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Edoxaban or standard therapy with warfarin for stroke prevention in patients with atrial fibrillation “...challenges with vitamin K antagonists [have] led to the discovery and development of target-specific oral anticoagulants...”
Anna Plitt1
Robert P Giugliano*,1,2
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting over 2.2 million people in the USA. It increases the risk of ischemic stroke by a factor of 4–5 and is associated with high mortality [1] . Vitamin K antagonists (VKAs) have been the standard of treatment for prevention of stroke in patients with AF as they reduce the risk of stroke by approximately 64% compared to placebo [2] . However numerous limitations such as a narrow therapeutic window, slow onset and offset of action, wide interpatient variability in metabolism, multiple drug–drug and food–drug interactions, and need for frequent level monitoring lead to poor patient adherence, inadequate anticoagulation [3] and, too often, lack of treatment [4] . These challenges with VKAs led to the discovery and development of target-specific oral anticoagulants (TSOACs). The newest oral factor Xa inhibitor to complete Phase III testing is edoxaban developed by Daiichi Sankyo (Tokyo, Japan). Edoxaban is a direct oral factor Xa inhibitor with 62% bioavailability, rapid onset of action (1–2 h), 50% renal clearance and a half life
of 10–14 h [5,6] . Edoxaban is approved for use in Japan to prevent venothromboembolism in patients undergoing hip and knee surgery. In a large double-blind, doubledummy trial of 8292 patients with symptomatic venothromboembolism known as HOKUSAI-VTE, edoxaban 60 mg once daily was shown to be as effective as warfarin and reduced bleeding [7] . A Phase II trial in patients with atrial fibrillation established that once daily edoxaban was safer than twice daily dosing, and led to Phase III testing [8] . Pharmacokinetic and pharmacodynamic analyses established that the nadir (trough) edoxaban level (rather than the peak or area-under-the-curve) was most predictive of bleeding [9] ; hence once-daily dosing, which achieves a lower nadir concentration, was associated with less bleeding than the same total daily dose administered twice daily. The ENGAGE AF-TIMI 48 trial was conducted in 1393 centers in 46 countries enrolling 21,105 patients with atrial fibrillation at moderate or high risk for stroke (CHADS2 score ≥2) [6] . Patients were
KEYWORDS
• anticoagulation • atrial fibrillation • edoxaban
“...numerous limitations ... lead to poor patient adherence, inadequate anticoagulation and, too often, lack of treatment.”
Harvard Medical School, MA 02115, USA TIMI Study Group, Division of Cardiovascular Medicine, Brigham & Women’s Hospital, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115, USA *Author for correspondence: Tel.: +1 617 732 4837; Fax: +1 617 734 7329; [email protected] 1 2
10.2217/FCA.14.3 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(2), 153–155
part of
ISSN 1479-6678
153
Editorial Plitt & Giugliano
“There are many reasons to select edoxaban (assuming regulatory approval) over warfarin in patients with atrial fibrillation.”
154
randomized in a double-blind, double-dummy fashion to receive either high-dose edoxaban, low-dose edoxaban or warfarin adjusted to achieve an international normalized ratio of 2.0–3.0. The high-dose regimen of edoxaban was 60 mg once daily and low-dose was 30 mg once daily. In both edoxaban groups, a 50% dose reduction was implemented in selected patients with anticipated reduced clearance of edoxaban (due to renal impairment, low body weight, or use of a strong P-glycoprotein inhibitor) to permit similar drug concentration as in patients without any of these factors. In the primary noninferiority analysis of patients while on treatment, both doses of once daily edoxaban were noninferior to warfarin in reducing stroke or systemic embolic events (SEE). The higher dose reduced SEE and stroke risk by 21%, while the lower dose was comparable to warfarin. In the formal superiority analysis using the intention-to-treat (ITT) principle, there was favorable trend for reduction of stroke/SEE with high-dose edoxaban (hazard ratio [HR]: 0.87; p = 0.08), with an unfavorable trend with low-dose edoxaban (HR: 1.13; p = 0.10) versus warfarin. Both regimens of edoxaban markedly reduced hemorrhagic stroke (HR: 0.54 and 0.33 for high and low-dose edoxaban vs warfarin, respectively; both p
Edoxaban or standard therapy with warfarin for stroke prevention in patients with atrial fibrillation “...challenges with vitamin K antagonists [have] led to the discovery and development of target-specific oral anticoagulants...”
Anna Plitt1
Robert P Giugliano*,1,2
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting over 2.2 million people in the USA. It increases the risk of ischemic stroke by a factor of 4–5 and is associated with high mortality [1] . Vitamin K antagonists (VKAs) have been the standard of treatment for prevention of stroke in patients with AF as they reduce the risk of stroke by approximately 64% compared to placebo [2] . However numerous limitations such as a narrow therapeutic window, slow onset and offset of action, wide interpatient variability in metabolism, multiple drug–drug and food–drug interactions, and need for frequent level monitoring lead to poor patient adherence, inadequate anticoagulation [3] and, too often, lack of treatment [4] . These challenges with VKAs led to the discovery and development of target-specific oral anticoagulants (TSOACs). The newest oral factor Xa inhibitor to complete Phase III testing is edoxaban developed by Daiichi Sankyo (Tokyo, Japan). Edoxaban is a direct oral factor Xa inhibitor with 62% bioavailability, rapid onset of action (1–2 h), 50% renal clearance and a half life
of 10–14 h [5,6] . Edoxaban is approved for use in Japan to prevent venothromboembolism in patients undergoing hip and knee surgery. In a large double-blind, doubledummy trial of 8292 patients with symptomatic venothromboembolism known as HOKUSAI-VTE, edoxaban 60 mg once daily was shown to be as effective as warfarin and reduced bleeding [7] . A Phase II trial in patients with atrial fibrillation established that once daily edoxaban was safer than twice daily dosing, and led to Phase III testing [8] . Pharmacokinetic and pharmacodynamic analyses established that the nadir (trough) edoxaban level (rather than the peak or area-under-the-curve) was most predictive of bleeding [9] ; hence once-daily dosing, which achieves a lower nadir concentration, was associated with less bleeding than the same total daily dose administered twice daily. The ENGAGE AF-TIMI 48 trial was conducted in 1393 centers in 46 countries enrolling 21,105 patients with atrial fibrillation at moderate or high risk for stroke (CHADS2 score ≥2) [6] . Patients were
KEYWORDS
• anticoagulation • atrial fibrillation • edoxaban
“...numerous limitations ... lead to poor patient adherence, inadequate anticoagulation and, too often, lack of treatment.”
Harvard Medical School, MA 02115, USA TIMI Study Group, Division of Cardiovascular Medicine, Brigham & Women’s Hospital, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115, USA *Author for correspondence: Tel.: +1 617 732 4837; Fax: +1 617 734 7329; [email protected] 1 2
10.2217/FCA.14.3 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(2), 153–155
part of
ISSN 1479-6678
153
Editorial Plitt & Giugliano
“There are many reasons to select edoxaban (assuming regulatory approval) over warfarin in patients with atrial fibrillation.”
154
randomized in a double-blind, double-dummy fashion to receive either high-dose edoxaban, low-dose edoxaban or warfarin adjusted to achieve an international normalized ratio of 2.0–3.0. The high-dose regimen of edoxaban was 60 mg once daily and low-dose was 30 mg once daily. In both edoxaban groups, a 50% dose reduction was implemented in selected patients with anticipated reduced clearance of edoxaban (due to renal impairment, low body weight, or use of a strong P-glycoprotein inhibitor) to permit similar drug concentration as in patients without any of these factors. In the primary noninferiority analysis of patients while on treatment, both doses of once daily edoxaban were noninferior to warfarin in reducing stroke or systemic embolic events (SEE). The higher dose reduced SEE and stroke risk by 21%, while the lower dose was comparable to warfarin. In the formal superiority analysis using the intention-to-treat (ITT) principle, there was favorable trend for reduction of stroke/SEE with high-dose edoxaban (hazard ratio [HR]: 0.87; p = 0.08), with an unfavorable trend with low-dose edoxaban (HR: 1.13; p = 0.10) versus warfarin. Both regimens of edoxaban markedly reduced hemorrhagic stroke (HR: 0.54 and 0.33 for high and low-dose edoxaban vs warfarin, respectively; both p
