Introduction
Background
General characteristics
Characteristics | Dabigatran | Rivaroxaban | Apixaban | Edoxaban |
---|---|---|---|---|
Renal clearance (%) | 80 | 35 | 25 | 50 |
Bioavailability (%) | pH dependenta 6–7 | Food dependentb 66–≥80 | Food independent 50 | Food independent 62 |
Medication storage | In original bottle or blister package | Room temperature | Room temperature | Room temperature |
Liver metabolism: CYP3A4 metabolism | No | Yes | Minor | Minor |
Impacted by P-glycoprotein transporter system | Yes | Yes | Yes | Yes |
Medications | Dabigatran | Rivaroxaban | Apixaban | Edoxaban |
---|---|---|---|---|
Quinidine | Use with cautiona
| Use with cautiona
| No data | Use with cautiona
|
Verapamil | Use with cautiona, b
| Minor effect | No data | Use with cautiona
|
Amiodarone | Use with cautiona
| Use with cautiona
| No data | Use with cautiona
|
Dronedarone | Avoid | Use with cautiona
| No data | 50 % dose reductionc
|
Ranolazine | No effect | Use with cautiona
| No data | No data |
Digoxin | No effect | Minimal effect | No effect | Minimal effect |
Atorvastatin | Minimal effect | No effect | No data | No effect |
Diltiazem | No effect | Use with cautiona
| Use with cautiona
| No data |
Carvedilol | No effect | Minimal effect | No data | No data |
Felodipine | Minimal effect | Use with cautiona
| No data | No data |
Prazosind
| Avoid | Avoid | Avoid | Avoid |
Comparative efficacy and safety
General trial characteristics
Characteristics | RE-LY (dabigatran) | ROCKET AF (rivaroxaban) | ARISTOTLE (apixaban) | ENGAGE AF (edoxaban) |
---|---|---|---|---|
Design | Randomized, open labela
| Randomized, DB/DD | Randomized, DB/DD | Randomized, DB/DD |
Dosing | 150 mg, 110 mg twice daily | 20 mg daily | 5 mg twice daily | 60 mg, 30 mg daily |
Dose adjustment/criteria | No | If CrCl 30–49 mL/min then 15 mg | If ≥2 factors: age ≥80 years, body weight <60 kg, creat ≥1.5 mg/dL then 2.5 mg | If CrCl 30–50 mL/min or weight ≤60 kg or potent P-gp inhibitorb then 50 % dose |
CrCl exclusion | 30 mL/min | 30 mL/min | 25 mL/min | 30 mL/min |
CHADS2 score inclusion criteria | ≥1 | ≥2 | ≥1 | ≥2 |
Primary efficacy endpoint | Stroke/TIA and SE | Stroke/TIA and SE | Stroke/TIA and SE | Stroke/TIA and SE |
Primary safety endpoint | Major bleeding | Major plus CRNM bleeding | Major bleeding | Major bleeding |
Trial size | 18,113 | 14,264 | 18,201 | 21,105 |
Age (years), median (IQR) | 72 ± 9c
| 73 (65–78) | 70 (63–76) | 72 (64–78) |
CHADS2 (mean) | 2.1 | 3.5 | 2.1 | 2.8 |
CHADS2 ≥3 (%) | 32 | 87 | 30 | 53 |
Heart failure | 32 | 62 | 35 | 57 |
Stroke/TIA or SE | 20d
| 55 | 19 | 28 |
Median follow-up (years) | 2.0 | 1.9 | 1.8 | 2.8 |
Early discontinuation | ||||
DOAC (%) | 20.7/21.2 | 35.4 | 25.3 | 33.0/34.3 |
VKA (%) | 16.6 | 34.6 | 27.5 | 34.4 |
Trial population characteristics
Individual effectiveness and safety in relation to warfarin
DOAC vs VKA HR (95 % CI) | RE-LYa (dabigatran) 110 mg | ROCKET AF (rivaroxaban) 20 mg | ARISTOTLE (apixaban) 5 mg | ENGAGE AF-TIMI 48 (edoxaban) 30 mg |
---|---|---|---|---|
150 mg | 60 mg | |||
Ischemic stroke | 1.11 (0.89–1.40)a
| 0.94 (0.75–1.17) | 0.92 (0.74–1.13) | 1.41 (1.19–1.67) p < 0.001 |
0.76 (0.60–0.98)
a
p = 0.03
| 1.00 (0.83–1.19) | |||
Systemic embolism | Not reported |
0.23 (0.09–0.61) p = 0.003
| 0.87 (0.44–1.75) | 1.24 (0.72–2.15) |
0.65 (0.34–1.24) | ||||
Hemorrhagic stroke |
0.31 (0.17–0.56) p < .0001
|
0.59 (0.37–0.93 p = 0.024)
|
0.51 (0.35–0.75) p < 0.001
|
0.33 (0.22–0.50) p < 0.001
|
0.26 (0.14–0.49 p < 0.001
|
0.54 (0.38–0.77) p < 0.001
| |||
Major bleed |
0.80 (0.69–0.93) p = 0.003
| 1.04 (0.90–1.20) |
0.69 (0.60–0.80) p < 0.001
|
0.47 (0.41–0.55) p < 0.001
|
0.93 (0.81–1.07) p = 0.3 |
0.80 (0.71–0.91) p < 0.001
| |||
Intracranial bleed |
0.31 (0.20–0.47) p < 0.001
|
0.67 (0.47–0.93) p = 0.02
|
0.42 (0.30–0.58) p < 0.001
|
0.30 (0.21–0.43) p < 0.001
|
0.40 (0.27–0.60) p < 0.001
|
0.47 (0.34–0.63) p < 0.001
| |||
Gastrointestinal bleed | 1.10 (0.86–1.41) | 3.2 vs 2.2
b
p < 0.001 | 0.89 (0.70–1.15) |
0.67 (0.53–0.83) p < 0.001
|
1.50 (1.19–1.89) p < 0.001 | 1.23 (1.02–1.50) p = 0.03 | |||
All-cause mortality | 0.91 (0.80–1.03) | 0.85 (0.70–1.02) |
0.89 (0.80–0.98) p = 0.047
|
0.87 (0.79–0.96) p = 0.006
|
0.88 (0.77–1.00) p = 0.051
| 0.92 (0.83–1.01) | |||
Cardiovascular mortality | 0.90 (0.77–1.06)a
| 0.89 (0.73–1.10) | 0.89 (0.76–1.04) |
0.85 (0.76–0.96) p = 0.008
|
0.85 (0.72–0.99)
a
p = 0.04
|
0.86 (0.77–0.97) p = 0.013
|
Comparison of DOACs amongst themselves
Limitations of trials
Controversies related to DOACs
DOACs reversal
Labile INR and the relative effectiveness of DOACs
Choosing a specific antithrombotic agent
To anticoagulate or not anticoagulate
Tailoring anticoagulant choice
Clinical situation | First choice | Second choice | Avoid |
---|---|---|---|
High thromboembolic and low bleeding risk | Dabigatran 150 mg | Apixaban, edoxaban 60 mg, rivaroxaban, dabigatran 110 mg | Edoxaban 30 mg |
Low thromboembolic and high bleeding risk | Edoxaban 30 mg Apixaban | Edoxaban 60 mg Dabigatran 110 mg | Dabigatran 150 mg Rivaroxaban |
Moderate thromboembolic and bleeding risk | Apixaban Edoxaban 60 mg Dabigatran 110 mg | Rivaroxaban Dabigatran 150 mg | Edoxaban 30 mg |
High thromboembolic and bleeding risk | Apixaban | Rivaroxaban Edoxaban 60 mg Dabigatran 150 mg | Edoxaban 30 mg |
Compliance concerns | Edoxaban 60 mg Rivaroxabana
| Edoxaban 30 mg | Dabigatran or apixaban |
Moderate renal dysfunctionb
| Apixaban | Rivaroxaban Dabigatran 110 mg Edoxaban 60 or 30 mg | Dabigatran 150 mg |