Introduction
Direct oral anticoagulants (DOACs) are mainstay drugs in anticoagulation
therapy for non-valvular atrial fibrillation (NVAF), the most prevalent
form of atrial fibrillation (AF) [1]. NVAF is associated with a
five-fold increased risk of ischemic stroke [2, 3] and up to
1.9-fold increased risk of mortality [3] as compared to the healthy
population. As a result of DOACs’ non-inferiority compared to warfarin
in preventing stroke and systemic embolism (SSE) and significantly
superior safety profile in AF patients [4], existing guidelines
recommend the use of DOACs over warfarin for eligible patients
[5-7]. Furthermore, unlike warfarin, routine monitoring for DOACs is
not required due to their better efficacy-to-safety ratio, predictable
anticoagulant effects [8] and pharmacokinetics [9].
The US Food and Drug Administration previously approved rivaroxaban and
apixaban, two direct oral factor Xa inhibitors [10, 11], for use in
SSE prevention in patients with AF in 2011 and 2012 respectively
[4]. The recommended dose for rivaroxaban is 20 mg daily, decreased
to 15 mg daily for patients with moderate-severe renal impairment
[5]. The recommended dose for apixaban is 5 mg twice daily,
decreased to 2.5 mg twice daily if patients have any two of (1) serum
creatinine ≥1.5 mg/dL, (2) ≥80 years old, and (3) body weight ≤60 kg
[5]. Unlike warfarin, these labeled indications recommend a fixed
dose regimen for both DOACs.
Studies have, however, demonstrated high inter-individual variability in
drug concentrations amongst patients on DOACs and suggested association
between peak and trough of drug concentrations with bleeding and SSE
events respectively [12-14]. This inter-individual variability may
be altered by various factors, including other co-morbidities or the use
of concomitant medications. Furthermore, Weber et al illustrated the
bleeding risk from the use of DOACs in AF patients with chronic kidney
disease [15], while concomitant use of rivaroxaban and apixaban with
inhibitors of CYP3A4 enzyme, P-glycoprotein (P-gp) transporters, or
both, have been associated with high DOAC concentrations in AF patients
[16].
Ng et al demonstrated that Singaporeans had lower steady state
rivaroxaban concentrations than Caucasians [17], while another
Taiwanese study also identified lower rivaroxaban concentrations in
their population as compared to published Western literature [18],
thus suggesting potential differences in clinical disposition towards
DOACs for the Asian population. However, an expanded retrospective
cohort study involving 1700 Singaporeans revealed a prevalence of
bleeding to be higher than published literature for rivaroxaban
(manuscript to be published), seemingly a contradiction to the study by
Ng et al. Furthermore, a three-fold increase in SSE with apixaban was
observed in comparison to warfarin. Therefore, it seems that there may
be other factors at play that result in conflicting observations. Hence,
we aim to identify the correlation between the peak and trough
concentrations of DOACs with bleeding or SSE in an Asian population, and
to characterize other potential predictors that could also contribute to
these complications.