In atrial fibrillation epilepsy risk differs between oral anticoagulants: active comparator, nested case-control study.

AIMS: Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC). METHODS AND RESULTS: We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]. CONCLUSION: In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy.

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA2 -mediated adverse reactions? A combined epidemiological-experimental approach.

AIM: Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA2 ) and induce flushing. It is not known whether HCA2 mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA2 -mediated. METHODS: We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA2 expression. RESULTS: Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" (OR 1.3 [0.7-2.6]) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA2 was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]). CONCLUSION: The gastrointestinal ADRs common to both substances may be mediated by HCA2 . Other ADRs not common to both substances are compound or indication-specific reactions and likely do not involve HCA2 .

Metamizole and the risk of drug-induced agranulocytosis and neutropenia in statutory health insurance data.

The non-opioid analgesic metamizole (dipyrone) is used for the treatment of acute and chronic pain and fever. Agranulocytosis is known as a serious adverse drug reaction of metamizole with potentially fatal outcome. However, its frequency is controversially discussed. The aim of our study was to determine the risk of metamizole-associated agranulocytosis and neutropenia using statutory health insurance data. We analyzed data from a large German health insurance fund in the period from 2010 to 2013. Metamizole-exposed subjects were identified and compared to a propensity score-matched control cohort. A total of 630,285 metamizole-treated subjects and 390,830 matched control subjects were included. In the metamizole cohort, ICD codes for agranulocytosis and neutropenia appeared more often than in non-users. The relative risk for drug-induced agranulocytosis and neutropenia (D70.1) was 3.03 (95% confidence interval, 2.49 to 3.69). The risk for developing drug-induced agranulocytosis and neutropenia after metamizole prescription was 1: 1602 (CI 95%, 1:1926 to 1:1371). Our results confirm the risk estimation of previous studies. However, the outcome of our study may be confounded by an association of metamizole treatment and chemotherapy. Therefore, consequences for treatment have to be drawn with care.

[Detection of drug risks after approval : Methods development for the use of routine statutory health insurance data]. / Aufdeckung von Arzneimittelrisiken nach der Zulassung : Methodenentwicklung zur Nutzung von Routinedaten der gesetzlichen Krankenversicherungen.

Adverse drug reactions are among the leading causes of death. Pharmacovigilance aims to monitor drugs after they have been released to the market in order to detect potential risks. Data sources commonly used to this end are spontaneous reports sent in by doctors or pharmaceutical companies. Reports alone are rather limited when it comes to detecting potential health risks. Routine statutory health insurance data, however, are a richer source since they not only provide a detailed picture of the patients' wellbeing over time, but also contain information on concomitant medication and comorbidities.To take advantage of their potential and to increase drug safety, we will further develop statistical methods that have shown their merit in other fields as a source of inspiration. A plethora of methods have been proposed over the years for spontaneous reporting data: a comprehensive comparison of these methods and their potential use for longitudinal data should be explored. In addition, we show how methods from machine learning could aid in identifying rare risks. We discuss these so-called enrichment analyses and how utilizing pharmaceutical similarities between drugs and similarities between comorbidities could help to construct risk profiles of the patients prone to experience an adverse drug event.Summarizing these methods will further push drug safety research based on healthcare claim data from German health insurances which form, due to their size, longitudinal coverage, and timeliness, an excellent basis for investigating adverse effects of drugs.