Table 4.
Pharmacologic and clinical trial comparisons between DOACs
| Dabigatran39 | Rivaroxaban42 | Apixaban50 | Edoxaban43 | |
|---|---|---|---|---|
|
| ||||
| Pharmacology | ||||
| Mechanism of action | Direct thrombin inhibitor | Factor Xa inhibitor | Factor Xa inhibitor | Factor Xa inhibitor |
| Indication | VTE, NVAF | VTE, NVAF, postoperative DVT prevention | VTE, NVAF, postoperative DVT prevention | VTE, NVAF |
| Metabolism/elimination | Hepatic (pro-drug)/80% renal | CYP 3A4/5 and CYP 2J2/36% renal; 7% fecal | CYP 1A2, 2C8, 2C9, 2C19, 2J2, P-gp/~25% renal | CYP 3A4/50% renal |
| Oral bioavailability (F%) | 3–7% | ~66% (increased with food) | 50% | 62% |
| Half-life (h) | 12–17 | 5–9 | ~12 | 10–14 |
| Volume of distribution (L) | 50–70 | ~50 | ~21 | 107 |
| Landmark clinical trial comparisons
| ||||||||
|---|---|---|---|---|---|---|---|---|
| VTE (year)/NVAF (year) | RE-COVER I8 (2009) | RE-LY4 (2009) | EINSTEIN-DVT/PE9–11 (2010/2012) | ROCKET-AF5 (2011) | AMPLIFY12 (2013) | ARISTOTLE6 (2011) | Hokusai-VTE13 (2013) | ENGAGE AF-TIMI 487 (2013) |
| Study design | DB, DD, RCT | RCT | OL, RCT | DB, RCT | DB, RCT | DB, DD, RCT | DB, DD, RCT | DB, DD, RCT |
| Intervention | Dabigatran vs warfarin | Rivaroxaban vs warfarin | Apixaban vs warfarin | Edoxaban vs warfarin | ||||
| N | 2,539 | 18,113 | 4,832/3,449 | 14,264 | 5,395 | 18,201 | 8,240 | 21,105 |
| Study population | ||||||||
| Age (mean) (years) | ~55 | ~72 | ~57 | ~73 (median) | ~57 | 70 (median) | ~55 | 72 (median) |
| Gender (%men) | 68 | 64 | 51–57 | 60 | 58 | 65 | 57 | 62 |
| Cancer (%) | 57–64 | – | 4.5–6.8 | – | – | – | ~9 | – |
| CHADS2 (score/majority%) | – | Even distribution (0–6) | – | 3 (43%) | – | 2 (36%) | – | <3 (72%) |
| Interventional drug regimen | 150 mg bid* | 110 mg bid or 150 mg bid | 15 mg bid × 3 weeks; 20 mg daily | 20 mg daily | 10 mg bid × 7 days; 5 mg bid | 5 mg bid | 60 mg daily* | 60 mg daily |
| Dosage adjustment | CrCl ≤30: NR | CrCl 15–30: 75 mg bid¥; CrCl ≤15: NR | CrCl<30: NR | CrCl 15–50: 15 mg daily; CrCl<15: NR | CrCl<25/SCr>2.5: NR | SCr≥1.5 and age≥80 years or weight ≤60 kg: 2.5 mg bid | CrCl 30: 30 mg daily, OR<60 kg | CrCl 30–50: 30 mg daily, or <60 kg or potent P-gp inhibitor; CrCl>95: NR |
| Mean TTR (INR 2–3) | 60% | 64% | 62.7% | 55% | 68% | 62% | 63.5% | 68% (median) |
| CrCl in landmark study | 105 (mean) | 50–79 (majority) | >80 (majority) | 67 (median) | >80 (majority) | >50 (majority) | >50 (majority) | >50 (majority) |
| Key exclusion criteria | ||||||||
| Renal dysfunction | CrCl<30 | CrCl<30 | CrCl<30 | CrCl<30 | CrCl<25; SCr>2.5 | CrCl<25; SCr>2.5 | CrCl<30 | CrCl<30 |
| Hepatic dysfunction | X | X | X | X | X | X | X | X |
| Stroke history | NS | <14 days or <6 months (severe) | NS | <14 days or <3 months (severe) | NS | <7 days | NS | <30 days |
| Hemodynamic instability | X | NS | SBP>180/DBP>110 | SBP>180/DBP>110 | SBP>180/DBP>110 | SBP>180/DBP>110 | SBP>170/DBP>110 | SBP>170/DBP>110 |
| Active/high risk for bleeding | X | X | X | X | X | X | X | X |
| Valvular disease | NS | X | NS | X | NS | X | NS | X |
| AP use | Indication for long-term AP | NS | NS | ASA>100 mg | ASA>165 mg; DAPT | ASA>165 mg; DAPT | ASA>100 mg;DAPT | DAPT |
| Drug interaction | NS | NS | Strong CYP 3A4 inhibitors/inducers | Strong CYP 3A4 inhibitors/inducers | Strong CYP 3A4 inhibitors/inducers | NS | Strong P-gp inhibitors/inducers | Cyclosporine use |
| Others | Symptoms >14 days; thrombolytic use; indication for VKA; life <6 months | IE; life<3 months; indication for VKA; thrombolytic exposure to AC | IE; LV thrombus; indication for VKA; thrombolytic | LMWH indication | IE; indication for VKA | LMWH indication; indication for VKA | LV thrombus; MI or planned PCI; active cancer | |
Notes:
Patients received parental AC prior to starting oral drug therapy for VTE trials. RECOVER had an average of 9 days of parental AC and patients received 5 days of parental AC in Hokusai-VTE.
Dosage adjustment as recommended in package insert, not studied in RE-LY. X, characteristic outlined in exclusion criteria.
Abbreviations: AC, anticoagulation; AP, antiplatelet; ASA, aspirin; CrCl, creatinine clearance (mL/min); DAPT, dual antiplatelet therapy; DB, double blind; DBP, diastolic blood pressure; DD, double dummy; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; IE, infectious endocarditis; INR, international normalized ratio; LMWH, low molecular weight heparin; NR, not recommended; LV thrombus, left ventricular thrombus; NS, not specified (in exclusion criteria); NVAF, nonvalvular atrial fibrillation; OL, open label; OR, odds ratio; P-gp, P-glycoprotein; RA, recommend against; RCT, randomized controlled trial; SBP, systolic blood pressure; TTR, time in therapeutic range; VKA, vitamin K antagonist; VTE, venous thromboembolism.