Dataset Information

Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports.

ABSTRACT: Introduction:Since vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, particularly in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases. Two recent case reports have found a potential link between intravitreal anti-VEGF use and Parkinson's disease (PD) and dementia. Aim:To evaluate disproportionality in a large spontaneous reporting database concerning intravitreal anti-VEGF drugs and PD or dementia, and related conditions. Methods:Using VigiBase, individual case safety reports (ICSRs) attributed to intravitreal ranibizumab, aflibercept, pegaptanib, and bevacizumab were identified from 2010 to 2016. Within Standardised Narrow Medical Dictionary for Regulatory Activities (MedDRA®) Queries (SMQs) for "Parkinson-like events" and "Dementia," suspected events were identified using preferred terms (PTs). The Proportional Reporting Ratio (PRR) was estimated with the lower 95% confidence intervals (CIs) for all drug-event pairs with ?3 suspected events. The vigiGrade completeness score was reported for the ICSRs. The analyses were repeated, including only persons aged 65 and over. Results:Out of 18.9 million ICSRs, 7,945 (0.004%) concerned intravitreal anti-VEGF drugs. Of these, 27 (0.34%) were identified concerning the SMQs "Dementia" (N = 17, 62.96%) and "Parkinson-like events" (N = 10, 37.94%) in persons of all ages. Among persons age 65 and over, 4,758 (59.88% of relevant ICSRs) ICSRs were identified for anti-VEGF drugs. When restricting disproportionality analysis to persons aged 65 and over, no disproportionality was seen for any of the drug-event pairs at the level of SMQ. However, on analysing disproportionality by PT, a potential signal emerged for intravitreal ranibizumab and Parkinson's disease [N = 6 ICSRs; PRR: 3.05 (95% CI: 1.36-6.81)]. In general, the vigiGrade completeness score was low for all the ICSRs of interest, as no ICSR had a score >0.8. Conclusion:Present findings suggest a potential signal for Parkinson's disease related to intravitreal ranibizumab. This is supported by several biologically plausible mechanisms but requires confirmation through pharmacoepidemiological studies, especially because of the low number of cases.

SUBMITTER: Sultana J

PROVIDER: S-EPMC7080978 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports.

Sultana Janet J Scondotto Giulia G Cutroneo Paola Maria PM Morgante Francesca F Trifirò Gianluca G

Frontiers in pharmacology 20200312

<h4>Introduction</h4>Since vascular endothelial growth factor (VEGF) regulates several aspects of the central nervous system, particularly in dopaminergic neurons, VEGF inhibitors may be linked to Parkinson-like events and dementia, or variants of these diseases. Two recent case reports have found a potential link between intravitreal anti-VEGF use and Parkinson's disease (PD) and dementia.<h4>Aim</h4>To evaluate disproportionality in a large spontaneous reporting database concerning intravitrea ...[more]

PMID: 32226387

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Project description:IntroductionThe safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs).ObjectiveThis study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing on remdesivir, including a disproportionality analysis (DA) of ADRs.MethodsA dedicated algorithm enabled retrieval of all COVID-19 treatment-specific ICSRs. A severity algorithm based on co-reported medicines and symptoms enabled selection of tocilizumab with its well established safety profile as comparator for remdesivir. Descriptive statistics were used for general ICSR demographics for all COVID-19-specific medicines, remdesivir and tocilizumab individually and furthermore to present treatment patterns of medicines co-reported with remdesivir. A COVID-19 indication-focused DA was deployed to minimize confounding from underlying polysymptomatic disease.Results14,574 COVID-19-related ICSRs were entered into VigiBase during 2020. Remdesivir was the most common medicine reported. Of 4944 remdesivir ICSRs, where tocilizumab was not co-reported, 93% described remdesivir as the sole suspect medicine. Sixty percent of ICSRs concerned males, median age was 63 years and the majority originated from the Americas (72%). In 1089 (21%) of remdesivir ICSRs, data indicated severe/critical disease. Co-reported medicines peaked during the first 3 days of remdesivir treatment. The DA for the established tocilizumab and the new remdesivir were mainly in line with the safety profiles for both medicines but suggested new safety concerns. The most reported ADRs for remdesivir represented liver dysfunction, kidney injury, death and bradycardia.ConclusionGlobal COVID-19-related ADR reporting proved useful in providing information on ADRs as well as on treatment patterns in this patient group. Indication-focused disproportionality analysis, together with the use of a comparator with a known safety profile, proved effective in identifying known safety information and suggested new safety concerns for remdesivir.

Project description:IntroductionAdverse event reporting patterns vary between countries, reflecting differences in reporting culture, clinical practice and underlying patient populations. Japan collects about 60,000 domestic adverse event reports yearly and shares serious reports with the World Health Organization (WHO) Programme for International Drug Monitoring in VigiBase, the WHO global database of individual case safety reports. Understanding these reports in the global context can be helpful for regulators worldwide and can aid hypothesis-generation for Japanese-specific vulnerabilities to adverse drug reactions.ObjectiveThe objective of this study was to explore differences in the reporting of adverse events between Japan and other countries.MethodsvigiPoint is a method for data-driven exploration in pharmacovigilance. It outlines data subsets, pinpoints key features and facilitates expert review, using odds ratios subjected to statistical shrinkage to distinguish one data subset from another. Here, we compared 260,000 Japanese reports in E2B format classified as serious and received in VigiBase between 2013 and 2018 with 2.5 million reports from the rest of the world (of which 51% are from the USA). Reporting patterns for which the 99% credibility interval of the shrunk log-odds ratios were above 0.5 or below - 0.5 were flagged as key features. The shrinkage was set to the vigiPoint default corresponding to 1% of the size of the Japanese data subset. As a sensitivity analysis, additional vigiPoint comparisons were performed between Japan and, in turn, Africa, the Americas, the Americas except the USA and Canada, Asia and Europe.ResultsThere were higher reporting rates in Japan from physicians (83% vs. 39%) and pharmacists (17% vs. 10%). It was also more common to see reports with more than five drugs per report (22% vs. 14%) and with a single adverse event (72% vs. 45%). More than half of the Japanese reports had a vigiGrade completeness score above 0.8 compared with about one in five from the rest of the world. There were more reports than expected for patients aged 70-89 years and fewer reports for adults aged 20-59 years. Adverse events reported more often in Japan included interstitial lung disease, abnormal hepatic function, decreased platelet count, decreased neutrophil count and drug eruption. Adverse events reported less often included death, fatigue, dyspnoea, pain and headache. Drugs reported more often in Japan included prednisolone, methotrexate and peginterferon alfa-2b. Drugs reported less often included rosiglitazone and adalimumab as well as blood substitutes and perfusion solutions. The findings were generally robust to the sensitivity analysis except for the less often reported drugs, many of which were rarely reported in most countries, except in the USA.ConclusionAnalysis of Japanese adverse event reporting patterns in a global context has revealed key features that may reflect possible pharmaco-ethnic vulnerabilities in the Japanese, as well as differences in adverse event reporting and clinical practice. This knowledge is essential in the global collaboration of signal detection afforded by the WHO Programme for International Drug Monitoring.

Project description:IntroductionAngioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes.MethodsAll spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162).ResultsMore patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6-2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5-57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0-17.9]) and fibrinolytics (OR 7.8 [1.1-57.2]) was reported more often in ACEi versus ARBs angioedema reports.ConclusionThe reported clinical phenotypes differed between ACEi versus ARBs and aliskiren angioedema reports. Differences between the patient populations as observed in our study or differences with regard to underlying pathomechanisms could account for this finding. Due to the methodological limitations of spontaneous reporting systems, we cannot draw a firm conclusion in this regard. Hence, further research is necessary to confirm our observation and elucidate the underyling causes.

Dataset Information

Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports.

Publications

Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports.

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