Inappropriate low dosing of direct oral anticoagulants in older patients with non-valvular atrial fibrillation: Impact on plasma drug levels

Comans, Anne Lore; Sennesael, Anne Laure; Bihin, Benoît; Regnier, Maxime; Mullier, François; Saint-Hubert, Marie de

doi:10.1016/j.thromres.2021.02.034

Cited by 3 publications

(4 citation statements)

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“…7 Our data show similar or even greater CVs compared to those of previous observational studies conducted in patients rather younger than ours. [21][22][23][25][26][27]42,43 Interestingly, we found that the intake of amiodarone, which is both a CYP3A4/5 and a P-gp inhibitor, as well as the additional intake of another CYP3A4/5 modulator, significantly contributed to the increase of rivaroxaban trough levels, explaining part of the concentration variability consistently with data from pivotal trials. 20 Besides, renal function is known to influence the clearance of rivaroxaban, justifying dose adjustment in case of moderate renal impairment: we only observed a trend towards higher concentrations at T min with low CrCl, suggesting that the 25% rivaroxaban dose reduction was appropriate in our patients.…”

Section: Discussionsupporting

confidence: 74%

“…than those reported in SmPC (i.e. around 30% from the ARISTOTLE data set, mean age 70 years) and in previous studies [11,[18][19]23,24,[27][28][29][42][43]. Interestingly, the apixaban dose regimen was the only covariate that was significantly associated with plasma Cmax and Cmin in multivariate analysis, in contrast to rivaroxaban; moreover, the apixaban regimen subsequently significantly impacted TG peakheight.…”

Section: Accepted Manuscriptmentioning

confidence: 60%

“…11 In addition, inter-individual variabilities were higher than those reported in SmPC (i.e., around 30% from the ARISTOTLE data set, mean age 70 years) and in previous studies. 11 18 19 23 24 27 28 29 42 43 Interestingly, the apixaban dose regimen was the only covariate that was significantly associated with plasma C max and C min in multivariate analysis, in contrast to rivaroxaban; moreover, the apixaban regimen subsequently significantly impacted TG peak height. If the apixaban dose regimen had been given according to the patient characteristics, one would have expected similar concentrations as for rivaroxaban.…”

Section: Discussionmentioning

confidence: 99%

“… 7 Our data show similar or even greater CVs compared to those of previous observational studies conducted in patients rather younger than ours. 21 22 23 25 26 27 42 43 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 74%

Section: Accepted Manuscriptmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

“… 7 Our data show similar or even greater CVs compared to those of previous observational studies conducted in patients rather younger than ours. 21 22 23 25 26 27 42 43 …”

Section: Discussionmentioning

confidence: 99%

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