Thrombosis and Haemostasis Assessment of DOAC in GEriatrics (ADAGE study): rivaroxaban/apixaban concentrations and thrombin generation profiles in NVAF very elderly patients academic prospective exploratory multicenter study

: Background: Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions and poly -pharmacy, receive direct oral anticoagulants (DOAC), few studies specifically investigated both apixaban/rivaroxaban pharma cokinetics and pharmacodynamics in such patients. Aims: To investigate: i/DOAC concentration-time profiles; ii/thrombin generation (TG); and iii/clinical outcomes 6-months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. Methods: ADAGE-NCT02464488 was an academic prospective exploratory multicenter study, enrolling AF in-patients aged 80-years, receiving DOAC for at least 4 days. Each patient had 1-5 blood samples at different time-points over 20-days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). Results: We included 215 patients (women 71.1%, mean age 87±4-years), 104-rivaroxaban and 111-apixaban, 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (CV) whatever the regimen, at Cmax [49-46%] and Cmin [75-61%] in 15mg-rivaroxaban and 2.5mg-apixaban patients, respectively. Dose regimen was associated with Cmax and Cmin plasma concentrations in apixaban (p=0.0058 and p=0.0222, respectively), but not in rivaroxaban samples (multi variate analysis). Moreover, substantial variability of thrombin peak-height (STG-Thromboscreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-pa -tients. After 6-month follow-up, major bleeding/thrombo-embolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. Conclusion: Our study provides original data in very elderly patients receiving DOAC in real-life setting, showing great interindividual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings. ABSTRACT Background: Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions and polypharmacy, receive direct oral anticoagulants (DOAC), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients. Aims: To investigate: i/DOAC concentration-time profiles; ii/thrombin generation (TG); and iii/clinical outcomes 6-months after inclusion in very elderly AF in-patients receiving rivaroxaban or apixaban. Methods: A an academic prospective exploratory multicenter study, enrolling AF in-patients aged  80-years, receiving DOAC for at least 4 days. Each patient had 1-5 blood samples at different time-points over 20-days. DOAC concentrations were determined using chromogenic assays. TG was investigated using ST-Genesia (STG-ThromboScreen, STG-DrugScreen). Results: We included 215 patients (women 71.1%, mean age 87±4-years), 104-rivaroxaban and 111-apixaban, 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (CV) whatever the regimen, at Cmax [49-46%] and Cmin [75-61%] in 15mg-rivaroxaban and 2.5mg-apixaban patients, respectively. concentrations in apixaban ( p= 0.0058 and p= 0.0222, respectively), but not in rivaroxaban samples (multivariate analysis). Moreover, substantial variability of thrombin peak-height (STG-Thromboscreen) was noticed at a given plasma concentration for both xabans, suggesting an impact of the underlying coagulation status on TG in elderly in-patients. After 6-month follow-up, major bleeding/thrombo-embolic event/death rates were 6.7%/1.0%/17.3% in rivaroxaban and 5.4%/3.6%/18.9% in apixaban patients, respectively. Conclusion: Our study provides original data in very elderly patients receiving DOAC in real-life setting, showing great inter-individual variability in plasma concentrations and TG parameters. Further research is needed to understand the potential clinical impact of these findings. deviation), and minimal and maximal values. Genetic