Abstract
Direct oral anticoagulants are recommended as first line therapy for patients with atrial fibrillation and venous thromboembolic disease. Measurement of drug levels or pharmacodynamic effect is not recommended during treatment. Dose adjustments are based on age, weight, kidney function and drug-drug interactions. These adjustments are generally based on an estimate of their effect on drug concentration. DOAC dosing recommendations differ across the world. These differences in prescribing recommendations result in different levels of DOAC exposure in patients with identical clinical characteristics. Additionally, data from clinical trials has shown that drug levels may vary significantly in individual patients with identical clinical characteristics despite taking the same prescribed dose. More concerning is that current prescribing recommendations provide cut points for dose adjustments, as an example age 80 or greater in the case of apixaban in atrial fibrillation, which may result in dramatically higher drug concentrations in patients with significantly higher bleeding risk.
Data from outcome trials in both atrial fibrillation and venous thromboembolism have provided mean-median drug concentrations for each of the DOACs. These trial results appear to demonstrate that once a threshold DOAC plasma concentration is reached, higher concentrations fail to provide significant added ischemic stroke reduction while at the same time add an increased risk of bleeding. Bleeding remains a significant problem with DOACs and is associated with an increase in short and long-term mortality, ischemic stroke, myocardial infarction, cost, and drug interruption and discontinuation.
Over the past years, our clinic has been assessing DOAC concentration in patients at risk for under or over exposure. Based on our experience, clinical characteristics alone appear to be insufficient, as a significant number of patients with characteristics suggesting high exposure would be under-dosed using a purely clinical approach and an even greater number, who are at elevated risk of bleeding would have had excessive levels, if prescribing were based strictly on the established dose reduction criteria. We propose, and provide our supporting clinical experience, that measuring DOAC levels in select patients will increase the margin of safety of these medications without compromising efficacy.