Safe and Effective Anticoagulation: What Does Drug Concentration Add?

Abstract

Patients with atrial fibrillation (AF), particularly older adults with multiple chronic conditions, have a high risk of stroke. Stroke is the number one concern of patients with AF and the main reason they take oral anticoagulation. The introduction of the direct-acting oral anticoagulants (DOACs), apixaban, rivaroxaban, dabigatran, and edoxaban, represents an important advancement in the safe and effective prevention of stroke in older patients with AF. There is solid evidence that apixaban, dosed according to label instructions for stroke prevention in AF, is associated with less stroke, less bleeding, and less death than warfarin. However, providers may undertreat and/or underdose the oldest patients with AF with a “start low and go slow” approach and with concern that older adults are underrepresented in US Food and Drug Administration registration trials. Indeed, up to 13% of older patients with AF are underdosed with DOACs in clinical practice, risking less effectiveness in stroke prevention for a possible reduction in bleeding. But there is no evidence to support this approach. In this issue of the Journal of the American Geriatrics Society, Sukumar et al present pharmacokinetic data on a convenience sample of 110 older patients with AF (average age, 80 years) to explore the effect of apixaban underdosing on drug concentrations. While nearly half of their population was underdosed based on apixaban’s labeling, apixaban concentrations outside the expected range were not related to underdosing. Apixaban concentrations lower than expected occurred in two patients (one receiving reducedand one receiving full-dose apixaban), and concentrations higher than expected occurred in 10 patients (four receiving reducedand six receiving full-dose apixaban). They also present information on median apixaban concentrations. Without bleeding or stroke outcomes, the significance of these observations is unclear. In our experience, few older patients with AF are interested in their apixaban concentrations; most want to know whether they are at risk for stroke or bleeding. If a patient’s sole priority is to avoid bleeding, the patient should not take an anticoagulant. If a patient’s priority includes preventing stroke, apixaban, as labeled, is much safer than warfarin and at least equally effective for stroke prevention, irrespective of age, polypharmacy, multimorbidity, or any single criterion for dose reduction. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, in which 31% of patients (n = 5678) were aged 75 years or older and 13% of patients (n = 2222) had high multimorbidity, more closely represented a community-based treated population than many prior trials. Therefore, the small sample (n = 110; age range = 66-100 years) studied by Sukumar et al is likely to match individuals in the ARISTOTLE trial. In this regard, subgroup analyses of ARISTOTLE that show consistent or greater benefit of apixaban over warfarin in the oldest patients, those with multimorbidity, and those with polypharmacy support use as labeled, even in high-risk subgroups. Apixaban, like all of the DOACs, was developed with the expressed advantage over warfarin that therapeutic drug monitoring was not required for use. The apixaban concentrations referenced by Sukumar et al were modeled (not observed) peak and trough values from samples collected in a series of phase 1 and 2 clinical trials at random time intervals from last apixaban dose and at the 2-month visit in a subset of ARISTOTLE (n = 2932). These are not therapeutic ranges; Sukumar et al found that 12 of 110 patients (11%) had an apixaban concentration outside of the 5th to 95th percentile expected range—exactly as expected. The dose-reduction strategy used for apixaban in ARISTOTLE, and included in the label, was developed to avoid exposing patients to high concentrations of apixaban if they had high risk of bleeding or apixaban exposure. Importantly, data from phase 2 studies establish a relationship between apixaban dose and concentration and bleeding (safety), but not stroke (efficacy). A subgroup analysis of ARISTOTLE suggests that apixaban, 2.5 mg twice daily (in those with two dose reduction criteria), results in similar reductions in stroke and bleeding compared with warfarin as apixaban, 5.0 mg twice daily (in those without two dose reduction criteria). However, the two DOAC programs that did randomize patients to lower and higher doses of anticoagulant—dabigatran randomized evaluation of long-term anticoagulation therapy (RE-LY) and edoxaban effective anticoagulation with factor xa next generation in atrial fibrillation (ENGAGE AF)— both found that lower doses were associated with more stroke than higher doses. Therefore, whether 2.5 mg of apixaban twice daily is adequate to prevent stroke in patients without two dose reduction criteria is unknown. The strongly held desire to do no harm to older patients is well founded, but must include using drugs at DOI: 10.1111/jgs.15981