Introduction
Compliance with Ethics Guidelines
Pharmacological Profile of Edoxaban in Comparison with Other NOACs
Dabigatran | Rivaroxaban | Apixaban | Edoxaban | |
---|---|---|---|---|
Target | Factor IIa (thrombin) | Factor Xa | Factor Xa | Factor Xa |
Prodrug | Yes | No | No | No |
Bioavailability | 0.06 | 100% (with food) | 0.5 | 0.62 |
Plasma protein binding | 0.35 | 0.93 | 0.87 | 0.5 |
Time to peak | 1.5–2 h | 2–3 h | 2–3 h | 1–2 h |
Elimination half-life | 12–17 h | 5–9 h (young), 11–13 h (elderly) | 12 h | 10–14 h |
Route of clearance | 80% renal | 35% renal | 27% renal | 50% renal |
The Registration Studies
ENGAGE AF-TIMI 48
HR (95% CI) |
P value | |
---|---|---|
Stroke/SEE | ||
mITT | 0.79 (0.63–0.99) | <0.001b
|
ITT | 0.87 (0.73–1.04)a
| 0.08b
|
Stroke | 0.88 (0.75–1.03) | 0.11 |
Hemorrhagic | 0.54 (0.38–0.77) | <0.001 |
Ischemic | 1.00 (0.83–1.19) | 0.97 |
Death | ||
All-cause | 0.92 (0.83–1.01) | 0.08 |
CV | 0.86 (0.77–0.97) | 0.013 |
Myocardial infarction | 0.94 (0.74–1.19) | 0.60 |
Bleeding | ||
Major | 0.80 (0.71–0.91) | <0.001 |
Life-threatening | 0.51 (0.38–0.70) | <0.001 |
Major or CRNM | 0.86 (0.80–0.92) | <0.001 |
Hokusai-VTE
Ten Selected Questions and Answers
Once Daily Administration: Which Patients Might Benefit Most From It?
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Patients with comorbidities, needing to take many tablets per day
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Elderly people, commonly using complex drugs regimens with multiple drugs, which can negatively affect medication adherence
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Patients with suspected low adherence
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Young active workers, reluctant to take medications
Few Interactions with Other Drugs: A Particular Advantage for Edoxaban?
Inhibitors | via | Dabigatran | Rivaroxaban | Apixaban | Edoxaban |
---|---|---|---|---|---|
Antiarrhythmics drugs | |||||
Dronedarone | P-gp competition and CYP3A4 inhibition | Contraindicated/not recommended | Moderate effect but no PK or PD data: caution and try to avoid | No PK or PD data: caution | Reduce from 60 mg to 30 mg |
Fungostatics | |||||
Itraconazole, ketoconazole, posaconazole, voriconazole | Potent P-gp and BCRP competition; CYP3A4 inhibition | Contraindicated/not recommended | Contraindicated/not recommended | Contraindicated/not recommended | Reduce from 60 mg to 30 mg |
Inducers | |||||
Carbamazepine, phenobarbital, phenytoin, St John’s wort | P-gp/BCRP and CYP3A4/CYP2 J inducers | Contraindication for simultaneous use | Contraindication for simultaneous use | Contraindication for simultaneous use | Co-administration is possible |
Association with Antiplatelet Drugs: How Safe is Edoxaban?
Is Edoxaban Attractive in Patients with Atrial Fibrillation and Chronic Kidney Disease?
Can Edoxaban be Suitable for Frail Elderly Patients?
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Edoxaban was widely tested in elderly patients at both dosages. The ENGAGE AF-TIMI 48 trial provides relevant data with respect to the use of edoxaban in elderly patients. Indeed [8], more than 8000 of the enrolled patients were 75 years or older, accounting for 40% of the 21,105 patients at moderate-to-high thromboembolic risk enrolled in the trial. The 60/30 mg edoxaban regimen was non-inferior to warfarin in preventing stroke/systemic embolism and was associated with significantly less overall major bleeding and intracranial hemorrhage (ICH). Results were consistent in different age and thromboembolic risk subgroups. Notably, edoxaban 60/30 mg also reduced the risk of ischemic stroke in the older group, in whom a risk reduction with edoxaban 60/30 mg compared with warfarin for ISTH major bleeding (event rate %/year edoxaban = 4; warfarin = 4.8; HR 0.83; 95% CI 0.70–0.99) and for ICH (event rate %/year edoxaban = 0.5 warfarin = 1.2; HR 0.40; 95% CI 0.26–0.62) was particularly evident in patients aged ≥75 years. Furthermore, only 18% and 41% of patients aged ≥65 and ≥75 years, respectively, received the reduced dose in each randomization arm, thus demonstrating that age alone does not demand a dose reduction. A recent post hoc analysis of very elderly patients (age ≥80 and age ≥85) showed that there were no significant treatment interactions between age groups and treatment for all major outcomes, demonstrating the robustness of the findings with edoxaban in the elderly. It should be highlighted that this post hoc analysis included a considerable number of very old patients, being 3591 patients (17.0%) aged ≥80 and 899 (4.3%) aged ≥85, thus reinforcing the perception of edoxaban safety even in very elderly patients [32] (Table 4).Table 4Efficacy and safety outcomes for edoxaban in patients aged >80 and >85WarfarinEvent rate (%/years)Edoxaban 60/30 mgEvent rate (%/years)Edoxaban 60/30 mg vs warfarinHR (95% CI)P intStroke/SSE (years)<801.61.40.87 (0.73–1.04)0.97≥802.92.50.88 (0.64–1.20)<851.71.50.88 (0.75–1.03)0.56≥853.52.50.73 (0.40–1.33)Ischemic stroke (years)<801.11.11.03 (0.84–1.27)0.54≥802.11.80.90 (0.63–1.30)<851.21.21.01 (0.84–1.22)0.5≥852.41.90.79 (0.39–1.60)Hemorrhagic stroke (years)<800.40.20.55 (0.37–0.82)0.93≥800.80.40.53 (0.26–1.06)<850.50.30.53 (0.37–0.76)0.78≥850.80.50.64 (0.18–2.28)Major bleeding (years)<8032.50.83 (0.71–0.96)0.54≥806.24.60.75 (0.58–0.98)<853.32.70.82 (0.72–0.94)0.17≥858.850.58 (0.35–0.94)ICH (years)<800.70.40.49 (0.34–0.69)0.64≥801.60.60.41 (0.22–0.77)<850.80.40.46 (0.33–0.62)0.62≥851.60.90.61 (0.20–1.88)Fatal bleeding (years)<800.30.20.57 (0.35–0.94)0.79≥800.80.40.50 (0.21–1.15)<850.40.20.52 (0.33–0.82)0.45≥850.60.60.99 (0.20–4.91)
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Edoxaban is safer than warfarin in patients at risk of falls. An increased risk of falls and associated neuropsychiatric disease is—besides age—a risk factor for ICH in the elderly [33, 34]. Patients with AF at high risk of falls are at substantially increased risk of ICH, especially traumatic ICH. However, because of their high stroke rate, they still appear to benefit from anticoagulant therapy if they have multiple stroke risk factors [33, 34]. Indeed, while the risks of fall and ICH with warfarin are often quoted as reasons to avoid anticoagulation, it has been estimated that if a patient has a 5% annual risk of stroke from AF, he/she would need to fall at least 295 times to offset the benefit of oral anticoagulation [35]. A subgroup analysis of the ENGAGE AF-TIMI 48 trial demonstrated that, in patients at increased risk of falls [defined by any of the following eight criteria at randomization: (1) prior history of falls; (2) lower extremity weakness; (3) poor balance; (4) cognitive impairment; (5) orthostatic hypotension; (6) use of psychotropic drugs; (7) severe arthritis; or (8) dizziness], edoxaban was associated with a sixfold lower risk of ICH and fatal bleeds [36].
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Edoxaban dosage can be safely modified when necessary. In the ENGAGE AF-TIMI 48 trial, dose adjustments were permitted after randomization [8]. Since factors that affect drug clearance may vary over time, especially in the elderly, thus requiring a dose reduction, the possibility of a dynamic dose adjustment (meaning increase or decrease of the daily dose in the presence of changing body weight and eCrCl, besides age), uniquely tested prospectively in the ENGAGE AF-TIMI 48 trial, is a relevant factor in the choice of the drug.
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Edoxaban can be administered relatively safely in patients on aspirin. See Section “Association with Antiplatelet Drugs: How Safe is Edoxaban?”
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Edoxaban administration OD enhances patients’ compliance compared with the BID dosing necessary with two other NOACs (see Section “Once Daily Administration: Which Patients Might Benefit Most From It?”).
Can Edoxaban be Suitable for Patients with Heart Failure?
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Have important frailty
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Are treated with multiple drugs, and their compliance to treatment may thus be improved with a NOAC given once daily
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Derive—for the same reason—advantages from an anticoagulant agent having low interference with other drugs frequently used in the presence of HF, such as amiodarone
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Have frequent fluctuations of creatinine clearance, with the ENGAGE AF-TIMI 48 trial specifically demonstrating the safety of edoxaban dynamic dose adjustments after randomization
Are There Concerns About Edoxaban in Patients with a Creatinine Clearance ≥95 mL/min?
What are the Main Strengths of Edoxaban in Patients with Acute Pulmonary Embolism?
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Edoxaban is a once daily dose regimen drug (60/30 mg OD).
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In frail patients, with renal impairment (eCrCL 15–50 mL/min) or low body weight (≤60 kg), the dose can be safely adapted to 30 mg OD.
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The drug is effective and safe in patients with PE and right ventricular dysfunction.