Assessment of DOAC in GEriatrics (Adage Study): Rivaroxaban/Apixaban Concentrations and Thrombin Generation Profiles in NVAF Very Elderly Patients

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: 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 (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.

Thrombosis and Haemostasis 2023 Editors' Choice Papers

“…We have published several studies last year, which investigated how age influences the management and efficacy of anticoagulation therapy. The Adage Study collaborators 2 collected real-life setting pharmacokinetic/pharmacodynamics data on the oral FXa inhibitors rivaroxaban and apixaban in aged atrial fibrillation (AF) patients. The high variability in drug levels observed should prompt improvement in DOAC dosing in this population.…”

Direct Oral Anticoagulants in the Very Elderly

“…The results of the study by Foulon-Pinto and colleagues must be interpreted with caution because there is no evidence that the reported pharmacokinetic or pharmacodynamic variables predict clinical outcomes. 13 Nonetheless, the findings provide valuable lessons for the management of very elderly patients with AF. First, although the pharmacokinetic and pharmacodynamic data do not inform the appropriateness of treating the very elderly with reduced DOAC doses in an off-label manner, the high variability in drug levels suggests that there is room for improvement in DOAC dosing in this population.…”

“…Drug levels were in turn correlated with measures of thrombin generation, but neither drug levels nor thrombin generation results were associated with clinical outcomes. 13 Six-month mortality rates ranged from 15 to 20% reflecting the advanced age of the study population. The incidence rates for major bleeding at 6 months with apixaban and rivaroxaban were 5 and 7%, respectively, and were higher than the incidence rates for thromboembolism of 4 and 1%, respectively.…”

“…In this issue of the journal, Foulon-Pinto and colleagues report the results of a study that explored the pharmacology of DOACs in very elderly patients with AF by measuring peak and trough blood levels of apixaban and rivaroxaban and their effects on thrombin generation in 215 hospitalized patients 80 years of age or older (mean: 87 years, 71% female). 13 Patients were eligible to participate if they had been treated with apixaban or rivaroxaban for at least 4 days. Blood samples collected 1 to 4 hours after the last DOAC dose were defined as peak levels and those taken 10 to 12 or 20 to 24 hours after the last dose of apixaban or rivaroxaban, respectively, were defined as trough levels.…”

“…Most patients (apixaban 85/111 [76.6%]; rivaroxaban 86/104 [82.7%]) enrolled in the study by Foulon-Pinto et al were receiving reduced DOAC doses. 13 Surprisingly, despite being under the care of health care providers at a major academic institution, one-third of those treated with reduced doses (62/171 [36.3%]) did not meet guideline criteria for dose reduction (“off-label” dosing), and an additional 10 patients (4.9%) were receiving a higher dose than recommended by the guidelines. Analyses restricted to results from patients receiving reduced DOAC doses revealed that despite the dose reduction, at peak, drug levels were above the 95th centile of those previously reported in the pivotal trials comparing the DOACs with warfarin for stroke prevention in AF in 32 and 31% of patients treated with apixaban and rivaroxaban, respectively, whereas at the trough, only 10 and 22%, respectively, of the levels were below the 5th centile.…”