One of the most important advantages of direct oral anticoagulants (DOACs) over warfarin
is that DOACs can be given in fixed doses without routine coagulation monitoring,
which simplifies patient management, leading to their recommendation in many guidelines
globally.[1]
[2] Apixaban and rivaroxaban, which inhibit factor Xa, are the DOACs that are used most
often, and real-world data comparing these agents have been published.[3] Guidelines recommend reduced doses of DOACs in a subset of patients with risk factors
for drug accumulation, including older age, lower body weight, impaired renal function,
or concomitant use of interacting drugs.[4]
Age is an important driver of stroke risk in patients with atrial fibrillation (AF).[5] Very elderly patients have the highest prevalence of comorbid conditions that predispose
them to drug accumulation and are also amongst those at the highest risk of bleeding
complications.[6] Consequently, clinicians are often reluctant to prescribe anticoagulants or to use
the recommended doses of DOACs in the very elderly. Community-based registries consistently
demonstrate that up to one-half of very elderly patients with AF who have guideline
indications for oral anticoagulation remain untreated,[7]
[8] and many of those treated with a DOAC receive lower than recommended doses.[9]
[10]
[11] Also, such elderly AF patients represent a clinically complex phenotype, which is
associated with a higher risk of stroke and bleeding, as well as a greater risk of
anticoagulant discontinuation.[12]
In this issue of the journal, Foulon-Pinto and colleagues report the results of a
study that explored the pharmacology of DOACs in very elderly patients with AF by
measuring peak and trough blood levels of apixaban and rivaroxaban and their effects
on thrombin generation in 215 hospitalized patients 80 years of age or older (mean:
87 years, 71% female).[13] Patients were eligible to participate if they had been treated with apixaban or
rivaroxaban for at least 4 days. Blood samples collected 1 to 4 hours after the last
DOAC dose were defined as peak levels and those taken 10 to 12 or 20 to 24 hours after
the last dose of apixaban or rivaroxaban, respectively, were defined as trough levels.
Patients also underwent DNA testing to detect common polymorphisms in the genes involved
in the metabolism or transport of apixaban and rivaroxaban (CYP2J2, CYP3A4/5, and
ATP-binding cassette subfamily B member 1 [ABCB1] encoding P-glycoprotein).
Most patients (apixaban 85/111 [76.6%]; rivaroxaban 86/104 [82.7%]) enrolled in the
study by Foulon-Pinto et al were receiving reduced DOAC doses.[13] Surprisingly, despite being under the care of health care providers at a major academic
institution, one-third of those treated with reduced doses (62/171 [36.3%]) did not
meet guideline criteria for dose reduction (“off-label” dosing), and an additional
10 patients (4.9%) were receiving a higher dose than recommended by the guidelines.
Analyses restricted to results from patients receiving reduced DOAC doses revealed
that despite the dose reduction, at peak, drug levels were above the 95th centile
of those previously reported in the pivotal trials comparing the DOACs with warfarin
for stroke prevention in AF in 32 and 31% of patients treated with apixaban and rivaroxaban,
respectively, whereas at the trough, only 10 and 22%, respectively, of the levels
were below the 5th centile. These interesting findings suggest that the frequent off-label
dose reduction in this elderly population did not result in systemic underexposure
to apixaban or rivaroxaban because most of the out-of-range drug levels were higher
than those reported in the pivotal trials.
Dosing was an important determinant of the trough and peak levels in patients treated
with apixaban, but not in those treated with rivaroxaban, presumably because the reduced
dose of apixaban is 50% lower than the full dose, whereas the reduced dose of rivaroxaban
is only 25% lower than the full dose.[11] Clinical factors, most notably amiodarone use with or without co-administration
of specific CYP3A4/5 or ABCB1 modulators or loss or gain of function polymorphisms,
are important independent determinants of the variability in both apixaban and rivaroxaban
drug levels ([Fig. 1]).
Fig. 1 Independent determinants of drug levels of apixaban and rivaroxaban and thrombin
generation inhibition in patients with atrial fibrillation.
Drug levels were in turn correlated with measures of thrombin generation, but neither
drug levels nor thrombin generation results were associated with clinical outcomes.[13] Six-month mortality rates ranged from 15 to 20% reflecting the advanced age of the
study population. The incidence rates for major bleeding at 6 months with apixaban
and rivaroxaban were 5 and 7%, respectively, and were higher than the incidence rates
for thromboembolism of 4 and 1%, respectively.
The results of the study by Foulon-Pinto and colleagues must be interpreted with caution
because there is no evidence that the reported pharmacokinetic or pharmacodynamic
variables predict clinical outcomes.[13] Nonetheless, the findings provide valuable lessons for the management of very elderly
patients with AF. First, although the pharmacokinetic and pharmacodynamic data do
not inform the appropriateness of treating the very elderly with reduced DOAC doses
in an off-label manner, the high variability in drug levels suggests that there is
room for improvement in DOAC dosing in this population. Previous studies have shown
that extremes of drug levels predict clinical outcomes,[14] and it is possible that a tailored dosing strategy that incorporates information
about genotype and the concomitant use of one or more interacting drugs could reduce
variability in drug levels, thereby improving clinical outcomes. However, demonstrating
an improvement in clinical outcomes with a tailored strategy would require such a
large number of patients that it is unlikely that such a study will be performed.[14] Second, the finding that reduced kidney function had minimal effects on the variability
in drug levels is consistent with the known pharmacology of apixaban and rivaroxaban,
both of which are cleared via predominantly extra-renal pathways. Although guidelines
recommend regular monitoring of kidney function in patients treated with DOACs,[4] there is accumulating evidence that apixaban and rivaroxaban can be safely used
in those with advanced kidney disease because of the low risk of clinically important
drug accumulation. Third, the high rates of major bleeding relative to thromboembolic
events at 6 months in very elderly patients with AF may prompt clinicians to question
the net benefit of anticoagulant therapy in this high-risk population. However, advanced
age is one of the most powerful risk factors for thromboembolism in patients with
AF, and randomized trials with both warfarin[15] and very low-dose edoxaban[16] have demonstrated the efficacy of anticoagulation over no treatment for stroke prevention
in the very elderly. The low incidence rates of thromboembolism with apixaban and
rivaroxaban reported in this study are therefore most likely explained by the efficacy
of these agents because both are expected to reduce the risk of stroke by about two-thirds.
Accordingly, despite the high incidence rates for major bleeding, the best strategy
to reduce morbidity and mortality in the very elderly with AF is to prescribe DOACs
using the dosage regimens recommended by the guidelines.
