Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study.

BACKGROUND: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. OBJECTIVES: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. METHODS: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. RESULTS: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). CONCLUSIONS: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study.

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Adverse drug reaction related to drug shortage: A retrospective study on the French National Pharmacovigilance Database.

AIM: Drug shortages are a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French National Pharmacovigilance Database. METHODS: All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. RESULTS: Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, 95% confidence interval [CI] 17.5-27.0%), the cardiovascular system (16.4%, 95% CI 11.9-21.4%) and anti-infectives for systemic use (14.3%, 95% CI 9.7-19.2%) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, 95% CI 18-24%), skin and subcutaneous (14%, 95% CI 11-17%), general (13%, 95% CI 10-17%) and gastrointestinal (8%, 95% CI 5-11%) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (MEs) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. CONCLUSION: This study emphasizes the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk.

Medicine misuse: A systematic review and proposed hierarchical terminology.

AIMS: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. METHODS: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles and Psychological and Behavioral Sciences Collection, using keywords related to "misuse", "appropriateness" and "medicine" between 1 November 2008 and 25 August 2020. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. RESULTS: Of 3404 identified records, 51 were included. A total of 71 definitions and 74 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to "intentional or unintentional prescribing not in line with clinical evidence". Based on context, they could prescribe medicines not clinically justified, i.e. overprescribing, or prescribe indicated medicines incorrectly, i.e. misprescribing. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out-of-scope. CONCLUSION: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse and errors.

Can We Define Termination Of Resuscitation Criteria In Out-Of-Hospital Hanging?

OBJECTIVE: Survival rate of cardiac arrest due to hanging (H-CA) victims is low. Hence, this leads to the question of the utility of resuscitation in these patients. The objective was to investigate whether there are predictive criteria for survival with a good neurological outcome or predictive criteria for non-survival or survival with a poor neurological outcome enabling us to define the termination of resuscitation rules in these patients. METHODS: Between July 1, 2011 and January 1, 2016, we included 1,689 out-of-hospital cardiac arrests due to hanging. We compared the characteristics of survivors with a good neurological outcome at day 30 with the others. RESULTS: The study population was mainly composed of males with a median age of 48 [37-60]. The overall survival was 2.1%, among which 48.6% had a good neurological outcome. Survivors benefited more often from immediate basic life support than the rest of the subjects, which was corroborated by the shorter no-flow durations. We did not record any difference in terms of advanced cardiac life support initiation frequency and technique between survivors with a good neurological outcome and the rest. Nevertheless, ACLS duration was longer in survivors with a good neurological outcome than in others. CONCLUSIONS: Basic life support (BLS) was the decisive criterion for 15/17 survivors. However, a detailed analysis showed 2 survivors presenting no BLS before the arrival of mobile medical teams and non-shockable rhythms who survived at day 30 with a good neurological outcome. These results lead us to consider that mobile medical team intervention and ACLS attempt are not futile, and the benefit justifies the cost. Thus, we cannot define any rule for the termination of resuscitation.

Impact of Covid-19 Vaccination on Spontaneous Pharmacovigilance Reporting in France.

INTRODUCTION: In 2021, the massive Covid-19 vaccination campaign in France was accompanied by an intensified pharmacovigilance monitoring of their potential adverse drug reactions. The importance of this reporting might have led to an important selective reporting and overloading of Pharmacovigilance Centres, delaying the recording of some reports in the national pharmacovigilance database. In this context, we aimed to evaluate the impact of the Covid-19 vaccination campaign in France and related reports on spontaneous reporting of adverse drug reactions that were not related to the Covid-19 vaccine. METHODS: We performed time-series analyses considering the monthly number of adverse drug reactions reported between January 1, 2018 and April 30, 2022 using the French Pharmacovigilance database. The impact of the Covid-19 vaccination campaign on the monthly reporting not Covid-19 vaccine related was estimated using interrupted time-series. January 2021, marking the start of the campaign, was the intervention date in the models. Analyses were run globally first considering all adverse drug reaction reports, and second according to notifier type and to case seriousness. RESULTS: We included 170,294 reports registered in the French Pharmacovigilance database between January 1, 2018 and April 30, 2022 that were not Covid-19 vaccine-related. Among these, 77,067 (45.3%) were serious and 146,683 (86.1%) had been reported by health care professionals. The campaign start was associated with a nearly 35.0% decrease in average monthly reporting that was not Covid-19 vaccine-related, with a significant level decrease in the monthly number of reports of -658.0 (p < 10-3) immediately after the vaccination campaign start and a subsequent slope decrease of -50.0 (p < 10-3). This decrease was mainly due to a significant level and slope decrease (level: -739.2 p < 10-3; slope: -39 [p < 10-2]) for health care professional reports. A similar level decrease was found for the monthly number of both serious and non-serious reports (-402.3, p < 10-3; and -311.9, p = 10-2, respectively). According to the ATC 1 level, the decrease in the monthly number of reports showed similar patterns for all drugs. However, a potential increase in the number of serious reports suspecting antineoplastic and immunomodulating drugs (ATC L) or drugs targeting blood was observed (ATC B). CONCLUSION: Our study showed a significant impact of the Covid-19 campaign vaccination in the reporting of adverse drug reactions that were not Covid-19 vaccine-related, of roughly 35%. This leads to a loss of information regarding the monitoring of drug safety that could have impacted the system capacity to detect safety signals for drugs other than Covid-19 vaccines.

Role of spontaneous reporting in investigating the relationship between mRNA COVID-19 vaccines and myocarditis: The French perspective.

AIM OF THE STUDY: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. METHODS: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). RESULTS: The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). CONCLUSION: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection.

General practitioners' compliance with benzodiazepine discontinuation guidelines in patients treated with long-term lorazepam: A case-vignette cross-sectional survey.

AIM: To study determinants associated with GPs' compliance with benzodiazepine discontinuation guidelines through a case-vignette of a patient with multimorbidity treated with long-term lorazepam for insomnia. METHODS: This cross-sectional survey was performed in a sample of French GPs. The questionnaire included items on their characteristics and questions related to the management of a case-vignette with long-term lorazepam use consulting for a prescription renewal. GPs who proposed a dedicated consultation to discuss discontinuation or progressive discontinuation were considered as "following guidelines", while they were considered as "out-of-guidelines" if they proposed immediate discontinuation or decided not to discontinue lorazepam. A backward selection process was used to select factors to be included in the final logistic regression model. The probabilities of out-of-guidelines practice and their 95% confidence interval (95% CI) were then plotted using a heatmap graph. RESULTS: Of 1,177 GPs, the majority (92.2%) were aware of the necessity to discontinue lorazepam and reported practice consistent with good practice guidelines. Women GPs aged under 50 years had the lowest estimated probability of out-of-guidelines practice. Conversely, men aged over 58 years with high consideration of patient preferences and low concern about the benefit-risk ratio of lorazepam had the highest probability of out-of-guidelines practice (27.3% [18.7%; 34.7%]). CONCLUSION: GPs largely reported practice compliant with benzodiazepine discontinuation guidelines, although some GPs, mainly older men who overemphasise patient preferences, were more likely to adopt out-of-guidelines practice.

Neuromodulation Treatments of Pathological Anxiety in Anxiety Disorders, Stressor-Related Disorders, and Major Depressive Disorder: A Dimensional Systematic Review and Meta-Analysis.

Background: Pathological anxiety is responsible for major functional impairments and resistance to conventional treatments in anxiety disorders (ADs), posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Focal neuromodulation therapies such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) are being developed to treat those disorders. Methods: We performed a dimensional systematic review and meta-analysis to assess the evidence of the efficacy of TMS, tDCS and DBS in reducing anxiety symptoms across ADs, PTSD and MDD. Reports were identified through systematic searches in PubMed/Medline, Scopus and Cochrane library (inception to November 2020), followed by review according to the PRISMA guidelines. Controlled clinical trials examining the effectiveness of brain stimulation techniques on generic anxiety symptoms in patients with ADs, PTSD or MDD were selected. Results: Nineteen studies (RCTs) met inclusion criteria, which included 589 participants. Overall, focal brain activity modulation interventions were associated with greater reduction of anxiety levels than controls [SMD: -0.56 (95% CI, -0.93 to-0.20, I 2 = 77%]. Subgroup analyses revealed positive effects for TMS across disorders, and of focal neuromodulation in generalized anxiety disorder and PTSD. Rates of clinical responses and remission were higher in the active conditions. However, the risk of bias was high in most studies. Conclusions: There is moderate quality evidence for the efficacy of neuromodulation in treating pathological anxiety. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=233084, identifier: PROSPERO CRD42021233084. It was submitted on January 29th, 2021, and registered on March 1st, 2021. No amendment was made to the recorded protocol. A change was applied for the subgroup analyses based on target brain regions, we added the putative nature (excitatory/inhibitory) of brain activity modulation.

Artificial Intelligence for Unstructured Healthcare Data: Application to Coding of Patient Reporting of Adverse Drug Reactions.

Adverse drug reaction (ADR) reporting is a major component of drug safety monitoring; its input will, however, only be optimized if systems can manage to deal with its tremendous flow of information, based primarily on unstructured text fields. The aim of this study was to develop an automated system allowing to code ADRs from patient reports. Our system was based on a knowledge base about drugs, enriched by supervised machine learning (ML) models trained on patients reporting data. To train our models, we selected all cases of ADRs reported by patients to a French Pharmacovigilance Centre through a national web-portal between March 2017 and March 2019 (n = 2,058 reports). We tested both conventional ML models and deep-learning models. We performed an external validation using a dataset constituted of a random sample of ADRs reported to the Marseille Pharmacovigilance Centre over the same period (n = 187). Here, we show that regarding area under the curve (AUC) and F-measure, the best model to identify ADRs was gradient boosting trees (LGBM), with an AUC of 0.93 (0.92-0.94) and F-measure of 0.72 (0.68-0.75). This model was run for external validation showing an AUC of 0.91 and a F-measure of 0.58. We evaluated an artificial intelligence pipeline that was found able to learn how to identify correctly ADRs from unstructured data. This result allowed us to start a new study using more data to further improve our performance and offer a tool that is useful in practice to efficiently manage drug safety information.

First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective.

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009-2011) and 30.6% (2018-2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018-2019 vs. 2009-2011 was found (non-squamous: HR: 0.95 CI95%: 0.92-0.98; squamous: HR: 0.94 CI95%: 0.90-0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed.