Supplement to Direct-Acting Oral Anticoagulants: Anticoagulant Activity in Understudied Older NVAF Patients

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PROJECT SUMMARY 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 older adults with the highest prevalence at ages over 80 years, yet very old adults have been largely excluded from efficacy trials of DOACs. This deficit is key as very old patients with NVAF differ from younger NVAF patients enrolled in clinical trials as they often have other chronic conditions treated with multiple medications, have a higher proportion of women than men, may have reduced renal and hepatic drug clearance, and increased risk of falls and bleeding. We hypothesize that very old NVAF patients will have higher DOAC concentrations than seen in the clinical trials. We have preliminary data showing that lower than recommended dosing achieved concentrations similar to recommended dosing and recommended dosing produced concentrations far in excess of those seen in the clinical trials for one DOAC (apixaban). We propose to measure rivaroxaban (renal clearance only) and apixaban (CYP3A4/5 metabolism and renal clearance) factor Xa concentrations in stable NVAF patients over age 75 receiving these DOACs for clinical indications at doses prescribed by their providers. We will compare the concentration data to reports from clinical efficacy trials and explore patient level characteristics (such as age, sex, race, obesity, renal function, clinical conditions, co-medications, frailty), to identify factors associated with trough and peak concentrations that lie outside ranges expected from clinical trials. If our work confirms that higher than expected DOAC concentrations are reached in older patients with NVAF, it has both implications for future research and current clinical care. The work will establish the need for larger definitive studies assessing clinical outcomes of varying dosing strategies in older patients, and, provide estimates of potential magnitudes of difference and variability in clinical populations to estimate sample sizes for these larger definitive studies. The data may also identify potential contributors to underlying mechanism responsible for clinical subgroup difference on which to base further hypothesis testing. The results may also immediately impact clinical care of older patients with NVAF that differ from those in randomized trials by suggesting a role for monitoring factor Xa inhibition or DOAC concentrations during clinical care or when considering dosing outside of published guidelines.