What is the clinical evidence from this study?

Study design: Observational. Population: Healthy subjects (n=66). Intervention: Rivaroxaban vs. Young subjects. Primary outcome: Percentage change from baseline for Endogenous Thrombin Potential (ETP) (p=0.002).

What does this research mean for the field?

Elderly subjects are inherently more sensitive to the pharmacological activity of rivaroxaban than young subjects, exhibiting significantly greater suppression of endogenous thrombin potential and prolongation of clotting parameters ex-vivo. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

November 1, 2020Open Access

Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing

Key Result

Ex-vivo exposure to rivaroxaban suppressed endogenous thrombin potential to a significantly greater extent in elderly subjects compared to young subjects (-35.0% vs -29.8%).

Study Design

Type

Observational (n=66)

Multicenter

Structured PICO

Does age intrinsically affect the ex-vivo anticoagulation response to rivaroxaban in fit subjects?

Population

66 fit subjects, comprising 36 elderly (median age 83) and 30 young (median age 30) individuals providing blood samples

Intervention

Ex-vivo incubation of plasma samples with rivaroxaban (100-500 ng/ml)

Comparator

Young subjects' plasma samples incubated with the same concentrations of rivaroxaban

Outcome

Pharmacological activity of rivaroxaban measured by prolongation of Prothrombin Time (PT) and modified Prothrombin Time (mPT)surrogate

Main Result

Absolute Event Rate: -35% vs -29.8%

p-value: p=0.002

Limitations

Coagulation tests were performed ex vivo with plasma spiked with rivaroxaban rather than in vivo after oral dosing.
Lack of prospective clinical data to confirm if dose adjustment based on these findings reduces bleeding or thromboembolic events.

Abstract

According to both trial and clinical data on direct oral anticoagulants (DOACs) elderly patients are at greatest risk of bleeding. It is unclear whether age intrinsically affects anticoagulation response. To investigate the age-related sensitivity to DOACs, we compared the pharmacological activity of the direct factor Xa inhibitor, rivaroxaban, between young and elderly subjects ex-vivo. 36 fit elderly and 30 fit young subjects median (IQR) age: 83(75-87) vs 30(26-38) years provided a blood sample. Clotting parameters were measured in the resultant plasma samples incubated with rivaroxaban (100-500 ng/ml). Parametric, non-parametric tests and regression lines adjusted for rivaroxaban concentration and baseline values were used to compare data. Rivaroxaban produced a greater prolongation of both Prothrombin Time (PT) and modified Prothrombin Time (mPT) (both p < 0.001) in the elderly compared to young subjects (with difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). Factor X and factor II activity was significantly lower in the elderly in the presence of rivaroxaban (p < 0.001 for both). Rivaroxaban prolonged time-based parameters and suppressed the amount of thrombin generation to a significantly greater extent in the elderly compared to young subjects %change from baseline for Endogenous Thrombin Potential (ETP): - 35.0 ± 4.4 vs - 29.8 ± 7.4 nM*min; p = 0.002. The use of validated DOAC assays will be of considerable benefit for monitoring elderly patients who, because of their increased sensitivity to rivaroxaban, may require lower doses of the drug for therapeutic anticoagulation.

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