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Identifying systemic safety signals following intravitreal bevacizumab: systematic review of the literature and the Canadian Adverse Drug Reaction Database

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      Abstract

      Objective: As the off-label use of intravitreal bevacizumab continues for an increasing number of ocular conditions, a systematic review of the literature aimed at detecting temporally associated systemic adverse events was undertaken.
      Design: Systematic review of the literature and a health regulatory database.
      Participants: A total of 22 different clinical studies representing 12 699 patients
      Methods: A systematic review indexed by Ovid MEDLINE, EMBASE, ISI Web of Science, the Cochrane database (CENTRAL), and the Canadian Adverse Drug Reaction Information System Database was performed. All clinical studies with at least 100 eyes injected with bevacizumab and case reports documenting suspected events were included for review.
      Results: A total of 22 different clinical studies were reviewed, including an international internet survey, 6 retrospective studies assessing the safety of intravitreal bevacizumab, and 15 clinical trials. The most common adverse systemic event reported in these studies, representing 12 699 patients was an increase in blood pressure (0.46% of patients), followed by cerebrovascular accidents (0.21% of patients), and myocardial infarction (0.19% of patients). The 6 case reports documented suspected events not previously identified and only 1 systemic event from the Health Canada database was retrieved.
      Conclusions: The systemic events temporally associated with intravitreal bevacizumab are mainly of cardiovascular and neurological origin and can be predicted from an exaggerated pharmacology, although a causal association cannot be established at this time. Health Canada's spontaneous drug reporting system is an underutilized resource and a more active surveillance system such as a patient registry may be better suited to establish the low rates of systemic adverse events following bevacizumab use in ophthalmology.

      Résumé

      Objet: Puisqu'on continue d'utiliser hors étiquette le bévacizumab intravitréen pour un nombre croissant de maladies oculaires, une étude systématique de la littérature a été menée pour détecter les effets systémiques indésirables qui y sont temporairement associés.
      Nature: Revue systématique de la littérature et d'une base de donnees régulatrices sur la santé.
      Participants: En tout, 22 études cliniques différentes, représentant 12 699 patients.
      Méthodes: Revue systématique indexée par Ovid MEDLINE, EMBASE, ISI Web of Science, la base de données Cochrane (CENTRAL) et la base de données du Système canadien d'information sur les effets indésirables des médicaments. La revue a compris toutes les études portant sur au moins 100 yeux injectés de bévacizumab et les observations documentant les cas suspects.
      Résultats: En tout, 22 études cliniques différentes ont été examinées, soit un sondage international par Internet, 6 études rétrospectives évaluant la sécurité du bévacizumab intravitréen et 15 essais cliniques. L'effet systémique indésirable le plus commun signalé dans ces études, représentant 12 699 patients, a été une hausse de la pression sanguine (0,46 % des patients), suivie des accidents cérébrovasculars (0,21 % des patients) et des infarctus du myocarde (0,19 % des patients). Les 6 comptes-rendus ont documenté les cas suspects non identifiés auparavant et l'on n'a releveé qu'un seul cas systeémique de la base de donneées de Santeé Canada.
      Conclusions: Les cas systeémiques temporairement associeés au beévacizumab intravitreéen sont surtout d'origine cardio-vasculaire et neurologique et peuvent être prévus à la suite d'une réponse pharmacologique exagérée, bien qu'un lien de causalité ne puisse être établi à ce moment-ci. Le système de comptes-rendus pharmaceutiques spontanés de Santé Canada est une ressource sous-utilisée et un système de surveillance plus efficace, tel un registre de patients, pourrait mieux convenir pour établir les faibles taux d'effets indésirables à la suite de l'utilisation du bévacizumab en ophtalmologie.

      Keywords

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