Adverse drugs reactions (ADR) suspected through phone triage and assessed by medically staffed ambulances: A pilot study.

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. Twenty-eight 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.

How to interact with medical terminologies? Formative usability evaluations comparing three approaches for supporting the use of MedDRA by pharmacovigilance specialists.

BACKGROUND: Medical terminologies are commonly used in medicine. For instance, to answer a pharmacovigilance question, pharmacovigilance specialists (PVS) search in a pharmacovigilance database for reports in relation to a given drug. To do that, they first need to identify all MedDRA terms that might have been used to code an adverse reaction in the database, but terms may be numerous and difficult to select as they may belong to different parts of the hierarchy. In previous studies, three tools have been developed to help PVS identify and group all relevant MedDRA terms using three different approaches: forms, structured query-builder, and icons. Yet, a poor usability of the tools may increase PVS' workload and reduce their performance. This study aims to evaluate, compare and improve the three tools during two rounds of formative usability evaluation. METHODS: First, a cognitive walkthrough was performed. Based on the design recommendations obtained from this evaluation, designers made modifications to their tools to improve usability. Once this re-engineering phase completed, six PVS took part in a usability test: difficulties, errors and verbalizations during their interaction with the three tools were collected. Their satisfaction was measured through the System Usability Scale. The design recommendations issued from the tests were used to adapt the tools. RESULTS: All tools had usability problems related to the lack of guidance in the graphical user interface (e.g., unintuitive labels). In two tools, the use of the SNOMED CT to find MedDRA terms hampered their use because French PVS were not used to it. For the most obvious and common terms, the icons-based interface would appear to be more useful. For the less frequently used MedDRA terms or those distributed in different parts of the hierarchy, the structured query-builder would be preferable thanks to its great power and flexibility. The form-based tool seems to be a compromise. CONCLUSION: These evaluations made it possible to identify the strengths of each tool but also their weaknesses to address them before further evaluation. Next step is to assess the acceptability of tools and the expressiveness of their results to help identify and group MedDRA terms.

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

OBJECTIVE: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. PATIENTS AND METHODS: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria. RESULTS: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001). CONCLUSION: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

[Automated grouping of terms associated to cardiac valve fibrosis in MedDRA]. / Groupement automatisé de termes liés aux valvulopathies médicamenteuses dans MedDRA.

AIM: To propose an alternative approach for building custom groupings of terms that complements the usual approach based on both hierarchical method (selection of reference groupings in medical dictionary for regulatory activities [MedDRA]) and/or textual method (string search), for case reports extraction from a pharmacovigilance database in response to a safety problem. Here we take cardiac valve fibrosis as an example. METHODS: The list of terms obtained by an automated approach, based on querying ontology of adverse drug reactions (OntoADR), a knowledge base defining MedDRA terms through relationships with systematized nomenclature of medicine-clinical terms (SNOMED CT) concepts, was compared with the reference list consisting of 53 preferred terms obtained by hierarchical and textual method. Two queries were performed on OntoADR by using a dedicated software: OntoADR query tools. Both queries excluded congenital diseases, and included a procedure or an auscultation method performed on cardiac valve structures. Query 1 also considered MedDRA terms related to fibrosis, narrowing or calcification of heart valves, and query 2 MedDRA terms described according to one of these four SNOMED CT terms: "Insufficiency", "Valvular sclerosis", "Heart valve calcification" or "Heart valve stenosis". RESULTS: The reference grouping consisted of 53 MedDRA preferred terms. Our automated method achieved recall of 79% and precision of 100% for query 1 privileging morphological abnormalities, and recall of 100% and precision of 96% for query 2 privileging functional abnormalities. CONCLUSION: An alternative approach to MedDRA reference groupings for building custom groupings is feasible for cardiac valve fibrosis. OntoADR is still in development. Its application to other adverse reactions would require significant work for a knowledge engineer to define every MedDRA term, but such definitions could then be queried as many times as necessary by pharmacovigilance professionals.

Vestibular disorders following BNT162b2 mRNA COVID-19 vaccination: A retrospective case series.

BACKGROUND: There are few publications regarding manifestations of vestibular disorders (VDs) following BNT162b2 mRNA COVID-19 vaccination. PURPOSE: We describe cases of VD potentially related to BNT162b2 vaccination and calculate its reporting rate, in order to enlarge knowledge about this adverse effect. METHODS: A 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. RESULTS: Among 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. CONCLUSION: Although the relationship between vaccination and VD cannot be established, clinicians should be aware of this rare adverse effect.

Heparin-induced thrombocytopenia in newborns: experience at a pediatric hospital and a literature review.

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.

Direct Oral Anticoagulants as Successful Treatment of Heparin-Induced Thrombocytopenia: A Parisian Retrospective Case Series.

Background: Heparin-induced thrombocytopenia (HIT) is a prothrombotic life-threatening disorder caused by an adverse reaction to heparin exposure. In this context, it is imperative to stop heparin immediately and to replace it by a non-heparin anticoagulant therapy. Despite their advantages, the use of direct oral anticoagulants (DOACs) is only emerging for HIT treatment, and their use remains rare. Objective: To improve our knowledge on the emerging role of DOACs as treatment of HIT and give an overview of our local practices in this context. Patients/Methods: This is a multi-centric retrospective case series of HIT patients referred to our Parisian pharmacovigilance network and treated with DOACs. Results: We report the cases of seven patients from four healthcare centers, diagnosed with HIT (4T score ≥ 4, positive anti-PF4/heparin immunoassay and positive serotonin-release assay) and treated with DOACs. After a few days on substitutive parenteral treatment (n = 6) or directly at HIT diagnosis (n = 1), these patients were treated with either rivaroxaban (n = 6) or apixaban (n = 1) during acute HIT phase. Mean time to platelet count recovery after heparin discontinuation was 3.3 days (range 3-5). No patient experienced major or clinically relevant non-major bleeding or thrombosis that could be related to DOAC treatment during follow-up. Conclusions: Our cases studies are consistent with recent guidelines credit to the potential and safe use of DOAC during acute HIT in clinically stable patients.

Delayed thrombocytopenia following administration of abciximab: Pharmacovigilance survey and literature review.

BACKGROUND: Abciximab (ABX) is used for acute coronary syndrome and unstable angina. Thrombocytopenia is a frequent adverse effect described as occurring in the first 24hours. 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 VigiBase®, 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. GPIIb/IIIa-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.

Heparin-induced thrombocytopenia: Construction of a pretest diagnostic score derived from the analysis of a prospective multinational database, with internal validation.

BACKGROUND: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays. OBJECTIVE: To develop a pretest score for HIT. DESIGN: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839). SETTING: Thirty-one tertiary hospitals in France, Switzerland, and Belgium. PATIENTS: Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts. MEASUREMENTS: Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results. RESULTS: Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥40% decrease in platelet count over ≤6 days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 (95% CI, 0.76-0.82). In the validation cohort, the area under the receiver operating characteristic curve was 0.77 (95% CI, 0.74-0.80). Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group. LIMITATION: The performance of the score may depend on settings and practices. CONCLUSION: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pretest score, which may guide clinical decisions regarding diagnostic testing and anticoagulation.

A qualitative approach to signal mining in pharmacovigilance using formal concept analysis.

"Pharmacovigilance is the process and science of monitoring the safety of medicines, consisting in (i) collecting and managing data on the safety of medicines (ii) looking at the data to detect 'signals' (any new or changing safety issue)" [1]. Pharmacovigilance is mainly based on spontaneous reports: when suspecting an adverse drug reaction, health care practitioners send a report to a spontaneous reporting system (SRS). This produces huge databases containing numerous reports and their manual exploration is both cost and time prohibitive. Existing techniques that automatically extract relevant signals rely on statistics or Bayesian models but do not provide information to the experts about possible biases lying in the data, nor about the specificity of a signal to a particular patient profile. Our extraction method combines numerical methods from the state of the art with a qualitative approach that helps interpretation. We build a synthetic representation of the database that is used to (i) identify unexpected patterns and biases (ii) extract potentially relevant signals w.r.t. patient profiles (iii) provide traceability facilities between extracted signals and raw data.

Documentation in pharmacovigilance: using an ontology to extend and normalize Pubmed queries.

OBJECTIVES: To assess and understand adverse drug reactions (ADRs), a systematic review of reference databases like Pubmed is a necessary and mandatory step in Pharmacovigilance. In order to assist pharmacovigilance team with a computerized tool, we performed a comparative study of 4 different approaches to query Pubmed through ADR-drug terms. The aim of this study is to assess how an ontology of adverse effects, used to normalize and extend queries, could improve this search. MATERIAL AND METHOD: The ontological resource OntoEIM contains 58,000 classes and integrates MedDRA terminology. The entry point is a ADR-Drug term and the four methods are (i) a direct search on Pubmed (ii) a search with a normalized query enhanced with domain-specific Mesh Heading criteria, (iii) a search with the same elaborated query extended to the MeSH sub-hierarchy of the adverse effect entry and (iv) a search with a set of MedDRA terms grouped by subsomption in the OntoEIM ontology. For each of the 16 queries performed and analysed, relevant publications are selected "manually" by two pharmacovigilant experts. RESULTS: The recall is respectively of 63%, 50%, 67% and 74%, the precision of 13%, 26%, 29% and 4%. The best recall is provided by the ontology-based method, for 4 cases out of 16 this method returns relevant publications when the others return no results. CONCLUSION: Results show that an ontology-based search tool improves the recall performance, but other tools and methods are needed to raise the precision.

Discrepancy Between Personal Experience and Negative Opinion with Human Papillomavirus Vaccine in Web Forums.

While vaccines are intended to protect people from infectious diseases, public confidence in vaccination has evolved as patients have reservation about vaccination, with a major concern about its safety. Social media may help regulatory authorities to better understand opposition to vaccination and make informed decisions for better promotion of vaccines' benefits towards the public. Our objective was to explore French web forums for potential pharmacovigilance signals associated with human papillomavirus infections (HPV) vaccines. Among 138 posts associated with a signal randomly chosen for manual review, 29% were actually adverse drug reactions to the vaccine described in clinical studies, and only 2 were personal experiences. Only 14% of the reviewed posts described positive opinion about the vaccine whereas 46% were neutral and 40% were negative. While few personal experiences of adverse reactions were actually reported by users, our case study showed a large proportion of negative opinions.

Use of Social Media for Pharmacovigilance Activities: Key Findings and Recommendations from the Vigi4Med Project.

The large-scale use of social media by the population has gained the attention of stakeholders and researchers in various fields. In the domain of pharmacovigilance, this new resource was initially considered as an opportunity to overcome underreporting and monitor the safety of drugs in real time in close connection with patients. Research is still required to overcome technical challenges related to data extraction, annotation, and filtering, and there is not yet a clear consensus concerning the systematic exploration and use of social media in pharmacovigilance. Although the literature has mainly considered signal detection, the potential value of social media to support other pharmacovigilance activities should also be explored. The objective of this paper is to present the main findings and subsequent recommendations from the French research project Vigi4Med, which evaluated the use of social media, mainly web forums, for pharmacovigilance activities. This project included an analysis of the existing literature, which contributed to the recommendations presented herein. The recommendations are categorized into three categories: ethical (related to privacy, confidentiality, and follow-up), qualitative (related to the quality of the information), and quantitative (related to statistical analysis). We argue that the progress in information technology and the societal need to consider patients' experiences should motivate future research on social media surveillance for the reinforcement of classical pharmacovigilance.

Acute Digital Ischemia After Arterial Injection of Crushed Zolpidem Tablets: Role of Microcrystalline Cellulose? A Case Report.

Literature is scarce on acute ischemia after intra-arterial injection of crushed tablets and no effective medical treatment against the progression of lesions is reported. The only factor able to modify the outcome is the delay between injection and management by a specialized vascular team. Moreover the risk of necrosis seems higher after benzodiazepine intra-arterial injection than with other drugs. We tried to find out mechanistic explanations. We report on the case of a 31-year-old drug addict woman who self-injected into her left brachial artery crushed tablets of zolpidem. She developed an acute ischemia of the left hand, with necrosis of the intermediate and distal phalanges of fingers II, III, and IV. Angiogram of the left upper arm confirmed the distal arterial occlusions with no run-off after the palmar arch in the necrotic fingers. Once she was admitted into our vascular unit, intravenous vasodilator therapy by iloprost, heparin and local protective care were rapidly introduced. After delineation between living and necrotic tissues, she required distal amputations of the affected fingers. The clinical severity of arterial injections of benzodiazepine tablets is linked to the association of several pathophysiological mechanisms. Rather than related benzodiazepine pharmacologic effects with tissue ischemia, by the inhibition of phosphodiesterase, a vasodilator intermediate, or through the peripheral benzodiazepine-type receptor, the predominant mechanism is more likely in relation with microcrystalline cellulose, one component of zolpidem tablets, known as potential embolic agents. They are insoluble and resistant to degradation in water. These properties are probably prominent in the case we described here. Through this case report we want to drag attention of physicians in charge of a patient with acute ischemia after crushed tablet accidental intra-arterial injection, not only to look at the drug injected but also the other components of the tablet and especially to microcrystalline cellulose.

Pharmacology and social media: Potentials and biases of web forums for drug mention analysis-case study of France.

The aim of this study is to analyze drug mentions in web forums to evaluate the utility of this data source for drug post-marketing studies. We automatically annotated over 60 million posts extracted from 21 French web forums. Drug mentions detected in this corpus were matched to drug names in a French drug database (Theriaque®). Our analysis showed that a high proportion of the most frequent drug mentions in the selected web forums correspond to drugs that are usually prescribed to young women, such as combined oral contraceptives. The most mentioned drugs in our corpus correlated weakly to the most prescribed drugs in France but seemed to be influenced by events widely reported in traditional media. In this article, we conclude that web forums have high potential for post-marketing drug-related studies, such as pharmacovigilance, and observation of drug utilization. However, the bias related to forum selection and the corresponding population representativeness should always be taken into account.