Introduction
Medication | Indication | Dosea
|
---|---|---|
Dabigatran | Stroke and systemic embolism prophylaxis in NVAF | 150 mg PO BID |
VTE prophylaxis for recurrent VTE | 150 mg PO BID | |
VTE treatment | 150 mg PO BID (5–10 days after parenteral anticoagulants) | |
Rivaroxaban | Stroke and systemic embolism prophylaxis in NVAF | 20 mg PO with evening meal |
VTE prophylaxis for recurrent VTE | 20 mg PO daily with evening meal | |
VTE treatment | 15 mg PO BID × 21 days, then 20 mg PO daily with food | |
VTE prophylaxis for THA or TKA surgery | 10 mg PO daily × 35 days (THA) 10 mg PO daily × 12 days (TKA) | |
Apixaban | Stroke and systemic embolism prophylaxis in NVAF | 5 mg PO BID |
VTE prophylaxis for recurrent VTE | 2.5 mg PO BID | |
VTE treatment | 10 mg PO BID × 7 days, then 5 mg PO BID | |
VTE prophylaxis for THA or TKA surgery | 2.5 mg PO BID × 35 days (THA) 2.5 mg PO BID × 12 days (TKA) | |
Edoxaban | Stroke and systemic embolism prophylaxis in NVAF | 60 mg PO daily |
VTE treatment | 60 mg PO daily (5–10 days after parenteral anticoagulants) |
Compliance with Ethics Guidelines
Edoxaban
Pharmacology
Pharmacokinetics
Reversal
Medication (Brand) | Warfarin (Coumadin, Jantoven) | Dabigatran (Pradaxa) | Rivaroxaban (Xarelto) | Apixaban (Eliquis) | Edoxaban (Savaysa) |
---|---|---|---|---|---|
Mechanism of action | VKOR (factors II, VII, IX, X) | Direct thrombin inhibitor | Factor Xa inhibitor | Factor Xa inhibitor | Factor Xa inhibitor |
Bioavailability | ~100% | 6.5% (prodrug) | 80% | ~50–66% | 62% |
Delayed absorption with food | No | Yes | Yes | No | No |
Distribution (% protein-bound) | 99% | 35% | 95% | 87% | 55% |
Metabolism | CYP2C9 (primary)
T
max: 72–96 h T
1/2: 40 h | Hepatic glucuronidation
T
max: 1–2 h T
1/2: 12–17 h | CYP3A4, CYP2J2
T
max: 2.5–4 h T
1/2: 5–9 h | CYP3A4 (primary)
T
max: 3 h T
1/2: 8–15 h | CYP3A4 (primary)
T
max: 1–2 h T
1/2: 10–14 h |
Renal excretion | 92% | 80% | 67% (33% active) | 25% | 50% |
Drug–drug interactions | Substrate: CYP2C9, 1A2, 3A4, 2C19 Weak inhibitor: CYP2C9, 2C19 | Substrate: P-gp Absorption decreased by acid reducers | Substrate: CYP3A4, 2J2, P-gp | Substrate: CYP3A4, 1A2, 2C9, 2C19, P-gp Weak inhibitor: CYP2C19 | Substate: CYP3A4, P-gp |
Adverse effects (non-bleeding) | Alopecia, tissue necrosis (<0.1%) | Dyspepsia 35% | Peripheral edema ≤6% | Rare | Rare |
Drug Interactions
Concomitant drug | Effects on pharmacokinetics | Dose considerations |
---|---|---|
Verapamil | Increase in AUC0–24: 52.7% Increase in C
max: 53.3% Increase in 24-h concentration: 29.1% | VTE: dose should be halved NVAF: dose should be halved |
Quinidine | Increase in AUC0–24: 76.7% Increase in C
max: 85.4% Increase in 24-h concentration: 11.8% | VTE: dose should be halved NVAF: dose should be halved |
Dronedarone | Increase in AUC0–inf: 84.5% Increase in C
max: 45.8% Increase in 24-h concentration: 157.6% | VTE: use is not recommended NVAF: dose should be halved |
Amiodarone | Increase in AUC0–inf: 39.8% Increase in C
max: 66.0% Decrease in 24-h concentration: 25.7% | No dose adjustment |
Digoxin | Increase in AUC0–τ
: 9.5% Increase in C
max: 15.6% Decrease in 24-h concentration: 9.4% | No dose adjustment |
Atorvastatin | Increase in AUC0–inf: 1.7% Decrease in C
max: 14.2% Increase in 24-h concentration: 7.9% | No dose adjustment |
Ketoconazole | Increase in AUC0-inf: 86.7% Increase in C
max: 66.9% Increase in 24-h concentration: 26.8% | VTE: dose should be halved NVAF: concomitant use should be avoided |
Erythromycin | Increase in AUC0–inf: 87.0% Increase in C
max: 63.1% Increase in 24-h concentration: 27.8% | VTE: dose should be halved NVAF: concomitant use should be avoided |
Atrial Fibrillation
ENGAGE-AF TIMI 48 trial outcomes | Warfarin (n = 7036) Patients/year, % | Edoxaban 30 mga (n = 7034) Patients/year, % | Hazard ratio | Edoxaban 60 mga (n = 7035) Patients/year, % | Hazard ratio | |
---|---|---|---|---|---|---|
Efficacy | Stroke and systemic embolism | 1.5 | 1.61 | 1.07 (97.5% CI 0.87–1.31) | 1.18 | 0.79 (97.5% CI 0.63–0.99) |
Stroke | 1.69 | 1.91 | 1.13 (95% CI 0.97–1.31) | 1.49 | 0.88 (95% CI 0.75–1.03) | |
Systemic embolism | 0.12 | 0.15 | 1.24 (95% CI 0.72–2.15) | 0.08 | 0.65 (95% CI 0.34–1.24) | |
Safety | Major bleedingb
| 3.43 | 1.61 | 0.47 (95% CI 0.41–0.55) | 2.75 | 0.80 (95% CI 0.71–0.91) |
CRNMBb
| 10.15 | 6.60 | 0.66 (95% CI 0.60–0.71) | 8.67 | 0.86 (95% CI 0.79–0.93) | |
CRNMB and major bleeding | 13.02 | 7.97 | 0.62 (95% CI 0.57–0.67) | 11.01 | 0.86 (95% CI 0.80–0.92) | |
Fatal bleeding | 0.38 | 0.13 | 0.35 (95% CI 0.21–0.57) | 0.21 | 0.55 (95% CI 0.36–0.84) | |
Intracranial hemorrhage | 0.85 | 0.26 | 0.30 (95% CI 0.21–0.43) | 0.39 | 0.47 (95% CI 0.34–0.63) | |
Life threatening bleeding | 0.78 | 0.25 | 0.32 (95% CI 0.23–0.46) | 0.40 | 0.51 (95% CI 0.38–0.70) | |
Gastrointestinal bleeding | 1.23 | 0.82 | 0.67 (95% CI 0.53–0.83) | 1.51 | 1.23 (95% CI 1.02–1.50) |
Venous Thromboembolism Prophylaxis
Venous Thromboembolism Treatment
Hokusai-VTE trial outcomes | Warfarin Patients/year (n = 4122), % | Edoxabanb
Patients/year (n = 4118), % | Hazard ratio | Patients who qualified for edoxaban 30 mga
Patients/year | Hazard ratio | ||
---|---|---|---|---|---|---|---|
Warfarin (n = 719), % | Edoxaban (n = 733), % | ||||||
Efficacy | Recurrent VTE or VTE-related death | 3.5 | 3.2 | 0.89 (95% CI 0.70–1.13)
p < 0.001 for non-inferiority | 4.2 | 3.0 | 0.73 (95% CI 0.42–1.26) |
Recurrent VTE or VTE-related death in patients with index DVT | 3.3 | 3.4 | 1.02 (95% CI 0.75–1.38) | ||||
Recurrent VTE or VTE-related death in patients with index PE | 3.9 | 2.8 | 0.73 (95% CI 0.50–1.06) | ||||
Safety | Major bleeding and CRNMB | 10.3 | 8.5 | 0.81 (95% CI 0.71–0.94)
p = 0.004 for superiority | 12.8 | 7.9 | 0.62 (95% CI 0.44–0.86) |
Major bleeding | 1.6 | 1.4 | 0.84 (95% CI 0.59–1.21)
p = 0.35 for superiority | 3.1 | 1.5 | 0.50 (95% CI 0.24–1.03) | |
CRNMB | 8.9 | 7.2 | 0.80 (95% CI 0.68–0.93)
p = 0.004 for superiority | ||||
Any bleeding | 25.6 | 21.7 | 0.82 (95% CI 0.75–0.90)
p < 0.001 for superiority | ||||
Fatal bleeding | 0.2 | <0.1 | |||||
Intracranial hemorrhage | 0.1 | 0 |