Current European Society of Cardiology guidelines recommend systematic troponin screening to detect potential cardiovascular (CV) immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICIs), increasing referrals to cardio-oncology services and broadening the spectrum of CV irAEs, including troponin elevation of uncertain significance. Management and outcomes in patients with suspected CV irAEs, are poorly defined. The safety of ICI rechallenge, particularly in patients fulfilling contemporary ICI-myocarditis diagnostic international cardio-oncology society (IC-OS) criteria, remains uncertain. Prospective single-centre cohort including consecutive adults referred for suspected CV irAEs. Objectives were to describe outcomes after initial assessment, identify predictors of mid-term CV events, and evaluate outcomes of ICI rechallenge in patients with and without initial CV irAEs. Among 175 patients (median age 61 years [IQR 48–72]; 77.1

Introduction/Objective Kidney transplantation is a vital therapeutic option for individuals with end-stage renal disease. Among the various immunosuppressive agents available, everolimus, a selective inhibitor of the mammalian target of rapamycin, is widely used. While previous studies have reported an increased risk of venous thromboembolism (VTE) in heart and lung transplant recipients treated with everolimus, its impact in kidney transplant patients remains less explored. This study aimed to investigate the association between everolimus and VTE in renal transplant recipients.Methods This study is a retrospective observational analysis combining a single-center case series of kidney transplant recipients and a review of cases retrieved from the French National Pharmacovigilance Database.Results From February 2017 to February 2022, in our center, 5 VTE occurred in five kidney transplant patients treated with everolimus. Among them, 3 patients had recurrent VTE. The median time between everolimus initiation and VTE onset was 11 months [IQR 3.8-15.0]. Everolimus was discontinued in one patient (20.0%) following the VTE event. From the French pharmacovigilance database, 16 additional cases of VTE associated with everolimus in the context of organ transplantation were identified. Among these, 12 (75.0%) patients were male, with a median age of 63 years [IQR 56.5-69.0]. Transplanted organs included heart (43.8%), lung (18.8%), and kidney (18.8%). Pulmonary embolism was the most common presentation, occurring in 11 (68.8%) patients, while 2 (12.5%) patients had isolated lower-limb DVT. Thrombosis at unusual sites was reported in three cases: one upper-limb DVT, one jugular vein thrombosis, and one right ventricular intracardiac thrombus. The median time to VTE onset after everolimus initiation was 24 months [IQR 7.5-42.0]. Everolimus therapy was continued in 13 (81.2%) patients, with dose reduction in 2 (12.5%) and discontinuation in 3 (18.9%).Discussion Everolimus may increase the risk of VTE in kidney transplant recipients. This risk appears to be higher in patients with a prior history of VTE before transplantation and during the first year following everolimus initiation.Conclusion Our findings suggest that everolimus may increase the risk of VTE in kidney transplant recipients. Further studies are needed to confirm this association and to evaluate the benefit-risk profile of everolimus compared with other immunosuppressive therapies in renal transplant patients.Type of Research Single-center and Pharmacovigilance Retrospective Observational Studies

Background: Venetoclax is the first representative of a new class of targeted therapy, that inhibits selectively B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein, frequently overexpressed in hematological malignancies. Venetoclax was approved by the Food and Drug Administration for chronic lymphocytic leukemia and for acute myeloid leukemia in 2016 and 2021, respectively. Because of its promising role in many hematological malignancies, several clinical trials are in progress and other extensions of indication are expected. An analysis of its long-term safety profile in real life is necessary. Objectives: The aim of our study was to evaluate all adverse events (AEs) reported to the French national pharmacovigilance database since its approval in France. Methods: We performed a retrospective study of all cases of AEs occurring under venetoclax recorded in the French national pharmacovigilance database since its market approval until March 2022 in France. Results: During the period study, a total of 209 AEs were spontaneously reported in 123 patients, of which 173 (82%) were serious. We confirmed that the most frequent toxicities described by the summary of product characteristic (SPC) and literature data on it, including hematological (21%), gastrointestinal (11%), dermatological (9%), infectious (8%) AEs, and tumor lysis syndrome (3%). Seventy-six (36%) AEs were not listed in the SPC for which the causal relationship of venetoclax could not be excluded including autoimmune hemolytic anemias (2%) or cardiac AEs (7%). Conclusion: These data especially in cardiac events provide important information on the safety of the venetoclax in a real-world setting.

BACKGROUND:Immune checkpoint inhibitors have changed cancer prognosis, at the expense of potential cardiovascular immune-related adverse events. Guidelines recommend troponin testing, prompting hospital admission if abnormal. AIM:To assess the safety of outpatient management of suspected cardiovascular immune-related adverse events. METHODS:This is a prospective cohort study of all consecutive adults referred for suspected cardiovascular immune-related adverse events. Hospital admission followed a prespecified algorithm. In the absence of cardiovascular or muscle symptoms, double immune checkpoint inhibitors, electrocardiogram changes, and cardiovascular or immune disease, patients were managed as outpatients. The primary objective was safety of outpatient management, with cardiovascular death at 30days as the main outcome; the secondary objective was identification of factors associated with cardiovascular immune-related adverse events at referral. RESULTS:Among the 175 patients enrolled between March 2022 and October 2023, 135 (72.11%) were female, the median age was 61 (interquartile range 48.0; 72.0) years, 146 (83.43%) were outpatients and 112 (64.00%) were referred for asymptomatic troponin increase. There were no cardiovascular deaths at 30days. Ninety-five (54.29%) patients had cardiovascular immune-related adverse events at referral, among whom 72 (41.14%) were diagnosed with immune checkpoint inhibitor-related myocarditis. History of cardiovascular disease (odds ratio 2.52, 95% confidence interval 1.12-5.40; P=0.017) and global longitudinal strain <16% (odds ratio 2.18, 95% confidence interval 1.03-4.63; P=0.042) were independently associated with cardiovascular immune-related adverse events at referral. CONCLUSIONS:Outpatient management is feasible in most patients when cardiovascular immune-related adverse events are suspected, provided that a FAST TRACK immune checkpoint inhibitor safety checklist is applied by the oncologists for triage. History of cardiovascular disease and global longitudinal strain are associated with the diagnosis of cardiovascular immune-related adverse events.

Leflunomide is an immunosuppressant indicated in the treatment of rheumatoid arthritis. This drug has a particular pharmacokinetics. Therapeutic Drug Monitoring (TDM) has been recommended for this drug because of its hepatic and hematological toxicities. We present here the prospective and retrospective analysis of a preliminary experience of the use of leflunomide as an alternative immunosuppressant in heart and/or lung transplantation of patients with or without cystic fibrosis. This study was conducted in 17 heart transplant patients (n=8) and/or lung transplant patients (n=9, 7 of whom had cystic fibrosis) who received treatment with leflunomide between April 2005 and June 2008. The indication for leflunomide was generally intolerance to the other immunosuppressants. The residual concentrations measured in patients with cystic fibrosis (C0 = 12.8 ± 5.5 mg/L) were statistically lower than those measured in patients without cystic fibrosis (C0 = 44.0 ± 24.2 mg/L) (p < 0.05). However, the dose related to weight in patients with cystic fibrosis (D = 0.32 ± 0.08 mg/Kg) tends to be slightly higher than that in patients without cystic fibrosis (D = 0.26 ± 0.10 mg/Kg). In terms of evolution, two patients died, one patient was lost to follow-up and leflunomide was stopped in 2 patients. With a mean follow-up of 12 months, the outcome was acceptable in the 12 patients in whom treatment was maintained. This experience must be evaluated over the longer term so that it can be extended to a larger cohort or proposed earlier after transplantation.

Abstract: Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy, mediated by immunoglobulin G (IgG) antibodies targeting platelet factor 4/heparin (PF4/H) complexes. Prompt and accurate diagnosis is critical to ensure appropriate treatment and improve outcomes. We aimed to evaluate the performance of the rapid chemiluminescent immunoassay (CLIA) HemosIL AcuStar HIT-IgG (Werfen) for detecting IgG anti-PF4/H antibodies for HIT diagnosis compared with the Zymutest HIA IgG (Hyphen BioMed) enzyme-linked immunosorbent assay (ELISA). This single-center retrospective cohort included all patients with suspected HIT (4Ts score >3). CLIA and ELISA were performed and compared, and results were evaluated against the serotonin-release assay. We included 113 patients with suspected HIT, and HIT was confirmed in 43 (38.1%). Discordant results occurred in 5 patients (4.4%) with confirmed HIT: 3 patients had positive ELISA and negative CLIA, one had both negative ELISA and CLIA, and one had negative ELISA and positive CLIA. CLIA demonstrated a high diagnostic accuracy, with a sensitivity of 90.7% (95% confidence interval [CI], 82.0-99.4) and specificity of 80.0% (95% CI, 70.6-89.3). ELISA showed a sensitivity of 95.3% (95% CI, 89.1-100.0) and negative predictive value of 96.3% (95% CI, 91.3-100.0) compared with 93.3% (95% CI, 87.0-99.6) for CLIA. No significant difference was observed between the 2 tests for sensitivity or specificity. Positive and negative percent agreements were 86.4% (95% CI, 77.7-95.2) and 96.3% (95% CI, 91.3-101.3), respectively. Overall percent agreement was 91.2% (95% CI, 85.9-96.4). This study supports the utility of CLIA as a rapid diagnostic tool for HIT optimizing clinical decision-making and patient management.

BackgroundThere are few publications regarding manifestations of vestibular disorders (VDs) following BNT162b2 mRNA COVID-19 vaccination. PurposeWe describe cases of VD potentially related to BNT162b2 vaccination and calculate its reporting rate, in order to enlarge knowledge about this adverse effect. MethodsA retrospective analysis of cases of VD following BNT162b2 vaccination reported to the pharmacovigilance centre of Georges-Pompidou European Hospital (France), in 2021 was performed. In order to identify these cases from the pharmacovigilance database containing all our registered cases, we used the Standardised MedDRA Query (SMQ) 'vestibular disorders'. Then we analysed cases with vestibular symptoms, based on the association of typical manifestations. The reporting rate was calculated based on the number of VD cases and the number of vaccinated patients. ResultsAmong 6608 cases reported to our centre related to COVID-19 vaccines during 2021, 34 VDs associated with BNT162b2 administration were included. They were mainly reported in females (79%), 62% occurred after the first dose and 32% were serious. Symptoms had completely resolved in 13 cases (38%). Vertigo was the most common symptom followed by balance disorders. Three patients received second dose without reappearance of VD. The final diagnosis was reported in 10 patients (six cases of vestibular neuritis, two cases of central VD, two cases of benign paroxysmal positional vertigo). The regional reporting rate was 26 [95% CI: 17-34] cases of VD per 1 million persons vaccinated. ConclusionAlthough the relationship between vaccination and VD cannot be established, clinicians should be aware of this rare adverse effect.

Articular manifestations should be screened before and during anti-IL-5/5R biologic treatment in severe asthma. Rigorous multidisciplinary team discussion should be carried out to assess the risk-benefit balance of withholding effective treatment. https://bit.ly/3vfPn4k.

Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6 weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6 months (late MACE). Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6 weeks and 6 months. Forty-nine patients (38 (77.6

Parasomnias and sleep-related movement disorders (SRMD) are major causes of sleep disorders and may be drug induced. The objective of this study was to conduct a systematic review of the literature to examine the association between drug use and the occurrence of parasomnias and SRMD. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews, we searched PubMed databases between January 2020 and June 2023. The searches retrieved 937 records, of which 174 publications were selected for full-text screening and 73 drugs were identified. The most common drug-induced parasomnias were nightmares and rapid eye movement (REM) sleep behaviour disorders and sleepwalking. In terms of drug-induced SRMD, restless legs syndrome, periodic limb movement disorders (PLMD), and sleep-related bruxism were most frequent. Medications that inhibit noradrenergic, serotonergic, or orexin transmission could induce REM sleep (e.g., nightmares). Regarding sleepwalking, dysregulation of serotoninergic neurone activity is implicated. Antipsychotics are mentioned, as well as medications involved in the gamma-aminobutyric acid (GABA) pathway. A mechanism of desensitisation-autoregulation of GABA receptors on serotoninergic neurones is a hypothesis. SRMD and PLMD could involve medications disrupting the dopamine pathway (e.g., antipsychotics or opioids). Opioids would act on mu receptors and increase dopamine release. The role of adenosine and iron is also hypothesised. Regarding bruxism, the hypotheses raised involve dysregulation of mesocortical pathway or a downregulation of nigrostriatal pathway, related to medications involving dopamine or serotonin. Parasomnias are rarely identified in drug product labels, likely due to the recent classification of their diagnoses. An analysis of pharmacovigilance data could be valuable to supplement existing literature data.

Du fait de la très large utilisation des héparines, la suspicion et le diagnostic de TIH peuvent survenir dans des contextes cliniques très différents et souvent complexes (contexte chirurgical oui/non, affection aiguë concomitante oui/non, autres médicaments suspects en particulier chimiothérapie, antibiotiques…). L'évaluation au cas par cas des suspicions de TIH, basée sur le seul avis d'experts n'est pas satisfaisante, car il s'agit d'une approche subjective, non standardisée sans reproductibilité. Alors que les connaissances sur les TIH ont évolué au fil du temps, l'analyse des caractéristiques des TIH aiguës a permis de proposer des algorithmes d'aide au diagnostic de TIH aiguë, applicables dans différentes situations cliniques. Ces algorithmes seront présentés avec en parallèle des exemples de diagnostic de TIH dans diverses situations cliniques inhabituelles pouvant poser des problèmes diagnostiques. Enfin, l'expérience acquise dans l'évaluation des TIH aiguës (ou ATCD de TIH) avec le binôme pharmacologue/hématologue depuis 25 ans sera présentée avec la mise en place d'une réunion multidisciplinaire des TIH et d'une consultation d'annonce du diagnostic de TIH.

Major bleedings have been described with cefazolin. The objective was to determine the frequency of bleeding events in cefazolin-treated patients and to identify risk factors for these complications. Monocenter prospective observational study of all consecutive cefazolin-treated patients. Patients benefited from a daily clinical assessment of bleedings and a twice-a-week blood sampling including hemostasis. Bleedings were classified according to the International Society on Thrombosis and Hemostasis classification: major, clinically relevant non-major bleedings (CRNMB) and minor bleedings. From September 2019 to July 2020, 120 patients were included, with a mean age of 59.4 (± 20.7) years; 70

Background Vancomycin is a reference antibiotic against methicillin-resistant staphylococci. Its administration is associated with infusion-related local complications (IRLC). To reduce this risk, it has been proposed to increase vancomycin dilution in the IV bag and to perform continuous infusion using the volumetric pump. The aim of our study was to assess the safety of peripheral infusion of vancomycin with the volumetric pump. Objectives To compare the frequency of IRLC between patients receiving vancomycin and those receiving beta-lactam (BL) antibiotics. Our secondary objective was to assess factors associated with the occurrence of IRLC. Patients and methods We conducted a prospective observational study in a French tertiary hospital. Between February 2021 and November 2021, we included all patients receiving continuous infusions of vancomycin or BL through a peripherally inserted venous catheter (PIVC). The primary endpoint was the occurrence of IRLC on Day 1 (D1). Results We included 168 patients (56 vancomycin, 112 BL). At D1, 14 patients (25%) presented IRLC in the vancomycin group versus 11 patients (10%) in the BL group (P = 0.01). There was significantly more IRLC in the group receiving vancomycin at an infused concentration above 5 mg/mL than those receiving BL (8/15, 53.3% versus 11/112, 10%, respectively, P < 0.01). However, no significant difference was observed between patients receiving infused vancomycin concentration <= 5 mg/mL and patients receiving BL (P = 0.4). Conclusion Our data support safe administration of vancomycin if infused at a concentration under 5 mg/mL, through the volumetric pump on PIVC.

Background:Heparin-induced thrombocytopenia (HIT) is a rare, difficult-to-diagnose, and potentially serious adverse drug reaction with thrombotic complications. Even though the immune system is still immature during the neonatal period, HIT has been described in newborns with reporting rates ranging from 0% to 2.3%. Therefore, it is important to clarify the risk of HIT in newborns because it can affect the management and monitoring of heparin treatment. Objectives:The objectives of the present study were to review the literature and determine the incidence of HIT after cardiac surgery in newborns in our pediatric hospital. Methods:We searched the literature from 1992 to 2021 for reports of HIT in newborns. Four raters then analyzed all the literature reports on HIT and classified them as "likely," "uncertain," or "unlikely." We also determined the incidence of HIT among newborns having undergone cardiac surgery in our pediatric hospital. Results:Eleven population-based studies and 12 case reports on suspected HIT in 17 newborns were reviewed. One study reported HIT in 14 out of 930 (1.5%) heparin-treated newborns, but the other studies (n = 467 newborns) did not mention HIT at all. None of the cases described in the literature was classified as "likely" by the raters. In our center, none of the 2997 newborns that had undergone cardiac surgery in the previous 16 years was diagnosed with HIT. Conclusion:We conclude that the incidence of HIT in newborns has been overestimated in the literature.

Introduction. - Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recentlyin cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity andoutcome in T and in K patients. Material and methods. - We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. Results. - Thirty-nine patients with mTOR-IP were diagnosed during this period, 24 T and 15 Kpatients. The average dosage of everolimus and sirolimus was 2,65 mg (+/- 1,78) and 2,75 mg(+/- 0,96) in T patients, respectively, versus 8,75 mg (+/- 2,26) for everolimus in K patients. Theoverall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P < 0.001) and occurred earlier (P < 0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differenceswere otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTORIP diagnosis were in the range of recommended therapeutic values. Conclusion. - Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease. (c) 2022 Societe francaise de pharmacologie et de therapeutique. Published by Elsevier Masson SAS. All rights reserved.

Dear Editor, Efficacy and safety of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was demonstrated,1.Rotshild V. Hirsh‐Raccah B. Miskin I. Muszkat M. Matok I. Comparing the clinical efficacy of COVID‐19 vaccines: a systematic review and network meta‐analysis.Sci Rep. 2021; 11: 22777Crossref PubMed Scopus (81) Google Scholar, 2.Smadja D.M. Yue Q.‐.Y. Chocron R. Sanchez O. Louet A.L.‐.L. Vaccination against COVID‐19: insight from arterial and venous thrombosis occurrence using data from VigiBase.Eur Respir J. 2021; 58: 2100956Crossref PubMed Scopus (87) Google Scholar however an additional booster dose is recommended in most countries. Intramuscular (IM) injections for patients with therapeutic anticoagulation3.Perrin G. Beller C.L. Darnige L. et al.Intramuscular vaccination in adults with therapeutic anticoagulation in the era of COVID‐19 vaccines outbreak: a practical review.TH Open Companion J Thromb Haemost. 2021; 5: e166-e170Google Scholar is a major concerns because of risk of bleeding and muscle hematomas.4.ACIP General Best Practice Guidelines for Immunization | Recommendations | CDC. https://www.cdc.gov/vaccines/hcp/acip‐recs/general‐recs/index.html. Accessed December 12, 2020.Google Scholar Regarding anticoagulants, the warning about IM administration is present in the monograph for vitamin K antagonist (VKA), but not for direct oral anticoagulants (DOACs). Evidence supporting IM injection in patients with anticoagulant exists but generally focused on IM influenza vaccination in patients treated with VKA therapy.3.Perrin G. Beller C.L. Darnige L. et al.Intramuscular vaccination in adults with therapeutic anticoagulation in the era of COVID‐19 vaccines outbreak: a practical review.TH Open Companion J Thromb Haemost. 2021; 5: e166-e170Google Scholar However, in line with the growing number of patients treated with DOACs, generalizing the conclusions of literature review3.Perrin G. Beller C.L. Darnige L. et al.Intramuscular vaccination in adults with therapeutic anticoagulation in the era of COVID‐19 vaccines outbreak: a practical review.TH Open Companion J Thromb Haemost. 2021; 5: e166-e170Google Scholar to patients treated with DOACs receiving IM vaccine was hazardous. Several national guidelines described the practical aspects of IM vaccination in patients treated with anticoagulants.5.RKI ‐ STIKO Recommendations ‐ STIKO vaccination recommendations 2017/18. https://www.rki.de/EN/Content/infections/Vaccination/recommandations/34_2017_engl.html. Accessed December 12, 2020.Google Scholar, 6.Direction générale de la Santé, Comité technique des vaccinations. Guide des vaccinations. Édition 2012.Google Scholar, 7.Public Health England. COVID‐19 vaccination programme Information for healthcare practitioners.Google Scholar Concerning the bleeding risk associated with IM vaccination, Public Health England addressed the specific case of administering COVID‐19 vaccine to individuals receiving anticoagulants.7.Public Health England. COVID‐19 vaccination programme Information for healthcare practitioners.Google Scholar These guidelines stated that individuals on stable anticoagulation therapy, including individuals on VKA who are up‐to‐date with their scheduled INR testing and whose latest INR was below the upper threshold of their therapeutic range, could receive IM vaccination. If there is any doubt, a consultation with the clinician responsible for prescribing or monitoring the individual's anticoagulant therapy is recommended. Overall, for IM route, the injection should be performed in the deltoid muscle,5.RKI ‐ STIKO Recommendations ‐ STIKO vaccination recommendations 2017/18. https://www.rki.de/EN/Content/infections/Vaccination/recommandations/34_2017_engl.html. Accessed December 12, 2020.Google Scholar with a fine needle (23‐gauge at least)4.ACIP General Best Practice Guidelines for Immunization | Recommendations | CDC. https://www.cdc.gov/vaccines/hcp/acip‐recs/general‐recs/index.html. Accessed December 12, 2020.Google Scholar, 6.Direction générale de la Santé, Comité technique des vaccinations. Guide des vaccinations. Édition 2012.Google Scholar and performed by medically trained personnel. A firm pressure, without rubbing, at the injection site should be maintained 2 to 5 min after.5.RKI ‐ STIKO Recommendations ‐ STIKO vaccination recommendations 2017/18. https://www.rki.de/EN/Content/infections/Vaccination/recommandations/34_2017_engl.html. Accessed December 12, 2020.Google Scholar The aim of our study was to evaluate the risk of bleeding events at the site of injection following IM vaccination in patients treated with therapeutic anticoagulation. We first performed a French multicenter prospective study including adult patients treated with anticoagulant therapy for venous thromboembolism (VTE) between May 2021 and September 2021 in the Georges Pompidou European Hospital (Paris, France) and Brest university hospital center (Brest, France). Consecutive patients were asked to report bleeding events at the site of COVID‐19 vaccine injection during a planned follow‐up for VTE. All bleeding events were classified according to International Society on Thrombosis and Haemostasis (ISTH) classification.8.Schulman S. Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and HaemostasisDefinition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients.J Thromb Haemost JTH. 2005; 3: 692-694Crossref PubMed Scopus (3174) Google Scholar, 9.Kaatz S. Ahmad D. Spyropoulos A.C. Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non‐major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non‐surgical patients: communication from the SSC of the ISTH.J Thromb Haemost JTH. 2015; 13: 2119-2126Crossref PubMed Scopus (653) Google Scholar The physician collected data from patients using a standardized questionnaire during patient consultation. No exclusion criteria were applied. The study was performed in accordance with the Declaration of Helsinki. The institutional review board of each center approved the study, and anonymous data collection was declared to the appropriate authorities (AnticoVax 20210917152943, CERAPHP.5, IRB registration: #00011928). The patients' non‐opposition to the use of their data for research was collected in accordance with the European regulation (General Data Protection Regulation, GDPR). Continuous data were expressed as median with interquartile range [IQR] (25th–75th percentiles). Categorical data were expressed in numbers (n) and percentages. Between May 2021 and September 2021, a total of 348 consecutive patients with anticoagulant therapy received 561 IM injections of COVID‐19 vaccines. Characteristics of patients are reported in Table 1. Briefly, median age of patients was 68.4 years (IQR 59.0–76.1) and 65.2% were males. Patients were treated for a first episode of non‐provoked VTE (49.1%) or recurrent VTE (35.6%) and for long‐term therapeutic anticoagulation in most cases (95.0%). Almost all patients were treated with DOACs (96.6%), 11 (3.2%) patients with VKA and only one (0.2%) with tinzaparin. During the study period, 234 (74.0%) patients had IM vaccination with BNT162b2 (BioNTech/Pfizer), 63 (19.9%) with ChAdOx1 nCov‐19 (Oxford–AstraZeneca), 15 (4.7%) with mRNA 1273 (Moderna) and four (1.2%) with Ad26.OV2.S (Johnson & Johnson/Janssen). Overall, patients received 561 IM injections of COVID‐19 vaccines of them; among them, 251 (72.1%) had one injection, 91 (26.1%) had two injections and six (1.7%) had three injections. For the majority of patients (86.7%), vaccination took place in vaccination centers (Table 2) and 17.9% of patients had pressure at the injection site during >2 min after the injection and 4.2% skipped an anticoagulant dose before vaccination. After IM injections, a total of three (0.6%) bleeding events were observed, two (0.4%) minor and one (0.2%) clinically relevant non‐major bleeding. These three patients were treated with rivaroxaban at the time of IM injection without any further risk factor of bleeding (i.e., age >75 years, presence of renal failure, liver failure, antiplatelet therapy, bleeding history, uncontrolled hypertension).TABLE 1Clinical characteristics of the vaccinated patients with anticoagulant therapyPatients (n = 348)Available dataAge, years ‐ median (IQR)68.4 (59.0–76.1)348Male ‐ n (%)227 (65.2)348BMI – kg/m², median (IQR)27.4 (25.0–31.0)328Plasma creatinine, µmol/L ‐ median (IQR)79.0 (68.0–93.0)143History of thrombosis ‐ n (%)First episode of non‐provoked VTE170 (49.1)346First episode of provoked VTE53 (15.3)Recurrent VTE123 (35.6)Duration of anticoagulationLong term anticoagulation324 (95.0)3413–6 months of anticoagulation17 (5.0)Anticoagulant therapy ‐ n (%)VKA11 (3.2)346Apixaban 10.0 mg BID4 (1.4)Apixaban 5.0 mg BID87 (25.0)Apixaban 2.5 mg BID54 (15.6)Rivaroxaban 20 mg OD114 (32.9)Rivaroxaban 10 mg OD75 (21.7)Tinzaparin 175 UI/kg per day1 (0.2)Antiplatelet therapy ‐ n (%)5 (1.5)339Comorbidities ‐ n (%)Hypertension126 (36.3)347Atrial fibrillation13 (3.7)347Stroke5 (1.4)347Coronary syndrome or heart failure11 (3.2)347Kidney failure13 (3.7)347Liver dysfunction1 (0.3)347Non‐metastatic cancer44 (12.7)347Metastatic cancer12 (3.5)347Chronic inflammatory disease14 (4.0)347History of major bleeding6 (1.7)347History of clinically relevant non‐major bleeding8 (2.3)347Anemia14 (4.0)347Thrombocytopenia2 (0.6)347COVID−19 vaccine type ‐ n (%)BNT162b2234 (74.0)316ChAdOx1 nCoV−1963 (19.9)mRNA 127315 (4.7)Ad26.OV2.S4 (1.2)Vaccine doses administered ‐ n (%)1251 (72.1)348291 (26.1)36 (1.7)Abbreviations: BID, twice daily; BMI, body mass index; IQR, interquartile range; OD, once daily; VKA, vitamin K antagonist; VTE, venous thromboembolism. Open table in a new tab TABLE 2Precautions used at the time of intramuscular vaccination and bleeding events after in patients with anticoagulant therapyVaccination ‐ n (%)Dose of vaccination (n = 561)Available dataVaccination center327 (86.7)377General practitioner33 (8.8)Pharmacist17 (4.5)Pressure at the injection site during >2 min82 (17.9)457Anticoagulant dose skipping22 (4.2)528Bleeding events ‐ n (%)3 (0.6)561Minor bleeding2 (0.4)aTwo patients had minor bleeding events after IM vaccination. Patient #1 was a 53‐years‐old man treated with rivaroxaban 20 mg OD for long‐term therapeutic anticoagulation. After IM injection with ChAdOx1 nCoV‐19 vaccine, he developed a 3‐cm superficial subcutaneous hematoma at the site of injection. Patient #2 was a 43‐years‐old man treated with rivaroxaban 10 mg OD for long‐term therapeutic anticoagulation. After IM injection with BNT162b2 vaccine, he developed a 2‐cm superficial subcutaneous hematoma at the site of injection. Both patients had no DOAC‐skipping dose and no pressure at the injection site during >2 min.Clinically relevant non major bleeding1 (0.2)bOne patient had clinically relevant non major bleeding events after IM vaccination. Patient #3 was a 63‐year‐old woman treated with rivaroxaban 10 mg OD for long‐term therapeutic anticoagulation. After IM injection with BNT162b2 vaccine, she developed a large superficial subcutaneous hematoma that spread all the way up her arm, leading her to consult her treating physician. She had no DOAC‐skipping dose and no pressure at the injection site during >2 min.Major bleeding0 (0.0)a Two patients had minor bleeding events after IM vaccination. Patient #1 was a 53‐years‐old man treated with rivaroxaban 20 mg OD for long‐term therapeutic anticoagulation. After IM injection with ChAdOx1 nCoV‐19 vaccine, he developed a 3‐cm superficial subcutaneous hematoma at the site of injection. Patient #2 was a 43‐years‐old man treated with rivaroxaban 10 mg OD for long‐term therapeutic anticoagulation. After IM injection with BNT162b2 vaccine, he developed a 2‐cm superficial subcutaneous hematoma at the site of injection. Both patients had no DOAC‐skipping dose and no pressure at the injection site during >2 min.b One patient had clinically relevant non major bleeding events after IM vaccination. Patient #3 was a 63‐year‐old woman treated with rivaroxaban 10 mg OD for long‐term therapeutic anticoagulation. After IM injection with BNT162b2 vaccine, she developed a large superficial subcutaneous hematoma that spread all the way up her arm, leading her to consult her treating physician. She had no DOAC‐skipping dose and no pressure at the injection site during >2 min. Open table in a new tab Abbreviations: BID, twice daily; BMI, body mass index; IQR, interquartile range; OD, once daily; VKA, vitamin K antagonist; VTE, venous thromboembolism. We next performed a request in the French national pharmacovigilance database (authorization protocol number: CNIL‐1922081) to identify cases of bleeding events at the site of injections following COVID‐19 vaccine in patients under therapeutic anticoagulation. In France, 69 089 410 doses of COVID‐19 vaccine were administered between December 27 2020 and June 30 2021. A total of 13 bleeding events at the injection site in patients with therapeutic anticoagulation were reported. All of these events were classified as minor bleeding according to ISTH criteria. Hence, these bleeding events correspond to a spontaneous notification rate of 0.19 cases (95% confidence interval, CI, 0.09–0.29) reported per million of doses administered in France. Based on our prospective cohort and on the pharmacovigilance database, our results suggest a very low risk of bleeding event at the site of vaccine injection. Thus, to our knowledge, this is the first study assessing IM vaccination in patients treated with therapeutic anticoagulation with a large proportion of DOACs. At the beginning of the COVID‐19 vaccination campaign, two strategies could be considered for patients treated with DOACs: either not to discontinue or to consider discontinuing DOAC on the day of the injection.10.Spyropoulos A.C. Al‐Badri A. Sherwood M.W. Douketis J.D. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.J Thromb Haemost JTH. 2016; 14: 875-885Crossref PubMed Scopus (109) Google Scholar The skipping strategy may apply to DOACs because of their favorable pharmacokinetics properties with shorter half‐life and shorter Cmax compared to VKA.11.Beyer‐Westendorf J. Gelbricht V. Förster K. et al.Peri‐interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry.Eur Heart J. 2014; 35: 1888-1896Crossref PubMed Scopus (278) Google Scholar For example, the French Working Group on Perioperative Hemostasis (GIHP) proposed not to administer DOAC the evening before and the morning of procedures at low bleeding risk.12.Albaladejo P. Bonhomme F. Blais N. et al.Management of direct oral anticoagulants in patients undergoing elective surgeries and invasive procedures: updated guidelines from the French working group on perioperative hemostasis (GIHP) ‐ September 2015.Anaesth Crit Care Pain Med. 2017; 36: 73-76Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar This could be applied to patients at low thrombosis risk, especially those at high bleeding risk. In the prospective Dresden NOAC registry,11.Beyer‐Westendorf J. Gelbricht V. Förster K. et al.Peri‐interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry.Eur Heart J. 2014; 35: 1888-1896Crossref PubMed Scopus (278) Google Scholar authors analyzed peri‐interventional safety data from 2179 DOAC‐treated patients and classified IM injections as minor procedures. Twenty‐nine bleeding events were observed after 641 minor procedures (4.5%, 95% CI 3.1–6.4). No major bleeding was reported after IM injection. Authors concluded that for non‐major invasive procedures, rate of complication was low and fatal complications seem to be very rare. However, the proportion of patients who underwent IM injection without holding DOACs was not reported. Only 4.2% of patients included in the present study had skipping dose strategy suggesting that IM vaccination in DOAC patient without skipping dose is safe. The value of firm compression >2 min is necessarily questioned by the small proportion of patients in whom it was performed (17.9%) but given its safety, it cannot be ruled out that it may have prevented some minor bleeding. In the present study, we showed 7 months later only 0.19 cases per million of doses of COVID‐19 vaccines administered, confirming again the safety of IM injection of vaccine under therapeutic anticoagulation. One limitation of our study is that the size of the needle for COVID‐19 vaccine was not reported. Overall, in patients receiving therapeutic anticoagulation, IM vaccination against COVID‐19 appears to be safe, in particular in patients treated with DOACs, and may not require a skipping dose strategy. While a reminder of general precautions is useful at a time of mass vaccination campaigns, our data support the statement that therapeutic anticoagulation is not a contraindication for being vaccinated against COVID‐19. All authors have nothing to disclose with the present study. NG, LK, CLB, BE, AG, SC, BB, TM, OS, CT, BP and FC included the patients. NG, LK, CLB, BE, CA, WA, TM, OS, CT, BP and FC generated the data NG and LK performed biostatistics analyses NG, LK and BP wrote the manuscript NG, LK, OS, BP and FC supervised the study All authors reviewed the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.

Background: Prompt and definitive diagnosis of adverse drug reactions (ADRs) is a challenge for health care providers. There is a global burden of ADRs worldwide associated with a negative impact on the patient's health, in parallel with increasing costs for the community.This study aims to determine the annual incidence of ADRs in the cohort of patients requiring immediate intervention of the French prehospital emergency medical service (PEMS). The definitive diagnosis of ADR was provided by the follow-up of the entire course of hospitalization from PEMS presentation to final discharge in each suspected case.Methods: A retrospective study examining the incidence of ADR at the Paris PEMS was performed in 2015.Results: From January the 1st to December the 31st, 2015, 485 cases of suspected ADR were selected. Twentyeight patients could not be identified at the hospital and were considered as lost to follow-up. For the 457 cases with the final diagnosis and outcome available, 359 had a definitive and new diagnosis of ADR, 9 were related to substance of abuse and alcohol, 14 were duplicates and 75 were excluded by drug causality was ruled out. Long-term follow-up was performed for 359 cases. Among them, 22 patients (6.1%) died of an ADR. Twenty-five severe ADRs were notified for children ages 2 to 16 with a cluster of 9 cases (36%) resulting from an accidental outbreak of poisonings with alimemazine in a classroom. No fatality was reported among children suffering from an ADR.Conclusion: The collaboration between PEMS and in hospital Pharmacovigilance Centre is feasible from the PEMS report to the long-term follow-up. The definition of a clinical pattern for some drugs is needed to allow the medical team to anticipate the clinical outcome of the involved patient and therefore adapting the patient's support as soon as possible. (c) 2022 Elsevier Inc. All rights reserved.

Background. Abciximab (ABX) is used for acute coronary syndrome and unstable angina. Thrombocytopenia is a frequent adverse effect described as occurring in the first 24 hours. The aim of this study was to evaluate, in a context of pharmacovigilance survey, the occurrence of delayed thrombocytopenia following ABX infusion in pharmacovigilance database reports and in the literature. Methods. Individual case safety reports (ICSRs) of delayed thrombocytopenia between 3 and 30 days - with ABX presented as a single suspect were selected in VigiBase, the WHO global database of ICSRs. The French cases were then extracted from the French national pharmacovigilance database. In addition, a literature review of published cases was performed using PubMed. Results. Among the 84 ICSRs selected from VigiBasec', 43 were also reported in the FPVD. Mean age was 60.1 +12.3 years with a majority of male patients (77.4%). The average time to onset (TTO) was 8.9 5.2 days. Thrombocytopenia regressed in 5.1 2.7 days. Haemorrhagic complications were reported in 15% of ICSRs. In the French cases, the median nadir of platelet count was 28 \ 109/L (range 1-110) with a majority of grade 4 thrombocytopenia (39.5%). The literature review identified 42 cases and provided additional information on administered therapies, which include platelet units, corticosteroids, and IV immunoglobulins. GPIlb/111a-ABX complex antibodies were described in 26 published cases. Conclusion. Delayed thrombocytopenia, probably due to immune reaction, is a possible life threatening adverse effect of ABX with a mean TTO of 9 days, supporting the recommendation of a platelet count monitoring during at least two weeks. This recommendation was added to the abcximab SmPC in 2019. (C) 2021 Societe francaise de pharmacologie et de therapeutique. Published by Elsevier Masson SAS. All rights reserved.