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CC BY-NC-ND 4.0 · Thromb Haemost 2023; 123(04): 402-414
DOI: 10.1055/a-1981-1763
Coagulation and Fibrinolysis

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

Geoffrey Foulon-Pinto   *
1   Université Paris Cité, INSERM UMR-S-1140, Innovations Thérapeutiques en Hémostase, Paris, France
2   Service d'Hématologie Biologique, AP-HP. Université Paris Cité, Hôpital Lariboisière, Paris, France
,
Carmelo Lafuente-Lafuente   *
3   Service de gériatrie à orientation cardiologique et neurologique, AP-HP, Sorbonne Université, Hôpitaux universitaires Pitié-Salpêtrière-Charles Foix, Ivry-sur-Seine, France
4   CEpiA Team (Clinical Epidemiology and Ageing), Université Paris Est Créteil, INSERM, IMRB, Créteil, France
,
Georges Jourdi
1   Université Paris Cité, INSERM UMR-S-1140, Innovations Thérapeutiques en Hémostase, Paris, France
5   Research Center, Institut de Cardiologie de Montréal - Université de Montréal, Montréal, QC, Canada
,
Julien Le Guen
6   Service de Gériatrie, AP-HP. Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France
,
Fatoumata Tall
7   Service de Gériatrie, AP-HP. Université Paris Cité, Hôpital Rothschild, Paris, France
,
Etienne Puymirat
8   Service de Cardiologie, AP-HP. Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, France
,
Maxime Delrue
2   Service d'Hématologie Biologique, AP-HP. Université Paris Cité, Hôpital Lariboisière, Paris, France
,
Léa Rivière
9   Service de gériatrie aiguë polyvalente, Hôpital Charles-Foix, AP-HP Sorbonne Université, Ivry-sur-Seine, France, UFR Médecine Sorbonne Université, Paris, France
,
Flora Ketz
9   Service de gériatrie aiguë polyvalente, Hôpital Charles-Foix, AP-HP Sorbonne Université, Ivry-sur-Seine, France, UFR Médecine Sorbonne Université, Paris, France
,
Isabelle Gouin-Thibault
10   INSERM, CIC 1414 (Centre d'Investigation Clinique de Rennes), Université de Rennes, CHU de Rennes, Rennes, France
11   Service d'Hématologie Biologique, CHU de Rennes, Rennes, France
,
François Mullier 
12   Department of Laboratory Medicine, Namur Thrombosis and Hemostasis Center (NTHC), Université Catholique de Louvain, Yvoir, Belgium
13   Hematology-Hemostasis Laboratory, CHU UCL Namur, Yvoir, Belgium
,
Pascale Gaussem
1   Université Paris Cité, INSERM UMR-S-1140, Innovations Thérapeutiques en Hémostase, Paris, France
14   Service d'Hématologie Biologique, AP-HP. Université Paris Cité, Hôpital Européen Georges Pompidou, Paris, France
,
Eric Pautas
1   Université Paris Cité, INSERM UMR-S-1140, Innovations Thérapeutiques en Hémostase, Paris, France
9   Service de gériatrie aiguë polyvalente, Hôpital Charles-Foix, AP-HP Sorbonne Université, Ivry-sur-Seine, France, UFR Médecine Sorbonne Université, Paris, France
,
Thomas Lecompte
11   Service d'Hématologie Biologique, CHU de Rennes, Rennes, France
15   Université de Lorraine, Faculté de médecine de Nancy, Nancy, France
,
Emmanuel Curis   *
16   Université de Paris Cité, UR 7537 BioSTM (Biostatistics), Faculté de Pharmacie, Paris, France
,
Virginie Siguret    *
1   Université Paris Cité, INSERM UMR-S-1140, Innovations Thérapeutiques en Hémostase, Paris, France
2   Service d'Hématologie Biologique, AP-HP. Université Paris Cité, Hôpital Lariboisière, Paris, France
› Author Affiliations Funding Reagents were purchased thanks to a CONNY-MAEVA Charitable Foundation grant and the Société Française de Cardiologie. The funding sources had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data.
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Abstract

Background Although a growing number of very elderly patients with atrial fibrillation (AF), multiple conditions, and polypharmacy receive direct oral anticoagulants (DOACs), few studies specifically investigated both apixaban/rivaroxaban pharmacokinetics and pharmacodynamics in such patients.

Aims To investigate: (1) DOAC concentration–time profiles; (2) thrombin generation (TG); and (3) 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 one to five 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, and 79.5% receiving reduced-dose regimen. We observed important inter-individual variabilities (coefficient of variation) whatever the regimen, at C max [49–46%] and C min [75–61%] in 15 mg rivaroxaban and 2.5 mg apixaban patients, respectively. The dose regimen was associated with C max and C min 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/thromboembolic 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 a 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.

Keywords

apixaban - atrial fibrillation - elderly - rivaroxaban - thrombin generation

Authors Contribution

G.F.-P., V.S., G.J., and E.C. wrote the manuscript; C.L-L, V.S., E.P., and I.G.-T designed the research; C.L-L, J.L, E.P., and M.D. were clinical investigators; G.F.-P., V.S., G.J., F.T., F.K., and L.R. performed the research; G.F.-P., V.S., G.J., T.L., and E.C. analyzed the data; all authors reviewed the manuscript.


* These authors share equal authorship.


Supplementary Material



Publication History

Received: 09 August 2022

Accepted: 18 October 2022

Accepted Manuscript online:
17 November 2022

Article published online:
09 January 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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