Abstract
We examined the time-to-onset of interstitial lung disease, cerebral hemorrhage, and gastrointestinal hemorrhage in very elderly patients with atrial fibrillation treated with direct oral anticoagulants (DOACs) by using data from the Japanese Adverse Drug Event Report Database (JADER). We compared the time-to-onset of each adverse drug reaction (ADR) based on age or dose for each DOACs. The median values of the time-to-onset ranged from 40 to 124 days for interstitial lung disease while those for gastrointestinal hemorrhage ranged from 60.5 to 91 days, they were no significant difference between the age or drug-dose groups. For cerebral hemorrhage, the median values ranged from 124.5 to 331.5 days, therefore the time-to-onset of cerebral hemorrhage was delayed compared to that of gastrointestinal hemorrhage. Especially, the median value of the factor Xa inhibitors (FXA) high dose (HD) and age 80≤ group showed 331.5 days, which was delayed compared to that in the FXA low dose (LD) and age 80≤ group’s 143 days or the FXA HD and age <80 group’s 175 days. The cerebral hemorrhage occurred not less than a year after dosing, and therefore symptoms of cerebral hemorrhage and continuous symptom management of hypertension need to be carefully monitored in not only early stage but also late treatment stages in FXA HD and age 80≤ patients. This study showed that the analysis using JEDAR could enhance understanding of the time-to-onset of ADRs in very elderly, which were difficult to be collected in clinical trials during drug development. Furthermore, it was suggested that time-to-onset of each ADRs was independently occurred. These findings contribute to grasp time-to-onset of the ADRs and appropriate management of ADRs in the clinical practice.
