Key result
Higher warfarin concentration is linked to ~32% higher cerebral small vessel disease risk per 100 ng/mL.
Why the study?
The associations between population pharmacokinetic-pharmacodynamic-derived warfarin exposure metrics, cerebral small vessel disease burden, and cognitive outcomes among older adults with ischemic stroke and non-valvular AF required investigation.
Do PopPK/PD-derived individualized warfarin exposure metrics better identify cerebral small vessel disease burden and cognitive impairment risk compared with conventional TTR and INR variability in elderly patients with ischemic stroke and non-valvular atrial fibrillation?
Cohort (n=300)
No
Do PopPK/PD-derived individualized warfarin exposure metrics better identify cerebral small vessel disease burden and cognitive impairment risk compared with conventional TTR and INR variability in elderly patients with ischemic stroke and non-valvular atrial fibrillation?
In elderly patients with ischemic stroke and non-valvular atrial fibrillation on warfarin, PopPK/PD-derived systemic drug exposure metrics (such as Cavgss and Cmaxss) better discriminate high cerebral small vessel disease burden and cognitive impairment risk than conventional TTR and INR variability.
Answers are grounded in this paper and cite their sources.
May warrant caution with higher warfarin exposure in older AF patients post-stroke; leaves open prospective validation of exposure-guided dosing.
Objective This study applied individual exposure metrics derived from population pharmacokinetic-pharmacodynamic (PopPK/PD) modelling to investigate the associations between warfarin anticoagulation quality, cerebral small vessel disease (CSVD) burden, and cognitive outcomes among older adults with ischemic stroke and non-valvular atrial fibrillation (NVAF). Methods We included 300 patients aged ≥65 years with ischemic stroke and AF who had received warfarin for ≥3 months between January and December 2025. A nonlinear mixed-effects model was used to estimate individualized pharmacokinetic parameters and steady-state exposure metrics. Multivariable regression was performed to assess the associations of these metrics with CSVD burden, cognitive impairment, and the composite endpoint; the ability to identify high CSVD burden was compared between model-derived exposure metrics and conventional anticoagulation quality metrics, including time in therapeutic range (TTR) and international normalized ratio (INR) variability. Results Steady-state average concentration (Cavg ss ) was significantly positively associated with CSVD burden (per 100 ng/mL increment: OR = 1.32, p < 0.001), whereas TTR was not associated with burden ( p = 0.444). High CSVD burden was significantly associated with cognitive impairment (Cox HR = 2.04, p = 0.007). The incidence of cognitive impairment increased stepwise across exposure tertiles (42.2%, 54.0%, and 75.4%, p < 0.001). The composite endpoint occurred significantly more often in patients with INR standard deviation (INR_SD) > 0.5 ( p = 0.009). For identifying high CSVD burden, PopPK/PD-derived exposure parameters demonstrated differing within-cohort discrimination for identifying high CSVD burden: steady-state peak concentration (Cmaxss), Cavgss, and degree of fluctuation (DF) (AUC = 0.695, 0.679, and 0.651, respectively), with better discrimination compared with INR_SD and TTR (AUC = 0.557 and 0.493, respectively; p < 0.05). Conclusion Within this cohort, PopPK/PD-derived individualized exposure parameters showed better discrimination for identifying patients with high CSVD burden compared with traditional TTR and INR variability, although discriminative ability remained modest for all markers, including those whose anticoagulation quality appeared adequate by conventional metrics. These findings provide a pharmacological foundation for refined anticoagulation quality assessment in this high-risk elderly population.
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Zhao et al. (2026) conducted a cohort in Ischemic stroke and non-valvular atrial fibrillation (n=300). Warfarin steady-state average concentration (Cavgss, per 100 ng/mL increase) vs. Conventional anticoagulation quality metrics (TTR, INR_SD) / lower Cavgss exposure was evaluated on High cerebral small vessel disease (CSVD) burden (total CSVD score ≥ 3) (OR 1.32, 95% CI 1.13–1.55, p=<0.001). Higher steady-state average warfarin concentration (Cavgss) was associated with increased risk of high cerebral small vessel disease burden (OR 1.32 per 100 ng/mL, p<0.001) and cognitive impairment.
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