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

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.

Is a Lower Dose of Rivaroxaban Required for Asians? A Systematic Review of a Population Pharmacokinetics and Pharmacodynamics Analysis of Rivaroxaban

“…The effect of age on CL/F was ≤30% and may not have significant clinical relevance as the drug label recommended by the FDA [ 45 ]. However, it should be noted that elderly patients in the real world have more concomitant diseases and are prone to have an unstable morbid state [ 51 ]. Besides the risk of increased PK exposure, elderly patients also have a higher risk of thrombotic and bleeding events.…”

Drug-related problems associated with direct oral anticoagulants: an observational cross-sectional study of medical record review by pharmacists in a large teaching hospital

“…Unlike our study, this study focused on DRPs in general and not specific to DOAC therapy [ 29 ]. Other studies showed that elderly patients on DOACs for AF were at higher risk of bleeding compared with younger patients [ 30 ], had multiple comorbidities and higher mortality risk, and required drug therapy optimization to prevent poor outcomes [ 31 ]. Our study population was heterogenous, with patients on DOACs for multiple indications, and had wider age distribution, and hence, we did not find an association between age and comorbidities with DOAC-associated DRPs.…”

Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients

“…We found that daily DOAC dose changes took place for a number of the patients in this cohort after the study was completed and these were decided independently of the present study findings. Apart from drug exposure, dose adjustment should also allow for elderly patients being inherently sensitive to DOACs as recent findings on rivaroxaban show 21 …”

“…Apart from drug exposure, dose adjustment should also allow for elderly patients being inherently sensitive to DOACs as recent findings on rivaroxaban show. 21 There are dose-response data available from phase III clinical trials of DOACs. A subanalysis of the RE-LY trial data by the manufacturer of dabigatran, Boehringer Ingelheim (Bracknell, Berkshire, UK), which included 9 183 patients (75% of patients in the RE-LY trial), with 112 ischaemic strokes/systemic emboli (1Á3%) and 323 major bleeds (3Á8%), showed that there were five-fold variations in plasma dabigatran concentration for each of the two doses (110 and 150 mg) that were tested.…”