Direct-Acting Oral Anticoagulants: Anticoagulant Activity in Understudied Older NVAF Patients
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PROJECT SUMMARY / ABSTRACT Direct acting oral anticoagulants (DOACs) are now the anticoagulants of choice for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) and are replacing warfarin for treatment of venous thromboembolic disease. NVAF is a common chronic condition in adults over age 55 with a lifetime risk of 37% and the highest prevalence at ages over 80 years. Yet, adults over 75-80 years of age have been under-represented in trials of DOACs. This deficit is key as many older adults with NVAF differ from younger adults with NVAF enrolled in clinical trials. Older NVAF patients often have multiple chronic conditions, reduced renal and hepatic drug clearance, receive multiple medications, have increased risks for falls and bleeding, and may include more women than men. We hypothesize that older adults with NVAF encountered clinically will have higher DOAC concentrations than expected from clinical trials. Our preliminary data shows higher than expected concentrations of the DOAC apixaban with under-dosing, and concentrations far in excess of those in clinical trials with recommended dosing. We propose to measure factor Xa-calibrated concentrations of rivaroxaban (renal clearance only) and apixaban (CYP3A4/5 metabolism and renal clearance) in medically stable adults over age 75 with NVAF receiving these DOACs for clinical indications at doses prescribed by providers. We will compare these concentration data to those from clinical trials and explore patient level characteristics (such as age, renal function, co-medications), associated with concentrations (peak and trough) that lie outside ranges expected from clinical trials. If the work determines that older adults with NVAF encountered clinically have different concentration responses to DOAC dosing compared to clinical trials, it will establish the need for further investigations to optimize DOAC efficacy and safety in older adults with NVAF, may identify unrecognized factors associated with high DOAC concentrations, and may support a role for monitoring DOAC concentrations in selected patients. If the work fails to detect different concentration responses to DOAC dosing in older adults with NVAF, it will support initiatives to reduce the current prevalence of lower than recommended DOAC dosing
