Introduction
Advantages | ✓ Fixed dosing ✓ Lack of clinically meaningful dietary interactions ✓ Predictable pharmacology ✓ Far fewer drug interactions ✓ No need for routine coagulation monitoring or regular dose adjustment ✓ Wider therapeutic range ✓ Fast on–off action eliminates need for bridging therapy with parenteral anticoagulants ✓ Shorter half-lives beneficial in urgent surgery situations ✓ Reduction in rate of stroke and systemic embolism equal to or superior to warfarin in clinical trials ✓ Reduced rates of intracranial hemorrhage and fatal bleeding events in clinical trials |
Disadvantages | ✗ Tests for measuring NOAC concentrations are not widely available ✗ No specific antidotes available (vitamin K for warfarin is slow-acting) ✗ Contraindicated or not recommended in patients with severe renal failure and in patients with prosthetic heart valves ✗ In theory, the shorter half-lives of the NOACs might be a potential concern in non-compliant patients; however, there is a paucity of pertinent data ✗ Possible interactions with rate-/rhythm-controlling drugs such as amiodarone and verapamil ✗ Scarce data about concomitant use of dual antiplatelet therapy, or use in patients with both atrial fibrillation and acute coronary syndrome |
Direct thrombin inhibitor | Direct factor Xa inhibitors | |||
---|---|---|---|---|
Prodrug | Dabigatran etexilate | No | No | No |
Oral bioavailability | ~6–7 % | 80–100 %a
| 50 % | ~61 % |
Plasma protein binding | 35 % | 92–95 % | 87 % | 40–59 % |
Half-life (h) | 12–14 | 5–9 (young) 11–13 (elderly) | 8–13.5 | 6–11 |
Time to maximum plasma concentration (h) | 1.25–3 | 2–4 | 3–4 | 1–2 |
Renal clearanceb
| 85 %c
| 33 % | 27 % | 35–39 % |
The Role of Oral Anticoagulants in Preventing Stroke in Patients with Atrial Fibrillation
How Effective Are Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation? Results from Phase III Trials
ROCKET AF [22] (rivaroxaban) | ARISTOTLE [23] (apixaban) | ENGAGE AF [25] (edoxaban) | ||
---|---|---|---|---|
Patients randomized | 18,113 | 14,264 | 18,201 | 21,105 |
Study blinding | Double-blind, randomized dose of dabigatran; open-label warfarin | Double-blind, double-dummy | Double-blind, double-dummy | Double-blind, double-dummy, randomized dose of edoxaban |
Study design | Non-inferiority, prespecified hierarchical superiority testing | |||
Comparator | Dose-adjusted warfarin (target INR 2–3) | |||
Doses tested | 110 mg bid or 150 mg bid | 20 mg od (15 mg od for patients with CrCl 30–49 mL/min) | 5 mg bid (2.5 mg bid for patients with ≥2 of: weight ≤60 kg, age ≥80 years, or serum creatinine ≥1.5 mg/dL) | 60 mg od or 30 mg od (dosage halved for patients with CrCl 30–50 mL/min, body weight ≤60 kg, or concomitant use of verapamil, quinidine, or dronedarone) |
ROCKET AF [22] (rivaroxaban) | ARISTOTLE [23] (apixaban) | ENGAGE AF [25] (edoxaban) | ||||
---|---|---|---|---|---|---|
110 mg bid | 150 mg bid | 30 mg od | 60 mg od | |||
Stroke or SE (%/year) | 1.54 vs 1.72†
| 1.12 vs 1.72*** | 2.1 vs 2.4†
| 1.27 vs 1.60** | 2.04 vs 1.80†
| 1.57 vs 1.80†
|
Ischemic stroke (%/year) | 1.34 vs 1.22†,b
| 0.93 vs 1.22*,b
| 1.34 vs 1.42†
| 0.97 vs 1.05†,b
| 1.77 vs 1.25*** | 1.25 vs 1.25†
|
Hemorrhagic stroke (%/year) | 0.12 vs 0.38*** | 0.10 vs 0.38*** | 0.26 vs 0.44* | 0.24 vs 0.47*** | 0.16 vs 0.47*** | 0.26 vs 0.47*** |
Bleeding Risk on Anticoagulation: Safety and Tolerability Profiles of Novel Oral Anticoagulants in Phase III Trials
ARISTOTLE [23] (apixaban) | ENGAGE AF [25] (edoxaban) | |||||
---|---|---|---|---|---|---|
110 mg bid | 150 mg bid | 30 mg od | 60 mg od | |||
Major bleeding (%/year) | 2.92 vs 3.61** | 3.40 vs 3.61†
| 3.60 vs 3.40†
| 2.13 vs 3.09*** | 1.61 vs 3.43*** | 2.75 vs 3.43*** |
Major and NMCR bleeding (%/year) | N/A | N/A | 14.90 vs 14.50†
| 4.07 vs 6.01*** | 7.97 vs 13.02*** | 11.10 vs 13.02*** |
Major GI bleeding (%/year) | 1.15 vs 1.07†
| 1.56 vs 1.07*** | 2.00 vs 1.24*** | 0.76 vs 0.86†
| 0.82 vs 1.23*** | 1.51 vs 1.23* |
Intracranial hemorrhage (%/year) | 0.23 vs 0.76*** | 0.32 vs 0.76*** | 0.50 vs 0.70* | 0.33 vs 0.80*** | 0.26 vs 0.85*** | 0.39 vs 0.85*** |
All-cause mortality (%/year) | 3.75 vs 4.13†
| 3.64 vs 4.13†
| 4.50 vs 4.90†
| 3.52 vs 3.94* | 3.80 vs 4.35** | 3.99 vs 4.35†
|
Myocardial infarction (%/year) | 0.82 vs 0.64†
| 0.81 vs 0.64†
| 0.91 vs 1.12†
| 0.53 vs 0.61†
| 0.89 vs 0.75†
| 0.70 vs 0.75†
|
Implications for Clinical Management of Specific Patient Populations
Standard dose | EU, US: 150 mg bid (CrCl ≥30 mL/min) | EU, US: 20 mg od To be taken with food | EU, US: 5 mg bid | EU: 60 mg od US: 60 mg od – do NOT use in patients with CrCl >95 mL/min |
Elderly | ||||
Dose adjustments | EU: Age ≥80 years: 110 mg bid; in patients aged 75–80 years a reduction to 110 mg bid may be considered | – | EU, US: 2.5 mg bid in patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, CrCl 15–50 mL/min | – |
Renal impairment | ||||
Dose adjustments | EU: 150 mg bid (reduction to 110 mg bid may be considered) (CrCl 30–49 mL/min) US: 75 mg bid (CrCl 15–30 mL/min or CrCl 30–50 mL/min and receiving concomitant treatment with dronedarone or systemic ketoconazole) | EU, US: 15 mg od (US: CrCl 15–50 mL/min; EU: CrCl 15–49 mL/min) | EU, US: 2.5 mg bid in patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 μmol/L) EU: 2.5 mg bid in patients with CrCl 15–29 mL/min US: No dose adjustment is recommended for patients with renal impairment alone, including those with end-stage renal disease maintained on hemodialysis | EU, US: 30 mg od (CrCl 15–50 mL/min) |
Caution/avoid | – | EU: Use with caution in patients with CrCl 15–29 mL/min; not recommended in patients with CrCl <15 mL/min US: Avoid use in patients with CrCl <15 mL/min | EU: Use with caution in patients with CrCl 15–29 mL/min; not recommended in patients with CrCl <15 mL/min | EU, US: Not recommended in patients with CrCl <15 mL/min |
Contraindications | EU: CrCl <30 mL/min US: No recommendation can be made for patients with CrCl <15 mL/min | – | – | – |
Gastritis, esophagitis, gastroesophageal reflux | ||||
Dose adjustments | EU: Consider dose reduction to 110 mg bid | – | – | – |
Hepatic function | ||||
Contraindications | EU: Hepatic impairment or liver disease expected to have an impact on survival | EU: Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child–Pugh B and C, severe liver disease | EU: Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, severe hepatic impairment | EU: Hepatic disease associated with coagulopathy and clinically relevant bleeding risk |
Caution/avoid | EU: Not recommended in patients with elevated liver enzymes (>2 × ULN) | US: Avoid use in patients with moderate (Child–Pugh B) and severe (Child–Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy | EU: Mild or moderate hepatic impairment (Child–Pugh A or B), elevated liver enzymes ALT/AST >2 × ULN or total bilirubin ≥1.5 × ULN US: Not recommended in patients with severe hepatic impairment; no dosing recommendations provided for patients with moderate hepatic impairment | EU: Not recommended in patients with severe hepatic impairment; use with caution in patients with mild-to-moderate hepatic impairment US: Not recommended in patients with moderate-to-severe hepatic impairment |