Dosing of Direct Oral Anticoagulants for stroke prevention in Atrial Fibrillation: Patterns, Consequences, and Guidance

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ABSTRACT Atrial fibrillation (AF) is a common disturbance in cardiac rhythm that impacts 5% of the U.S. population over age 65 and is associated with a five-fold increase in the risk of stroke. Anticoagulants are recommended for many elderly patients with AF to reduce the risk of stroke. Since 2010, four new oral anticoagulants for use in non-valvular AF have been approved in the U.S. These drugs are often referred to as ‘direct oral anticoagulants’ (DOAC) and include dabigatran, rivaroxaban, apixaban, and edoxaban. These new drugs have multiple advantages over previous options for anticoagulation, resulting in a rapid increase in use. In 2014, more than 10 million prescriptions for the new drugs were dispensed. DOACs are believed to have a predictable anticoagulation response in most patients. Nevertheless, some variability in drug absorption and elimination across patients exists, possibly resulting in drug concentrations that are either too high (leading to increased bleeding risk), or too low (leading to inadequate stroke prevention). Age and age-related chronic conditions such as renal impairment are key factors that impact drug absorption and elimination, and therefore effectiveness and safety. For most patients, standard doses are appropriate (e.g., dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily). Lower doses of each DOAC were also approved for specific patient subsets, such as those with impaired renal function). Unfortunately, information about the efficacy of low dose DOACs is sparse. For example, the low dose dabigatran (75 mg) was not included in the RE-LY clinical trial that was the basis for approving dabigatran for AF-related stroke prevention, while low dose apixaban (2.5 mg) was given to fewer than 5% of patients in the ARISTOTLE trial that was the basis for approving apixaban. Recent data indicates that the use of low dose DOACs is increasing, despite the paucity of evidence regarding outcomes in patients taking low dose DOACs. Moreover, data suggests that DOACs are often not dosed according to manufacturer guidelines. Proper DOAC dosing is particularly important for the elderly. Bleeding and stroke risk both increase with age, as does the presence of other conditions that impact drug elimination and absorption. In particular, the kidney undergoes age-related changes that translate into a progressive decline in renal function as people age. Thus, our specific aims are: 1. Evaluate DOAC dosing in elderly patients with new AF, and identify characteristics of patients who are frequently under- and over- anticoagulated according to approved guidelines. 2. Compare outcomes among elderly patients who are under, over, or adequately anti-coagulated, according to guidelines. Outcomes include medication use (e.g., adherence, persistence, change in dose), clinical outcomes (e.g., death, stroke, bleeding), and resource use (e.g., costs). 3. Explore additional patient characteristics that impact the safety of low or high dose DOACs.