Causality assessment between reported fatal cerebral haemorrhage and suspected drugs: developing a new algorithm based on the analysis of the Japanese Adverse Event Report (JADER) database and literature review.

Abstract

Cerebral haemorrhage is a life-threatening event with various causes including adverse drug reactions (ADRs). Several methods have been proposed for the causality assessment of ADRs, but none specific for cerebral haemorrhage. The purpose of this study was to develop an algorithm for causality assessment between drugs and fatal cerebral haemorrhage, based on the analysis of data from the Japanese Adverse Drug Event Report (JADER) database and literature review. All fatal ADRs reported in the JADER database between April 2004 and March 2020 were searched, and literature on drug-related cerebral haemorrhage or general causality assessment was reviewed to summarise the information on causality between cerebral haemorrhage and ADRs. Of the 50,095 cases identified in the JADER database, cerebral haemorrhage was the fifth most reported cause of fatal ADRs, but the causality of >80% of the events was published as 'Unassessable'. The literature review identified articles on drug-related cerebral haemorrhage and causality assessment methods in general. Based on these articles, information on five categories (temporal relationship, previous knowledge about the relationship between drug action and ADRs, alternative aetiological candidate, appropriateness of drug use, and the relationship between death and ADRs) was determined for causality assessment between a suspected drug and fatal cerebral haemorrhage; a new algorithm was created using this information. In this study, the information considered necessary for causality assessment between drugs and fatal cerebral haemorrhage was reviewed and an assessment algorithm was developed. Future studies are needed to validate the usefulness of this method.