption through off-label use, which adds to the co-prescription, especially in vulnerable population groups, mainly concerns FGAP prescriptions by GPs who do not have psychiatric training and limited contact with psychiatrists. Attention should then be brought to the regulatory advisory agencies in order to better inform and train the prescribers.

The Changing Face of Artificial Urinary Sphincter Use in France: The Future is Female.

Analyzing concurrently data from the manufacturer and from a national comprehensive administrative claim database (PMSI)we found that, overall, the total number of AUS implanted (male+female) increased from 2012 to 2017 (+8.8%). This growth was driven by a strong increase in the number of female implants from 2015 to 2017 (+28.9%). Meanwhile, the number of AUS implanted in male patients remained roughly stable and the total number of anti-incontinence surgery in men (slings+AUS) decreased steadily over the period studied.

Early discharge in selected patients with low-grade renal trauma.

INTRODUCTION: The aim of this study was to assess whether early discharge could be non-inferior to inpatient management in selected patients with low-grade renal trauma (AAST grades 1-3). MATERIALS AND METHODS: A retrospective national multicenter study was conducted including all patients who presented with renal trauma at 17 hospitals between 2005 and 2015. Exclusion criteria were iatrogenic and AAST grades 4 and 5 trauma, non-conservative initial management, Hb < 10 g/dl or transfusion within the first 24 h, and patients with concomitant injuries. Patients were divided into two groups according to the length of hospital stay: ≤ 48 h (early discharge), and > 48 h (inpatient). The primary outcome was "Intervention" defined as any interventional procedure needed within the first 30 days. A Stabilized Inverse Probability of Treatment Weighting (SIPTW) propensity score based binary response model was used to estimate risk difference. RESULTS: Out of 1764 patients with renal trauma, 311 were included in the analysis (44 in the early discharge and 267 in the inpatient group). In the early discharge group, only one patient required an intervention within the first 30 days vs. 10 in the inpatient group (3.7% vs. 5.2%; p = 0.99). Adjusted analysis using SIPTW propensity score showed a risk difference of - 2.8% [- 9.3% to + 3.7%] of "interventions" between the two groups meeting the non-inferiority criteria. CONCLUSION: In a highly selected cohort, early discharge management of low-grade renal trauma was not associated with an increased risk of early "intervention" compared to inpatient management. Further prospective randomized controlled trials are needed to confirm these findings.