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The risk of cancer associated with persons with multiple sclerosis (pwMS) prescribed with disease modifying therapies (DMTs) is not well established. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database: VigiBase®. All consecutive reports of DMTs prescribed to pwMS (alemtuzumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon-β, natalizumab, ocrelizumab, and teriflunomide), and their serious adverse event cases were eligible, excluding those reporting immunosuppressant DMTs used as anticancer therapies. The primary outcome was the multivariate odds ratio of cancer reporting (r-OR) for DMTs prescribed to pwMS after imputation of missing data. There were 5966 cancer cases from 240,993 reports of DMTs prescribed to pwMS. After adjustments on age, sex, and geographical region, natalizumab (r-OR 1.74, 95% CI 1.63–1.87), interferon-β (r-OR 1.39, 95% CI 1.30–1.49), dimethyl fumarate (r-OR 1.35, 95% CI 1.25–1.46), and fingolimod (r-OR 1.15, 95% CI 1.06–1.24) were significantly associated with a greater cancer reporting, whereas alemtuzumab, glatiramer acetate, ocrelizumab, and teriflunomide were not, in the disproportionality analysis. As exploratory analyses, upper aerodigestive tract, breast, urinary including the male genitourinary tract, and nervous system cancers were associated with natalizumab, interferon-β, and dimethyl fumarate. Fingolimod was only associated with skin cancer types. Cancer cases reporting these four DMTs prescribed to pwMS were younger in age than for non-pwMS drugs in the VigiBase® (p

Summary Background Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO's pharmacovigilance database (VigiBase). Methods We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov . If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov , publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov , NCT04326023 . Findings For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13–6·14], p=0·026) with no between-study heterogeneity (I2=0%, χ2 p=0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50–1·07; I2=0%, χ2 p=0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26–0·85; I2=0%, χ2 p=1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6–17·4; n=96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4–29·2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. Interpretation PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. Funding None.

Aim: Mitochondrial dysfunction (MD) has been associated with poor outcomes after coronary artery bypass graft surgery. Methods: 58 consecutive patients from the ALDO-POAF Study (NCT02814903) were prospectively included. Plasma aldosterone was assessed at the time of the preoperative consultation and mitochondrial functional studies were performed using atrial appendage tissue collected during surgery. Results: Patients with the highest preoperative plasma aldosterone level had a lower mitochondrial respiratory chain functioning and a lower calcium retention capacity. Chronic kidney disease, patient’s age and preoperative high-aldosterone were independent predictors of MD in multivariate analysis. Conclusion: These exploratory data support the use of preventive strategies targeting aldosterone and/or mineralocorticoid receptor activation, in order to prevent perioperative MD and associated poor outcomes.

An increase in left ventricular volumes between baseline and follow-up imaging is the main criteria for the quantification of left ventricular remodelling (LVR) after ST-elevation myocardial infarction (STEMI), but without consensual definition. We aimed to review the criteria used for the definition of LVR based on cardiac magnetic resonance imaging (CMR) in STEMI patients. A systematic literature search was conducted using MEDLINE and the Cochrane Library from January 2010 to August 2019. Thirty-seven studies involving 4209 patients were included. Among these studies, 30 (81%) used a cut-off value for defining LVR, with a pooled LVR prevalence estimate of 22.8%, 95% CI [19.4-26.7%] and a major between-study heterogeneity (I2 = 82%). The seven remaining studies (19%) defined LVR as a continuous variable. The definition of LVR using CMR following STEMI is highly variable, among studies including highly selected patients. A 20% increase or a 15% increase in left ventricular volumes between a baseline and a follow-up CMR imaging were the two most common criterion (13 [35%] and 9 [24%] studies, respectively). The most frequent LVR criterion was a 20% increase in end-diastolic volumes or a 15% increase in end-systolic volumes. A composite cut-off value of a 12 to 15% increase in end-systolic volume and a 12 to 20% increase in end-diastolic volume using a follow-up CMR imaging 3 months after STEMI might be proposed as a consensual cut-off for defining adverse LVR for future large-sized, prospective studies with serial CMR imaging and long-term follow-up in unselected patients.

BackgroundClozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database.MethodsWe performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report.ResultsOf the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75–10.77) and leukaemia (aROR 3.54, 95% CI 2.97–4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2–9.9) for malignant lymphoma and 2.5 years (IQR 0.6–7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association.ConclusionsClozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

Background Patients with cancer admitted for an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) represent a growing and high-risk population. The influence of co-existing cancer on mortality remains unclear in such patients. We aimed to assess the impact of cancer on early and late, all-cause and cardiac mortality in the setting of ACS and/or PCI. Methods We performed a systematic review and meta-analysis of studies comparing outcomes of patients with and without a history of cancer admitted for ACS and/or PCI. Results Six studies including 294,528 ACS patients and three studies including 39,973 PCI patients were selected for our meta-analysis. Patients with cancer had increased rates of in-hospital all-cause death (RR 1.74 [1.22; 2.47]), cardiac death (RR 2.44 [1.73; 3.44]) and bleeding (RR 1.64 [1.35; 1.98]) as well as one-year all-cause death (RR 2.62 [1.2; 5.73]) and cardiac death (RR 1.89 [1.25; 2.86]) in ACS studies. Rates of long term all-cause (RR 1.96 [1.52; 2.53]) but not cardiac death were higher in cancer patients admitted for PCI. Conclusion Cancer patients represent a high-risk population both in the acute phase and at long-term after an ACS or PCI. The magnitude of the risk of mortality should however be tempered by the heterogeneity among studies. Early and long term optimal management of such patients should be promoted in clinical practice.

Importance In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor–associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed. Observations Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte–associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis. Conclusion and Relevance This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.

Introduction : La notification spontanee des effets indesirables medicamenteux (EIMs) est un des piliers de la surveillance en post-AMM. Une des principales limites de cette derniere concerne la qualite de l’information de ces notifications.L’objectif principal de cette etude etait d’evaluer l’informativite des observations d’EIMs enregistrees dans la Base Nationale de PharmacoVigilance (BNPV) a partir des declarations des medecins generalistes (MGs). L’objectif secondaire etait d’identifier les facteurs associes a une declaration complete.Methode : Toutes les observations d’EIMs declarees en France, en 2015, par les MGs ont ete extraites. Apres analyse du contenu de ces declarations (EIM, date d’apparition, description clinique, medicament impute, etc.), l’informativite etait analysee a partir de plusieurs criteres obligatoires (âge, genre, EIM et medicament(s) suspecte(s)) et facultatifs (antecedents medicaux, medicaments concomitants, evolution de la symptomatologie et examens complementaires) ; cela a permis de classifier les declarations en « bien renseignee », « moyennement renseignee » et « mal renseignee ».Resultats : Durant l’annee 2015, la BNPV comportait 3 020 declarations realisees par les MGs francais. Seulement 16,4 % des declarations de pharmacovigilance rapportees etaient « bien renseignees ». Les criteres les moins bien documentes etaient les medicaments concomitants (41,4 %) et les examens complementaires (37,4 %). Les observations completes etaient associees a la gravite des cas (OR = 3,02 [IC 95 % 2,44 ; 3,23], p

Monoclonal antibodies are therapeutic monoclonal Ig that act by highly specific binding to their target antigen and by interacting with the immune system. Their side effects are mainly related to their mechanism of action. The most frequent adverse effects are infusion reactions. Post-marketing surveillance is essential for identifying adverse reactions and improving knowledge of their mechanism of action.

Background and aim Evidences suggest that androgen deficiency is associated with sudden cardiac death (SCD). Our purpose was to analyse some electrocardiographic (ECG) markers of repolarization phase in hypogonadal patients either at baseline or after testosterone replacement therapy (TRT). Patients and Methods Baseline and after 6 months of testosterone replacement therapy, 14 hypogonadal patients and 10 age-matched controls underwent a short-term ECG recordings at rest and immediately after a maximal exercise test. The following ECG parameters have been collected: QTe (the interval between the q wave the end of T wave), QTp (the interval between the q wave and the peak of T wave), and Te (the interval between the peak and the end of T wave). Results At baseline, in the hypogonadal patients, corrected QTe and QTp values were longer at rest than in the controls at rest (p < 0.05), whereas, during the recovery phase, only the QTp remained significantly longer (p < 0.05). After TRT, hypogonadal patients showed an improvement only in Te (p < 0.05). Conversely, any difference between hypogonadal patients and control subjects was found with respect to the markers of temporal dispersion of repolarization phases, except for a worse QTp → Te coherence (p = 0.001) obtained during the recovery phase. Conclusions In conclusion, at rest, hypogonadal patients suffer from a stable increase in the myocardial repolarization phase without an increase in its temporal dispersion and, hence, the SCD risk seems to be low.

Drug-induced hypertension was described with several pharmacological classes, especially with serotonin reuptake inhibitors (SRIs). However, this link has remained controversial: the French summary of product characteristics specify a risk of hypertension only with paroxetine and sertraline. To identify a possible class effect common to all SRIs, our study investigated the reports of hypertension associated with SRIs in two pharmacovigilance databases. Two different types of investigations were performed: (i) a comparative study in VigiBase® , which is the World Health Organization (WHO) pharmacovigilance database (PVDB), from where notifications of hypertension with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were extracted. The relationship between the suspected SRIs and the occurrence of hypertension was assessed by calculating reporting odds ratio (ROR) in a case/non-case design; (ii) a descriptive study of hypertension reports associated with SRIs in the French pharmacovigilance database (FPVDB). In VigiBase® , 14 824 notifications of SRI-induced hypertension (2.5%) were identified (mean age 54.3 years, mainly women 69.1%). Among them, 3 879 (26.2%) were associated to sertraline; 3 118 (21.0%) to fluoxetine; 2 725 (18.4%) to paroxetine; 2 570 (17.3%) to citalopram; 2 295 (15.5%) to escitalopram; and 237 (1.6%) to fluvoxamine. A significant ROR value was found with all six SRIs (ROR range from 1.16 to 1.92). In the FPVDB, 24 reports of hypertension were found with all six SRIs used at standard doses, mainly in women (66.7%) with a mean age of 57.8 years and a median time of onset of 6 days. In 10 cases (42%), patients had a history of hypertension. This study, performed in real conditions of life, shows a significant pharmacovigilance safety signal between the use of SRIs and the development or worsening of hypertension.

Dear Editor, Dupilumab is a human monoclonal antibody that blocks the shared receptor unit for interleukin (IL)-4 and IL-13, and is approved in several indications, including moderate-to-severe atopic dermatitis (AD). According to a recent meta-analysis dupilumab treatment versus placebo resulted in a significant increase in the number of patients who achieved Eczema Area and Severity Index-75 (Rate-Ratio 3.09; 95% CI 2.45-3.89) in different ethnical populations.

Aims The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. Methods and results We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56–12.50, P Conclusion In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis.

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OBJECTIVE The literature supporting the role of a specific drug in the onset of drug-induced antineutrophil cytoplasmic antibody-associated vasculitis (AAV) mainly relies on case reports or short series and implicates old treatments. The advent of new treatments may have modified the epidemiology of these adverse drug reactions. This study was undertaken to update the list of drugs associated with AAV by using a pharmacovigilance-based data mining approach. METHODS We collected data on adverse drug reactions reported using the Medical Dictionary for Regulatory Activities preferred term "anti-neutrophil cytoplasmic antibody positive vasculitis" up to November 2020 from the World Health Organization pharmacovigilance database (VigiBase). For each retrieved drug, a case-noncase analysis was performed, and disproportionate reporting was calculated by using the information component (IC). A positive IC025 value, which is the lower end of the 95% credibility interval, was considered significant. RESULTS A total of 483 deduplicated individual case safety reports of drug-induced AAV involving 15 drugs with an IC025 >0 were retrieved. Of the individuals with drug-induced AAV for whom data on sex were available (n = 371), 264 (71.2%) were women. The median age at onset of drug-induced AAV was 62 years (quartile 1 [Q1]-Q3 45-72 years), and the median time from the introduction of the suspected drug to the onset of drug-induced AAV was 9 months (Q1-Q3 1-36 months). Drug-induced AAV was considered serious in 472 (98.1%), and was fatal in 43 (8.9%), of 481 cases. The drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron, and nintedanib. CONCLUSION Our findings strengthen the evidence of an association of AAV with previously suspected drugs, but also identify 3 new drugs that may cause drug-induced AAV. Particular attention should be given to these drugs by prescribers and in experimental studies.

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Introduction: Immune checkpoint inhibitor (ICI)-myocarditis is a new syndrome with estimated 50% mortality. Similar to acute cellular rejection (ACR), it is pathologically characterized by lymphocytic infiltration. We aimed to characterize the electrocardiograph features of ICI-myocarditis, compare them to ACR, and evaluate their association with adverse outcome. Methods: Presenting ECG of 130 cases of ICI-myocarditis were collected from a multicenter network spanning 12 countries and compared to 50 cases of ACR. ECG were quantified and interpreted by two blinded cardiologists. 53 patients with ICI-myocarditis had baseline ECG available for comparison via paired univariate analysis. Cox models correcting for age and sex determined association with a composite outcome of life-threatening arrhythmia or myocarditis-related death. Results: ICI-myocarditis patients had average age of 68(58-76), were 61.2% male, and 64.8% had prior cardiovascular disease. QRS prolongation (26% vs 13%, p=0.008), conduction disorders (67% vs 44%, p=0.007) such as left bundle branch block (LBBB) (18% vs 4% p=0.008), ST/T wave changes (50% vs 24%, p=0.004), and PVCs (16% vs 6%, p=0.020) were more prevalent on presenting ECG compared to baseline. ICI-myocarditis showed more PVCs (16% vs 2%, p=0.011) and less ST/T wave changes (41% vs 66%, p=0.002) when compared to ACR. On multivariate analysis, the combined outcome of life-threatening arrhythmia or myocarditis-related death was associated with pathological Q waves (HR=3.60 (1.78-7.27) p Conclusions: ICI-myocarditis manifests as new conduction delays, ST/T-wave changes, and PVCs. QRS prolongation, LBBB, pathological Q waves, and supraventricular arrhythmias were associated with subsequent adverse outcomes.

Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). Methods Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. Results We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10-5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 μM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. Conclusion We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.

Clozapine is an atypical antipsychotic indicated in patients with treatment-resistant schizophrenia which remains underused due to safety issues. Mechanisms behind these adverse effects are complex and not fully understood. They may involve immune-related mechanisms, direct toxic effects and oxidative stress. Clozapine-induced oxidative stress might indeed notably be involved in the onset of neutropenia, agranulocytosis, myocarditis, sialorrhea, and metabolic alterations. Therefore, the association of N-acetylcysteine (NAC), an easily accessible, low-cost and well tolerated antioxidant drug could be of interest in clozapine-treated patients to improve clozapine safety. Furthermore, according to recent studies NAC could help to improve schizophrenia symptoms. We believe that the use of NAC in the context of clozapine prescribing merits further study, as it could improve clozapine safety which may lead to a wider use and ultimately improve the healthcare of thousands of patients. NAC could also secondarily show positive knock-on effects for the patients by improving clinical symptoms of schizophrenia in synergy with clozapine, and by reducing substance abuse and thus by improving the patient's overall condition. However, given the rarity of clozapine-induced severe adverse effects, only a large volume of data (e.g., National adverse events monitoring) could assess the benefits of NAC on clozapine safety.

Background/Introduction An increase in left ventricular volumes between baseline and follow-up imaging is the main criteria for the quantification of left ventricular remodeling after ST-elevation myocardial infarction, but without consensual definition. Purpose We aimed to review the criterion used for the definition of left ventricular remodeling based on cardiac magnetic resonance imaging in studies including patients with ST-elevation myocardial infarction. Methods A systematic literature search was conducted using MEDLINE and the Cochrane Library from January 2010 to August 2019. Thirty-seven studies involving a total of 4209 patients were included. Results The median age of the patients was 59 years, 82% were male, and 93% underwent primary percutaneous coronary intervention. The median follow-up duration was 6 months (range, 3–12), and the second cardiac magnetic resonance session was performed at 6 months in 14 (38%) studies. Among these studies, 30 (81%) used a cut-off value for defining left ventricular remodeling, with a pooled left ventricular remodeling prevalence estimate of 22.8%, 95%-CI[19.4%-26.7%], and a major between-study heterogeneity (I2=82%). The seven remaining studies (19%) defined left ventricular remodeling as a continuous variable. A 20% increase in end-diastolic volumes or a 15% increase in end-systolic volumes between a baseline and a follow-up cardiac magnetic resonance imaging were the two most common criterion (13 [35%] and 9 [24%] studies, respectively). Seven studies used both end-diastolic and end-systolic vleft ventricular volumes. Conclusion(s) The definition of left ventricular remodeling using cardiac magnetic resonance following ST-elevation myocardial infarction is highly variable, among studies including highly selected patients. The most frequent left ventricular remodeling criterion were a 20% increase in end-diastolic volumes or a 15% increase in end-systolic volumes. A composite cut-off value of a 12% to 15% increase in end-systolic volume and a 12% to 20% increase in end-diastolic volume using a follow-up cardiac magnetic resonance imaging 1 to 3 months after myocardial infarction might be proposed as a consensual cut-off for defining adverse left ventricular remodeling for future large-sized, prospective studies with serial cardiac magnetic resonance imaging and long-term follow-up in unselected patients. Funding Acknowledgement Type of funding source: None

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short‐ and long‐term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio‐oncology expert panel from the French Working Group of Cardio‐Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.

Some concerns about the prescription of drugs acting on the renin-angiotensin system (angiotensin-converting enzyme 1 (ACE1) inhibitors, ACEi; angiotensin II type 1 receptor blockers, ARB) have emerged due to SARS COV2 and COVID-19 pandemic. These very legitimate questions are directly the consequence of the recent recognition of the fundamental role of ACE2 (angiotensin-converting enzyme 2) in COVID-19 infection. Indeed, SARS COV2 utilizes ACE2 as a membrane receptor to enter target cells. Consequently, the putative impact of drugs modulating the renin-angiotensin system on the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection emerged. As a membrane-bound enzyme (carboxypeptidase), ACE2 inactivates angiotensin II and therefore physiologically counters its effects. Due to a different structure compared with ACE1, ACE2 is insensitive to ACEIs. In vitro, both ARBs and ACEi appear able to upregulate ACE2 tissue expression and activity but these results were not confirmed in Humans. The exact impact of both ARBs and ACEis on COVID-19 infection is definitively known and preliminary results are even in favor of a protective role confers by these drugs. Due to the crucial role of ACE2, some groups support the hypothesis that a modulation of ACE2 expression could represent a valuable therapeutic target could confer protective properties against inflammatory tissue damage in COVID-19 infection. So, studies are currently ongoing to test the impact of elevated ACE2 membrane expression, administration of ARB and infusion of soluble ACE2. In summary, based on the currently available evidences and as recommended by several medical societies, ACEi or ARB should not be systematically discontinued because to date no safety signal was raised with the use of these drugs.

Office white-coat effect tail (OWCET) is defined as a decrease of ≥10 mmHg in systolic blood pressure (SBP) between successive measurements after its waxing during an office visit. The influence of sex on the incidence of long-term major fatal and non-fatal cardiovascular events was studied in two Italian populational cohorts [from the Gubbio Study and the Italian Rural Areas of the Seven Countries Study (IRA)]. OWCET increased risk of cardiovascular disease (CVD) [HR: 1.591 (95% CI: 1.204-2.103)], coronary heart disease (CHD) [HR: 1.614 (95% CI: 1.037-2.512)] and stroke (STR) [HR: 1.696 (95% CI: 1.123-2.563)] events independently of age, serum and high density lipoprotein (HDL) cholesterol, cigarettes, body mass index (BMI) and SBP in women included in Gubbio study over an almost 20-year follow-up. However, risks of CVD, CHD or STR increased in men with OWCET neither in the Gubbio 20-year follow-up nor in the IRA 50-year follow-up. The correction of the regression dilutions bias between the first and the subsequent SBP measurements did not significantly change these outcomes. Primary care physicians should evaluate OWCET, especially in women, to improve stratification of long-term CVD, CHD and STR risks.

Background The left ventricular ejection fraction (LVEF) is the key selection criterion for an implanted cardioverter defibrillator (ICD) in primary prevention of sudden cardiac death. LVEF is usually assessed by two-dimensional echocardiography, but cardiovascular magnetic resonance (CMR) imaging is increasingly used. The aim of our study was to evaluate whether LVEF assessment using CMR imaging (CMR-LVEF) or two-dimensional echocardiography (2D echo-LVEF) may predict differently the occurrence of clinical outcomes. Methods In this retrospective study, we reviewed patients referred for primary prevention ICD implantation to Caen University Hospital from 2005 to 2014. We included 173 patients with either ischemic (n = 120) or dilated cardiomyopathy (n = 53) and who had undergone pre-ICD CMR imaging. The primary composite end point was the time to death from any cause or first appropriate device therapy. Results The mean CMR-LVEF was significantly lower than the mean 2D echo-LVEF (24% ± 6 vs 28% ± 6, respectively; p p = 0.002) than 2D echo-LVEF with a cut-off value of 26% (HR = 1.61; 95% CI [0.99–2.61]; p = 0.056). Combination of the presence of scar with CMR-LVEFp p = 0.026), whereas 2D echo-LVEF was not associated with death. Conclusions CMR-LVEF is better associated with clinical outcomes than 2D echo-LVEF in primary prevention using an ICD. Scar identification further improved the outcome prediction. The combination of CMR imaging and echocardiography should be encouraged in addition to other risk markers to better select patients.

International audience; Importance Limited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after an immune-related adverse event (irAE). Objective To identify the recurrence rate of the same irAE that prompted discontinuation of ICI therapy after an ICI rechallenge in patients with cancer and to identify the clinical features associated with such recurrences. Design, Setting, and Participants This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase, which contains case reports from more than 130 countries. Case reports were extracted from database inception (1967) to September 1, 2019. All consecutive ICI cases with at least 1 associated irAE were included. Main Outcomes and Measures The primary outcome was the rate of recurrence of the initial irAE after an ICI rechallenge. Secondary outcomes included the factors associated with the recurrence after a rechallenge among informative rechallenges, the recurrence rate according to the ICI regimen (anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy, anti-cytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy), and the rate of occurrence of a different irAE after a rechallenge. Results A total of 24 079 irAE cases associated with at least 1 ICI were identified. Among the irAEs, 452 of 6123 irAEs associated with ICI rechallenges (7.4%) were informative rechallenges. One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. In a rechallenge, colitis (reporting odds ratio [OR], 1.77; 95% CI, 1.14-2.75; P = .01), hepatitis (reporting OR, 3.38; 95% CI, 1.31-8.74; P = .01), and pneumonitis (reporting OR, 2.26; 95% CI, 1.18-4.32; P = .01) were associated with a higher recurrence rate, whereas adrenal events were associated with a lower recurrence rate (reporting OR, 0.33; 95% CI, 0.13-0.86; P = .03) compared with other irAEs. Conclusions and Relevance This cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI. Resuming ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.

Keywords: azithromycin;cardiotoxicity;hydroxychloroquine;phamacovigilance EN azithromycin cardiotoxicity hydroxychloroquine phamacovigilance 303 305 3 07/23/20 20200721 NES 200721 Although hydroxychloroquine and azithromycin, alone or in combination, have been proposed for treatment of patients with coronavirus disease 2019 (COVID-19),[1] their potential cardiovascular toxicities had limited consideration in this new clinical environment The proportion that resulted in death for TdP/VT cases was 8 4% (7/83) with hydroxychloroquine and 20 2% (52/257) with azithromycin versus 0% (0/53) and 5 4% (12/223) for LQT without TdP/VT with hydroxychloroquine and azithromycin, respectively ( I P i 0 001 for both) [Extracted from the article] Copyright of Circulation is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

Aims The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF. Methods and results A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-CD20 monoclonal antibody. Conclusion Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of haematologic malignancies.

International audience; Isolated cases of acute coronary syndrome (ACS) associated with immune checkpoint inhibitors (ICIs) have been described without the establishment of a formal cause-and-effect relationship between treatment and adverse event. We reported a case of ACS after the first administration of an ICI and with a fatal recurrence in another coronary area immediately after readministration. According to guidelines, causality was considered to be certain. Subsequently, we queried the French pharmacovigilance database and found 4 cases of ACS with coronary artery thrombosis. Causality was probable in those patients. These data suggest that ACS may be another life-threatening cardiac adverse event occurring with ICI exposure.

We aimed to investigate the association between use of anticancer drugs and cardiovascular-related hospitalization (CVRH) among patients with metastatic colorectal cancer (mCRC). A cohort study, the Anticancer Vigilance of Cardiac Events (AVOCETTE) Study, was conducted using data from the digestive tumor registry of a French county, the Département du Calvados. Incident mCRC cases diagnosed between 2008 and 2014 were included. The follow-up end date was December 31, 2016. Data from the county hospital center pharmacy and medical information departments were matched with the registry data. A competing-risks approach was used. Statistical tests were 2-sided. A total of 1,116 mCRC patients were included, and they were administered 12,374 rounds of treatment; fluorouracil, oxaliplatin, irinotecan, and bevacizumab were most common drugs used. A total of 208 CVRH events occurred in 145 patients (13.0%). The International Cancer Survival Standards type 1 standardized incidence was 84.0 CVRH per 1,000 person-years (95% confidence interval: 72.6, 95.5). Anticancer drugs were not associated with a higher incidence of CVRH. Male sex, increasing age, a prior history of CVRH, and a higher Charlson comorbidity index score were associated with a higher incidence of CVRH. CVRH was significantly associated with higher all-cause mortality (multivariable hazard ratio = 1.58, 95% confidence interval: 1.28, 1.95). In this study, anticancer drugs were not associated with a higher incidence of CVRH in mCRC patients.

BackgroundImmune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described.MethodsFirst, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of ResultsIn the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively).ConclusionsLate CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD.Trial registration numbersNCT03678337,NCT03882580, andNCT03492528.

OBJECTIVE The aim was to investigate whether office white-coat effect tail (OWCET), the waning of blood pressure (BP) after its waxing during office visit, predicted long-term major fatal and nonfatal events in the Gubbio residential cohort. METHODS There were 3572 persons (44% men, 54 ± 11 years old) included. OWCET was defined as a decrease of 10 mmHg or more in SBP between the third and first measurement out of a series obtained a few min apart in which the second and third were considered actual baseline SBP at enrollment. Cardiovascular (CVD), including strokes and coronary heart disease (CHD) hard criteria incidences and deaths along with all-cause deaths were considered. RESULTS Over 185 months median follow-up, individuals with OWCET had significantly higher risk factors except for smoking, which was less frequent. OWCET was associated with an increased risk of both CVD [HR 1.25 (95% CI 1.02-1.52)] and CHD [HR 1.35 (95% CI 1.01-1.80)] events independently of traditional risk factors (age, sex, total cholesterol, HDL, cigarettes and BMI) including SBP. When effective antihypertensive treatment was considered, there was a significant higher CVD risk in individuals with OWCET (P

This cross-sectional study uses pharmacovigilance data to investigate the occurrence of pancytopenia among patients with cancer treated with poly(adenosine diphosphate–ribose) polymerase inhibitors and examines the clinical features of pancytopenia related to these drugs.

Summary Introduction Several studies have investigated the occurrence of venous thromboembolic events (phlebitis and pulmonary embolism) [VTE] and fibrates. Fibrates could be associated with VTE although published data are contradictory. The objective of this study is to confirm the link between VTE and fibrates. Materials and methods Retrospective disproportionality analysis (case/non-case method) from observations recorded consecutively in the French pharmacovigilance database between 1985 and 2016. Cases were defined as embolic and thrombotic events, thrombophlebitis; Non-cases were other adverse events reported over the same period. We measured the disproportionality of exposure to each fibrate among cases and no-cases. The analysis was validated with a positive control (drospirenone) and a negative control (paracetamol). Results We compared 19,436 cases (including 161 mentioning fibrates) to 563,310 non-cases (including 3228 fibrates). Reports of VTE were significantly associated with fenofibrate (ROR = 1.83; 95% CI = [1.53; 2.2]) but not with other fibrates: bezafibrate (ROR = 0.44; 95% CI = [0.2; 0.99]), ciprofibrate (ROR = 1.15; 95% CI = [0.76; 1.73]) and gemfibrozil (ROR = 0.91; 95% CI = [0.45; 1.84]). Conclusion With this study, we confirm the link between VTE and fenofibrate. It is therefore advisable to remain cautious when prescribing fenofibrate, in particular in case of past history of VTE and to declare systematically any venous thromboembolic adverse events observed with these drugs.

Patients over 75 account for more than one third of those presenting with myocardial infarction and more than 50% of intrahospital mortality. There are no specific guidelines for the management of acute coronary syndromes (ACS) in the elderly. Although antithrombotic therapy seems to be effective and safe in such patients, it requires specific precautions and treatment adjustments because of the higher bleeding risk due to comorbidities such as renal function impairment and malnutrition. Scientific evidence concerning elderly patients is scarce as they are either excluded or underrepresented in most randomized trials. Overall, the antithrombotic therapy needs to be adapted to avoid complications, mainly bleeding complications, without compromising the effectiveness of the treatment in this high-risk population. In the present paper, we review the current treatment strategies in ACS while focusing on data concerning the elderly, according to available data in pivotal trials and in both AHA/ACC and ESC guidelines.

Summary Background The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized. Aim To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting. Methods We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data. Results MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58–7.07), peripheral oedema (OR 2.87 95% CI 1.93–4.27) and syncope (OR 6.71, 95% CI 3.00–14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03–10.09), peripheral oedema (arOR 1.39, 95% CI 1.17–1.66), syncope (arOR 1.56, 95% CI 1.22–1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04–7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21–1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach. Conclusions In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.

International audience; We thank Brož et al. for their interest in our study aiming to determine if drug-induced hypoglycemia could be a class effect for opioids [1] and for their useful comments.The French PharmacoVigilance Database (FPVD) contains a narrative description of cases provided by the declarant, which we examined for this study. The description of the report’s narrative in pharmacovigilance study is a complement to disproportionality analysis that may identify potential mechanisms underlying the associations found between drugs and adverse drug reactions. We are glad that they shared our interest in finding such mechanisms to further investigate the link between hypoglycemia and opioids. As they accurately mentioned, 45 of the 93 tramadol-associated hypoglycemia cases included in our descriptive study in the FPVD were related to diabetic patients. Indeed, hypoglycemia in these patients could have been favored by the antihyperglycemic treatment they received. We agree with them that sleepiness, one of the common side effect of opioids, combined to the use of those antihyperglycemic treatments could have been one of the factors leading to the onset of hypoglycemia in those patients. However, not all the reports mentioned sleepiness and the prescription of opioids appeared to be the trigger factor causing the hypoglycemia even in diabetic patients, regardless of the underlying mechanism.

Background Mineralocorticoid receptor antagonists ( MRA s) have emerged as potential atrial fibrillation ( AF ) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRA s on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRA s on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta‐analyses to compute odds ratios with 95% CI s. Meta‐regression was then applied to explore the sources of between‐study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow‐up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta‐analyses showed a significant overall reduction in AF occurrence in the MRA ‐treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI , 0.44–0.70 [ P AF episodes ( odds ratio , 0.42; 95% CI , 0.31–0.59 [ P I 2 =54%; P =0.0008). Meta‐regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups. Conclusions MRA s seem to be effective in AF prevention, especially regarding recurrent AF episodes.

To assess the impact of sex on office white-coat effect tail (OWCET), the waning of systolic blood pressure (SBP) after its waxing during office visit, on the incidence of long-term major fatal and non-fatal events in two Italian residential cohorts [from the Gubbio Study and the Italian Rural Areas of the Seven Countries Study (IRA)]. There were 3565 persons (92 with missing data, 44% men, 54 ± 11 years) included in the Gubbio and 1712 men (49 ± 5 years) in the IRA studies. OWCET was defined as a decrease of ≥10 mmHg in SBP between successive measurements with slight measurement differences between the two cohorts. Cardiovascular (CVD), coronary heart disease (CHD) and stroke (STR) incidences were considered. Over an approximately 20-year follow-up, women with OWCET had an increased risk of CVD [HR: 1.591 (95%CI: 1.204–2.103)], CHD [HR: 1.614 (95%CI: 1.037–2.512)] and STR [HR: 1.696 (95%CI: 1.123–2.563)] events independently of age, serum and HDL cholesterol, cigarettes, BMI and SBP in the Gubbio study. However, there was no increased risk of CVD, CHD or STR in men with OWCET neither in the Gubbio 20-year follow-up nor in the IRA 50-year follow-up. These results were not modified significantly by the correction of the regression dilutions bias between the first and the subsequent SBP measurements. Thus, in primary care, OWCET should be actively evaluated in women as it can improve stratification of long-term CVD, CHD and STR risks.

Background Same-day home discharge after common atrial flutter catheter ablation (CAFCA) is a feasible, safe, and cost-effective practice, but there are currently no data for patients treated with direct oral anticoagulants (DOAs). Objective We evaluated the safety, efficacy, and feasibility of ambulatory CAFCA in patients treated with DOAs compared with those treated with vitamin K antagonists (VKAs). Methods Patients scheduled for isolated and elective ambulatory CAFCA in our tertiary university center between 2009 and 2019 were included. Propensity score for anticoagulant type was calculated from age, sex, body mass index, HAS-BLED and CHA2DS2-VASc scores, chronic kidney disease, associated antiplatelet treatment, procedure duration, and number of femoral venipunctures. Results Propensity score matching yielded 820 patients (mean age 67 ± 11 years). Catheter ablation was performed under uninterrupted VKA (n = 410; international normalized ratio 2.5 ± 0.6) or uninterrupted DOA (n = 410). The procedural success rate was 91%, and the effective same-day discharge rate was 93%. The occurrence of the primary end point, defined as any early and clinically significant bleeding (Bleeding Academic Research Consortium classification ≥ 2) at 1 week, was similar between patients treated with DOAs and those treated with VKAs (2.9% vs 3.7%; P = .70). Female sex, high HAS-BLED score, and prolonged procedure duration were independently associated with the primary end point. Conclusion Uninterrupted DOA regimens are safe for patients undergoing ambulatory CAFCA in a high-volume center with a dedicated ambulatory unit and standardized procedural and postoperative management.

International audience; Objective: Drug-induced hypoglycaemia has been described with the use of tramadol and methadone. The authors aimed to determine if drug-induced hypoglycaemia could be a class effect for opioids. Methods: The authors performed a disproportionality analysis in VigiBase®, the WHO global individual case safety report database with nine opioids (codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, tramadol, buprenorphine and nalbuphine) using the broad Standardised MedDRA Query for hypoglycaemia. The authors also carried out a descriptive study of opioid-induced hypoglycaemia in the French PharmacoVigilance DataBase (FPVDB) using the MedDRA Preferred Term 'hypoglycaemia'. Results: The global adjusted Reporting Odds Ratio (aROR) value for the 9 opioids was 1.53 (95% CI 1.52-1.54). The aROR ranged from 1.09 to 1.97 depending on the opioid, but all were statistically significant. A sex ratio of 0.74 was found for the reports of opioid-induced hypoglycaemia in Vigibase®. The authors also found 133 reports of hypoglycaemia in the FPVDB related to opioids. Among the reports, 55 were glycaemic imbalances in diabetics occurring shortly after the start of opioid treatment. Conclusion: This work highlighted a significant association between all opioids and hypoglycaemia, thereby indicating that opioid-induced hypoglycaemia is probably a class effect. Women and/or diabetics seem to be more at risk for developing opioid-induced hypoglycaemia.

Summary Aim Previous studies highlighted a significant association between fibrates and venous thromboembolism (VTE) events in dyslipidemia diabetic patients. Studies in non-diabetic patients are divergent. The present study investigated the association between VTE events and fibrates in diabetic and non-diabetic patients. Methods Two approaches were used: (1) a disproportionality analysis using the World health organization pharmacovigilance database VigiBase® was used to evaluate the reporting odds-ratio (ROR) of fibrates for VTE events. Clinical and demographic characterizations of patients with fibrates-related VTE reports are described; (2) a case control-study was performed using the Caen university hospital medical information database between January 2008 and December 2012. Cases were dyslipidemia patients who were hospitalized for VTE without an evident provoking factor. Up to four controls per case were selected in dyslipidemia patients hospitalized for a non-VTE event. Controls were matched to cases by age, gender, date of hospitalization, diabetes, chronic kidney disease and hospitalization department. A multivariate conditional logistic regression was performed. Results Disproportionality analysis: a total of 946 notifications were identified in VigiBase® (32.9% of diabetic patients). Fibrates were significantly associated with an increased report of VTE (ROR 1.14, CI 1.07–1.22). Case-control study: a total of 163 cases (21.5% of diabetic patients) and 514 matched controls were recruited. Fibrates were significantly associated with a higher risk of VTE events that required hospitalization in multivariate analysis (odds-ratio (OR) 3.67, CI 1.82–7.37, P = 0.0003). The association was only significant for fenofibrate in both approaches. Conclusion Fenofibrate was associated with a higher incidence of VTE events in diabetic and non-diabetic patients.

BackgroundWhite-coat hypertension (WCH) is also referred to as 'isolated clinic hypertension'. While it is a frequently encountered phenomenon, WCH is not systematically evoked, and its management remains unclear due to the contradictory guidelines provided by professional societies.AimTo examine WCH management by GPs in Europe and Canada.Design & settingA clinical vignette of a possible case of WCH was created from the literature, and the responses of GPs to WCH-specific questions in a cross-sectional electronic questionnaire were compared.MethodComplete electronic questionnaire responses from Europe and Canada were systematically analysed.ResultsAmong 770 eligible questionnaires (useful response rate: 10.6%), 43.5% were from France, 19.2% from Belgium, 7.8% from England, 19.5% from Switzerland, and 10.0% from Canada. Based on the clinical information provided in the vignette, GPs overall diagnosed hypertension and WCH equally (50.7% versus 49.3%, respectively). Canadian GPs suggested hypertension more frequently than European GPs in general (64.2% versus 46.1%, P–4), and more frequently used ambulatory blood pressure monitoring ([ABPM] 42.3% versus 26.1%, P = 0.01). In both groups of GPs, WCH was managed similarly (no treatment, 100% versus 97.3%, P = 0.39). Generally, the GPs all followed WCH patients for 3–6 months (51.3% versus 66.2%, P = 0.1), and they were not aware of the WCH guidelines (47.3% versus 52.1%, P = 0.54).ConclusionAlthough WCH guidelines are different, WCH management by GPs is very similar except for diagnosis. Homogeneity in WCH guidelines is required and should be systematically implemented in hypertension guidelines to avoid inappropriate management of the condition.