BACKGROUND:The present study was performed to investigate which antiepileptic drug (AED) has the highest risk of drug-induced parkinsonism (DIP). OBJECTIVE:The aim was to evaluate associations between AEDs and DIP reports in the World Health Organization pharmacovigilance database, Vigibase. METHODS:Individual case safety reports (ICSRs) in patients ≥45 years registered between January 1, 2000 and June 31, 2024 with carbamazepine, lamotrigine, levetiracetam, or sodium valproate as "Parkinson-like events" (PLE) were extracted. Disproportionality analyses were performed, with cases being PLE and non-cases all other ICSRs. Results are shown as reporting odds ratios (ROR). RESULTS:Among 16,174,796 ICSRs, 3339 reported PLE with the four AEDs, mainly in females between 45 and 64 years. The highest ROR value was with valproate sodium (3.09 [2.01-3.29]), followed by lamotrigine (2.14 [2.01-2.28]), levetiracetam (1.43 [1.32-1.55]), and carbamazepine (1.09 [1.01-1.17]). DIP risk increased with the number of associated AEDs. CONCLUSIONS:Among AEDs, valproate sodium is associated with the higher risk of PLE and carbamazepine with the lowest.

OBJECTIVE:The present study was performed to investigate putative sex differences in the reporting of acetyl salicylic acid (ASA)-related bleeding in the global pharmacovigilance database. METHODS:Using Vigibase, the global pharmacovigilance database, all bleeding reports with ASA between January 1, 2008, and December 31, 2021, in adults were included. The main bleeding locations with ASA were compared in men versus women. A secondary objective was to analyze possible age differences. Results are presented as reporting odds ratios (RORs) with their 95% confidence interval. RESULTS:Among 29 034 bleeding with ASA, the most frequent were gastrointestinal (41.2%), neurological (21.3%), and nasal (13.6%). Higher ROR values were found in men for all bleeding in general (ROR = 1.56 [1.51-1.61]) but also for gastrointestinal, neurological, nasal, and renal locations. Similar trends were found for "serious" reports (except for gastrointestinal bleeding). Neurological fatal reports were more frequently reported in men. These sex differences were also found in all the age categories. Higher ROR values were found in patients from 65 years. CONCLUSION:The risk of total, "serious," and fatal bleeding reporting with ASA was higher in men than in women and after 65 years. Similar conclusions can be made for the most frequent locations of ASA-associated bleeding: gastrointestinal followed by neurological and nasal ones.

INTRODUCTION:Patient satisfaction is a key element in medical practice. Few studies have investigated patient satisfaction or dissatisfaction with their drug treatment. METHOD:Using the World Health Organization (WHO) global pharmacovigilance database, we investigated, through disproportionality analyses, potential associations between exposure to drugs and "patient dissatisfaction with treatment" reports. All reports of "patient dissatisfaction with treatment" in adults until 31/12/2024 were included. RESULTS/DISCUSSION:Results are expressed as reporting odds ratio (ROR). Among 506 reports, three quarters came from consumers, involving mainly women aged between 45 and 64. The main coreported term was drug inefficacy (before adverse drug reactions). The first anatomical therapeutic chemical (ATC) group was dermatological drugs (25.5%) followed by alimentary tract and metabolism (24.3%), nervous system (22.5%) drugs. A significant association was found with 22 drugs with the highest ROR values for plecanatide, efinaconazole and avatrombopag. CONCLUSION:Despite its mandatory limitations (underreporting, selective reporting…), this study shows that pharmacovigilance data could help to understand some aspects of social pharmacology, here, patient dissatisfaction with their drug treatment.

Bruxism is a movement disorder of uncertain aetiology. Beside local peripheral and central psychological factors, drugs were suspected. Using the World Health Organization (WHO) global pharmacovigilance database, Vigibase®, we investigated through disproportionality analyses potential associations between exposure to drugs and bruxism reports. All reports of bruxism in adults between 01/01/2000 and 31/12/2022 were included. Results are expressed as reporting odds ratio (ROR). Among the 564 reports of bruxism, an association was found with eight antidepressants (first sertraline followed by escitalopram, venlafaxine, vortioxetine, citalopram, paroxetine, fluoxetine, duloxetine) and four antipsychotics (first ziprasidone followed by aripiprazole, olanzapine, risperidone). A signal was also described for oxybate sodium and metoclopramide. For antidepressants, a negative association was found between ROR values and NET (norepinephrine transporter) but not SERT (serotonin transporter) pKi values, suggesting this ADR is more closely linked to norepinephrine than serotonin reuptake inhibition.

Rhabdomyolysis is a serious adverse drug reaction of statins. There are few studies comparing the risk of rhabdomyolysis between the different statins. Using the WHO pharmacovigilance database, VigiBase (R), we compared the risk of rhabdomyolysis reporting of seven statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, with cerivastatin excluded). All reports of rhabdomyolysis in VigiBase (R) in adults with statins until 31 December 2022 were included. Results are expressed as reporting odds ratio (ROR, 95% CI). Among 10 657 reports with rhabdomyolysis with statins, simvastatin was the highest risk statin in comparison with others: ROR = 2.20 (2.11-2.29). The risk was higher in men, older than 74 years and in cases of drug interactions.

Chaque année, près de 600 000 patients suivent une cure thermale dans les 90 stations thermales françaises. L’activité de médecine thermale avec ses 850 médecins thermaux donne lieu à 10 millions de journées de soins chaque année et correspond à 0,14 % des dépenses de l’assurance-maladie. Depuis 1947, les cures thermales sont prises en charge par la Sécurité Sociale, selon une grille de soins normalisés et adaptés à chaque pathologie. La cure thermale correspond à l’ensemble des thérapeutiques appliquées au patient pendant les 3 semaines de son séjour en station thermale. Ceci inclut, d’une part la crénothérapie, c’est-à-dire l’ensemble des soins thermaux (bains, douches, massages...) utilisant les eaux minérales et les produits dérivés (vapeurs, gaz thermaux, boues), mais aussi d’autre part, le changement de mode de vie, le repos associé à la cure et les soins non thermaux (rééducation fonctionnelle, éducation thérapeutique). Comme toute thérapeutique ancienne, les cures thermales doivent être évaluées de façon rigoureuse selon les méthodes modernes de la recherche clinique. Depuis 2004, l’Association Française de REcherche Thermale (AFRETh) promeut la recherche scientifique appliquée à l’évaluation du Service Médical Rendu des cures. Les études cliniques constituent la priorité de l’AFRETh mais celle-ci porte également son attention sur les travaux plus fondamentaux permettant une meilleure connaissance des produits thermaux et de leur mécanisme d’action, ainsi que sur les aspects populationnels comme les apports de la cure thermale en matière d’éducation de santé. Dans cet exposé, nous détaillerons les spécificités de cette recherche clinique en médecine thermale. L’essai clinique comparatif avec tirage au sort est la référence (gold standard) pour l’évaluation des médicaments. Son application stricto sensu s’avère plus délicate pour les cures thermales. Des méthodologies spéciales ont donc été développées (essai de type cure immédiate/cure retardée, méthode de Zelen…). Celles-ci ont permis la réalisation d’une vingtaine de grands essais thermaux dans notre pays. Nous présenterons les principaux résultats de ces essais en indiquant quelques pistes de développement méthodologique pour l’avenir.

The present study investigated the risk of bleeding when antidepressants are added to antithrombotics. Using data registered in VigiBase®, the WHO pharmacovigilance database, between 01/01/2000 and 31/12/2022, we compared the risk of reporting “serious” bleeding (Reporting Odds Ratio, ROR) with antidepressants + antithrombotics versus antithrombotics alone. Increased values of ROR were found for the association Serotonin Reuptake Inhibitors (SRIs) + Direct Oral Anticoagulants (DOACs) versus DOACs alone (ROR=1.49(1.17-1.89)). Similar results were found for Factor Xa inhibitors or Thrombin inhibitors. This association was also found for other antithrombotics: Vitamin K Antagonists (ROR=1.37(1.12-1.68)), Platelet Aggregation Inhibitors PAIs (ROR=1.38(1.21-1.57)) and Heparins (2.04(1.59-2.62)) but not with other antidepressants (Non-Selective Monoamine Reuptake Inhibitors, NSMRIs). The present study suggests an increased risk of “serious” bleeding when SRIs (but not NSMRIs) are associated with antithrombotics (all antithrombotics and not only DOACs).

Aims Clinical trials have found differences in bleeding locations between direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA). The present study was performed to investigate these differences in real life using reports of adverse drug reactions registered in the World Health Organization's pharmacovigilance database, VigiBase®. Methods All bleeding registered between 1 January 2008 and 31 December 2021 in adults were included. The main objective was to compare bleeding locations reported with DOAC with those with VKA. As a secondary objective, we performed the same comparison with Xa vs . thrombin inhibitors. Results were presented as reporting odds ratios (RORs) adjusted on age, gender, origin of reports and co‐medications with their 95% confidence interval. Results During this 14‐year period, 142 228 instances of bleeding were registered with oral anticoagulants, including 39 570 with VKA and 102 658 with DOAC. Mean time to event was lower with DOAC (7.6 months) than with VKA (29.9 months) ( P < .001). Significant differences in bleeding locations were found in the reports with less cerebral, urologic and nasal bleeding, more gynaecologic bleeding with DOAC than with VKA, without any significant differences in digestive and cutaneous locations. A higher risk of bleeding reports was found with Xa inhibitors vs . dabigatran whatever the locations (except digestive bleeding). Conclusion This real‐life study shows that the differences in bleeding locations between DOAC and VKA are not limited to the brain or gastrointestinal tracts. Significant differences were also found between Xa and thrombin inhibitors.

Aims Adverse drug reactions (ADRs) represent a significant public health burden. There are few data on fatal ADRs in children. This population is particularly at risk due to metabolic and physiological immaturity, frequent off-label drug use and limited paediatric clinical pharmacology studies. The study investigated the main characteristics of drug-related deaths registered in World Health Organization pharmacovigilance database, during the past decade. Methods Fatal outcomes registered between 2010 and 2019 in children (<18 y) and reported by physicians were investigated. Age, sex and suspected drugs were described and disproportionality analyses investigated differences according to sex, age and continents with calculation of reporting odds ratio and its 95% confidence interval. Results Among the 1 198 560 reports registered in children, 1585 (0.13%) were fatal. They occurred mainly in boys, aged 28 days-23 months. Reports mostly came from the Americas and Europe and involved, besides anti-infectious drugs (mainly vaccines), central nervous system (vigabatrin, paracetamol, methylphenidate horizontal ellipsis ) and antineoplastic/immunomodulating (mainly thalidomide) and cardiovascular (mainly bosentan) drugs without major differences between boys and girls. Large differences were found according to continents and age. The risk of reporting was higher in boys, in children aged <23 months, in the Americas and Africa. Conclusion Fatal ADRs represented a small part (around 1/1000) of total registered ADRs, occurred more frequently in boys and during the first 2 years of life. Beside anti-infectious drugs (vaccines), neuropsychiatric drugs were the most frequently involved, with large differences according to continents and classes of age.

A fifth vaccine against Covid-19, NVX-CoV2373 Nuvavoxid® (Novavax), a protein-based adjuvanted vaccine, was recently marketed in Europe. The main clinical trial before marketing concluded to a 'vaccine efficacy' of 89.7% without talking about other validated efficacy parameters. We further analysed the data of this clinical trial using the different validated methods of risk expression: absolute risks (AR), AR reduction (ARR) and number needed to treat (NNT). ARR and NNT values were 1.22% and 82, respectively, for an RR value of 0.10. Description of these parameters allowed defining some interesting characteristics of NVX-CoV2373 efficacy according to age, race, variant and coexisting illness. Finally, we ask that the results of clinical trials be systematically presented, using not only RR but also including AR, ARR and NNT.

Les essais cliniques ne représentent que la première phase d’évaluation des médicaments chez l’Homme. Ils restent bien sûr indispensables et irremplaçables. Cependant, les essais cliniques sont construits pour l’évaluation de l’efficacité des médicaments et non pas pour l’analyse des risques et des effets indésirables. Ils souffrent en effet de plusieurs insuffisances obligatoires, comme le petit nombre de sujets inclus, la sélection des participants, leur durée obligatoirement trop brève… par rapport à l’utilisation des médicaments dans la pratique clinique quotidienne. C’est dire tout l’intérêt de l’évaluation, dans la vraie vie, de la balance bénéfices/risques des médicaments après leur commercialisation. La pharmacovigilance est une partie majeure de cette analyse. Elle détecte les premiers signaux de sécurité par son rôle unique d’alerte et assure ensuite la quantification du risque à l’échelle populationnelle. Cette approche est désormais rendue plus performante grâce à l’utilisation des très grandes bases de pharmacovigilance, comme, par exemple, la Banque Nationale Française de PharmacoVigilance (BNPV) ou celle de l’OMS, VigiBase®. La BNPV comprend à ce jour 1 111 000 notifications d’effets indésirables médicamenteux et VigiBase® regroupe à ce jour près de 29 millions de notifications d’effets indésirables rapportés par plus de 160 pays répartis à travers le monde. Dans la base de Pharmacovigilance de l’OMS, 514 071 effets indésirables médicamenteux concernent les AVK et les AOD. Parmi ceux-ci, plus de la moitié (259 864) sont des saignements qui correspondent pour 35 % aux AVK, pour 14 % aux inhibiteurs de la thrombine et 51 % aux inhibiteurs du facteur Xa. Les saignements déclarés avec les AOD surviennent plus fréquemment chez les hommes que chez les femmes, pour 40 % dans la tranche d’âge de 75 ans et plus et concernent d’abord les hémorragies gastro-intestinales (19,9 %) puis les hémorragies (sans plus de précision) (9,3 %) et enfin les épistaxis (8,0 %). Dans cet exposé, nous discuterons les principales caractéristiques cliniques (âge, genre, localisation, médicaments associés, « gravité », létalité) des effets indésirables hémorragiques des AOD puis nous présenterons les différences entre inhibiteurs de la thrombine, inhibiteurs du facteur Xa et AVK. Nous terminerons en soulignant quelques interactions médicamenteuses méconnues à risque de saignements avec les AOD.