Development of apixaban: a novel anticoagulant for prevention of stroke in patients with atrial fibrillation

Abstract

The factor Xa inhibitor apixaban is one of the novel anticoagulants to emerge as alternatives to long-standing standards of care that include low-molecular-weight heparin and warfarin. The development of apixaban reflects a strategy to optimize the clinical pharmacology profile, dosing posology, trial designs, and statistical analyses across multiple indications, and to seek alignment with global health authorities. The primary objective of dose selection was to maintain balance between efficacy and bleeding risk. Twice-daily dosing of apixaban, rather than once daily, was chosen to lower peak concentrations and reduce fluctuations between peak and trough levels. Our discussion here focuses on the use of apixaban for stroke prevention in nonvalvular atrial fibrillation (NVAF). Supporting this indication, a pair of registrational trials was conducted that enrolled the full spectrum of patients who, by guidelines, were eligible for anticoagulation. In the AVERROES study of patients who were unsuitable for warfarin therapy, apixaban was superior to aspirin in reducing the risk of stroke or systemic embolism (SSE), without a significant increase in major bleeding (MB). In the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation) study, apixaban was superior to warfarin on the rates of SSE, MB, and all-cause mortality. Overall, these studies have demonstrated a substantially favorable benefit-risk profile for apixaban over warfarin and aspirin in NVAF.

Keywords: anticoagulation; apixaban; atrial fibrillation; factor Xa inhibition; stroke prevention.

Figure 1

Efficacy and bleeding outcomes in the phase II dose-ranging trial of apixaban for prevention of VTE following elective knee replacement surgery (APROPOS trial). Three total daily dose levels of apixaban were tested (5, 10, 20 mg), administered either qd (5 mg qd, 10 mg qd, 20 mg qd) or in divided doses bid (2.5 mg bid, 5 mg bid, 10 mg bid). Reflecting clinical practice patterns in the United States, two comparators were tested: enoxaparin 30 mg bid (subcutaneous administration) and warfarin (target INR range of 2–3). The phase III dose studied in trials for prevention of VTE was 2.5 mg bid, and the phase III dose studied in trials for stroke prevention in AF was 5 mg bid. Modified, with permission, from Lassen et al.

Figure 2

Kaplan–Meier curves for the primary efficacy and safety outcomes in the phase III warfarin-controlled trial of apixaban for stroke prevention in atrial prevention (ARISTOTLE trial). The primary efficacy outcome (Panel A) was stroke or systemic embolism. The primary safety outcome (Panel B) was major bleeding, as defined according to the criteria of the ISTH. Modified, with permission, from Granger et al.

Figure 3

Relative efficacy and safety of apixaban compared with warfarin as a function of center-based time-in-therapeutic range (TTR) in the phase III trial for stroke prevention in AF (ARISTOTLE trial). As previously described, a center-based TTR was calculated for each investigative site in the trial and comparisons of outcomes on apixaban and warfarin were made at each site. For each level of center-based TTR from 1% to 80% on the y-axis, an HR for apixaban versus warfarin was calculated from all sites with a TTR greater than or equal to each value on the y-axis. The bolded curves are the HRs for the efficacy and safety outcomes on apixaban versus warfarin at each level of TTR; also shown are the 95% CIs. The estimated HR remains below unity for both efficacy and bleeding; this suggests a persistent benefit of apixaban over warfarin over a wide range of TTR values. The dashed vertical line at a TTR = 70% indicates the site level mean TTR above which European Society of Cardiology guidelines, consider warfarin to be well controlled. Overall in ARISTOTLE, 75% of sites had a TTR >60%, 50% of sites had a TTR ≥66%, and 25% of sites had a TTR ≥71%. At sites in the United States, the overall TTR was 72%.

Figure 4

Relative efficacy and safety of novel oral anticoagulants in AF. HRs and 95% CIs are shown for the primary efficacy end point of stroke or systemic embolism (solid symbols) and for ISTH major bleeding (open symbols) in the phase III warfarin-controlled registrational trials for apixaban, rivaroxaban, and dabigatran.,,