Risk impact of edoxaban in the management of stroke and venous thromboembolism

Figures & data

Table 1 Edoxaban: summary information

Mode of action	Direct inhibitor of factor Xa
Indication/license	Treatment of DVT or PE and prevention of recurrence of symptomatic VTE Prevention of stroke and systemic embolic events in patients with AF
Dosage	30–60 mg
Dose regimen	Once daily
Reversal	Specific reversal not available. Consider prothrombin complex concentrate in emergency setting
Monitoring	No routine monitoring required
Periprocedure management	Edoxaban should be discontinued a minimum of 12 hours prior to procedure, and enoxaparin commenced at the same time as the next scheduled NOAC dose
Prodrug	None; edoxaban is a direct factor Xa inhibitor and active upon administration
Half-life	10–14 hours
Peak serum levels	1–2 hours
Excretion	Excretion predominantly in feces and urine Approximately 35% renal elimination
Use in pregnancy	Not recommended. Risks cannot be ruled out at present
Reduces efficacy of edoxaban, risk of stroke/embolism	CYP3A4 and P-gp inhibitors: HIV protease inhibitors, itraconazole, ketoconazole, clarithromycin
Increases edoxaban serum levels, risk of bleeding	CYP3A4 and P-gp inducers: carbamazepine, phenytoin, rifampicin Avoid edoxaban administration
Dose in renal impairment	50% dose reduction if GFR is 15–29 mL/min Do not use if GFR <15 mL/min
Bridging	Edoxaban should be discontinued and enoxaparin commenced at the same time as the next scheduled NOAC dose For conversion to warfarin, edoxaban should be discontinued once the patient’s INR is in therapeutic range
Monitoring	aPTT and PT and anti-factor Xa are all sensitive to edoxaban concentrations

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism; P-gp, p-glycoprotein; AF, atrial fibrillation; GFR, glomerular filtration rate; NOAC, new oral anticoagulant; INR, international normalized ratio; aPTT, activated partial thromboplastin time; PT, prothrombin time.

Table 2 RCT comparing edoxaban to warfarin therapy in the prevention of AF-related ischemic strokes

Study	Study information	Jadad score	Key outcomes (numbers expressed as %)
Weitz et al^Citation19	Number of participants; 1,146 Randomized open-label drug, double blinded 3-month follow-up Comparison: Edoxaban 30 mg OD (N: 235) Edoxaban 30 mg BD (N: 245) Edoxaban 60 mg OD (N: 235) Edoxaban 60 mg BD (N: 180) and standardized warfarin therapy INR 2–3 (N: 251)	5	Edoxaban OD noninferior to warfarin. Bleeding:  30 mg OD; 5.5 (P=0.367)  30 mg BD; 12.7 (P=0.104)  60 mg OD; 3.9 (P=0.864)  60 mg BD; 18.3 (P=0.002)  Warfarin; 8.0 Major bleeding:  30 mg OD; 3.0 (P=1.0)  30 mg BD; 7.8 (P=0.029)  60 mg OD; 3.9 (P=0.807)  60 mg BD; 10.6 (P=0.002)  Warfarin; 3.2 Major cardiovascular event:  30 mg OD; 1.7  30 mg BD; 2.5  60 mg OD; 4.3  60 mg BD; 1.1  Warfarin; 2.4
Chung et al^Citation24	Number of participants; 234 Randomized open-label, double-blinded dose. 3-month follow-up Comparison: Edoxaban 30 mg OD Edoxaban 60 mg OD to warfarin (INR 2–3)	5	Edoxaban noninferior to warfarin. Bleeding:  30 mg OD; 20.3  60 mg OD; 23.8  Warfarin; 29.3 Major bleeding:  30 mg OD; 0  60 mg OD; 7.5  Warfarin; 6.6 Major cardiovascular event:  30 mg OD; 2.5  60 mg OD; 3.8  Warfarin; 1.3
Yamashita et al^Citation25	Number of participants; 546 Randomized, double-blinded trial. 3-month follow-up Comparison: Edoxaban 30 mg OD Edoxaban 45 mg OD Edoxaban 60 mg OD with warfarin treatment (INR 2–3)	5	Edoxaban noninferior to warfarin. Bleeding:  30 mg OD; 18.5  45 mg OD; 22.4  60 mg OD; 27.7  Warfarin; 20 Major bleeding:  30 mg OD; 1.5  45 mg OD; 5.2  60 mg OD; 5.4  Warfarin; 3.2

Abbreviations: BD, twice daily; OD, once daily; RCTs, randomized controlled trials; AF, atrial fibrillation; INR, international normalized ratio.

Table 3 The key outcomes of the ENGAGE-AF TIMI 48 trial,¹⁶ comparing edoxaban 30 and 60 mg to warfarin treatment

Complications	Low-dose edoxaban (30 mg)	High-dose edoxaban (60 mg)	Warfarin (therapeutic)	Outcome
Stroke and embolism prevention	1.61% (P=0.005)	1.18% (P=0.001)	1.50%	Reduced by up to 0.32%
Bleeding rates	1.61% (P=0.001)	2.75% (P=0.001)	3.43%	Reduced by up to 1.82%
Intracranial hemorrhage	0.26% (P=0.001)	0.39% (P=0.001)	0.85%	Reduced by up to 0.59%
Cardiovascular death	2.71% (P=0.008)	2.74% (P=0.013)	3.17%	Reduced by up to 0.46%

Table 4 Evidence for edoxaban in the prevention of VTE, including RCTs and meta-analysis

Study	Study information	Jadad score	Key outcomes (numbers expressed as %)
Robertson et al^Citation31	Number of participants: 27,945 11 RCTs Three studies on direct thrombin inhibitors, eight studies on oral factor Xa inhibitors; (four rivaroxaban, two apixaban, and two edoxaban)	n/a	Oral factor Xa inhibitors demonstrated a similar rate of recurrent VTE compared to warfarin (OR 0.89; 95% CI 0.73–1.07) and a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57–0.98)
Fuji et al (STARS E-3)^Citation29	Number of participants: 716 RCT. All patients undergoing unilateral total knee arthroscopy Comparison: edoxaban 30 mg and subcutaneous enoxaparin 20 mg BD	5	Edoxiban superior when compared to enoxaparin in the prevention of VTE. Absolute risk reduction of 6.5% Efficacy: 7.4 vs 13.0 (P<0.001) Safety: 6.2 vs 3.7 (P=0.129)
Fuji et al (STARS J-4)^Citation32	Number of participants: 92 RCT. Patients undergoing surgery for trochanteric or subtrochanteric fractures Edoxaban 30 mg compared to subcutaneous enoxaparin 20 mg BD	5	Rates of VTE with edoxaban and enoxaparin were 6.5% and 3.7%, respectively, and bleeding rates were 3.4% and 6.9%, respectively
Fuji et al (STARS J-V)^Citation30	Number of participants: 610 Phase III, double-blinded study. Patients undergoing elective, unilateral total knee arthroplasty Edoxaban 30 mg OD or enoxaparin 2,000 IU twice daily for 11–14 days.	5	Edoxaban superior to subcutaneous enoxaparin in the prevention of VTE; 2.4 vs 6.9 (P=0.0157). Major or clinically relevant nonmajor bleeding; 2.6 vs 3.7 (0.465)

Abbreviations: BD, twice daily; CI, confidence interval; DVT, deep vein thrombosis; OD, once daily; OR, odds ratio; RCTs, randomized controlled trials; VTE, venous thromboembolism; n/a, not applicable; IU, international units.

Table 5 Trial information for Nakamura et al – the only RCT comparing edoxaban to enoxaparin and warfarin therapy in the treatment of VTE

Study name	Number of participants	Jadad score	Key outcomes (numbers expressed as %)
Nakamura et al^Citation37	8,292 patients from 439 centers worldwide RCT, double blinded of patients with DVT ± PE Edoxaban 60 mg OD compared to warfarin therapy. (For patients with CrCl 30–50 mL or weight <60 kg 50% dose reduction in edoxaban)	5	Edoxaban noninferior in efficacy to warfarin but superior when comparing bleeding complications VTE  Edoxaban 3.2  Warfarin 3.5 Bleeding:  Edoxaban 8.5  Warfarin 10.3

Abbreviations: RCT, randomized controlled trial; VTE, venous thromboembolism; DVT, deep vein thrombosis; OD, once daily; PE, pulmonary embolism.

Table 6 Meta-analyses reporting on the safety of edoxaban in comparison to alternative oral anticoagulants

Study	Trial information	Comparators	Key outcomes
Caldeira et al^Citation38	Meta-analysis of eleven Phase III RCTs	Comparison of NOACs with VKAs or low-molecular-weight heparin followed by VKAs	NOACs decrease the risk of fatality in cases related to major bleeding events, particularly in AF patients Results support the safety profile of NOACs even without having a widely available drug-specific antidote
Loffredo et al^Citation39	Meta-analysis of eleven RCTs (29,482 patients)	Comparison of 30 and 60 mg doses of edoxaban with warfarin, for rates of recurrent VTE and death	Treatment with NOACs in patients with acute VTE is noninferior to conventional therapy with warfarin for recurrent VTE or death, but there might be an increased incidence of myocardial infarction
Sardar et al^Citation40	Meta-analysis of 50 RCTs (155,537 patients)	Comparison of NOACs (rivaroxaban, dabigatran, apixaban, edoxaban, and darexaban) with VKAs	No significant difference between NOACs and comparators in the treatment of AF and extended treatment of VTE NOACs caused significantly less major bleeding compared to VKAs. Risk of major bleeding varied with indication for use NOACs may increase the risk of major bleeding after hip surgery, ACS and acute medically ill patients, but may be associated with less bleeding in treatment of acute VTE/PE

Abbreviations: RCTs, randomized controlled trials; VTE, venous thromboembolism; PE, pulmonary embolism; VKAs, vitamin K antagonists; NOACs, new oral anticoagulants; AF, atrial fibrillation; ACS, acute coronary syndromes.

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