Table 5 Clinical and pharmacologic properties of apixaban, rivaroxaban, dabigatran, and edoxaban

Anemia

Contraindicated

Contraindicated in patients with hemoglobin <10 g/dL

Contraindicated in patients with hemoglobin <9 g/dL

NA

Bleeding risk

Concomitant drugs affecting hemostasis can increase bleeding risk, including platelet aggregation inhibitors, heparin, fibrinolytic therapy, and chronic use of NSAIDs

Concomitant drugs affecting hemostasis can increase bleeding risk, including NSAIDs, heparin, aspirin, platelet aggregation inhibitors, other antithrombotic drugs, and fibrinolytic therapy

Concomitant drugs affecting hemostasis can increase bleeding risk, including platelet aggregation inhibitors, other antithrombotic drugs, heparin, thrombolytic agents, SSRIs, SNRIs, and chronic use of NSAIDs

Concomitant use of drugs affecting hemostasis may increase the risk of bleeding, including aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, and chronic use of NSAIDs

Interruption for surgery/procedures

To reduce risk of bleeding, discontinue dabigatran 1–2 d (CrCl ≥50 mL/min) or 3–5 d (CrCl <50 mL/min) before invasive or surgical procedures

To reduce risk of bleeding, discontinue rivaroxaban at least 24 h prior to surgical or other invasive procedures

To reduce risk of bleeding, discontinue apixaban at least 48 h prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding, and at least 24 h prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled

To reduce the risk of bleeding, discontinue edoxaban at least 24 hours before invasive or surgical procedure

Drug interactions

Avoid concomitant use with P-gp inducers (e.g., rifampin)

Avoid concomitant use with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) or inducers (carbamazepine, phenytoin, rifampin, St. John’s wort)

Reduce apixaban dosage to 2.5 mg bid or avoid concomitant use with strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin)

Co-administration with anticoagulants, antiplatelet drugs and thrombolytics may increase the risk of bleeding

For patients with moderate renal impairment (CrCl 30–50 mL/min), dabigatran dose may be reduced to 75 mg bid when administered concomitantly with the P-gp inhibitor dronedarone or systemic ketoconazole. Dose adjustment not required with P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin)

For patients with CrCl 15–50 mL/min, rivaroxaban may be used concomitantly with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) only if the potential benefit justifies the potential risk

Avoid concomitant use with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban

Avoid concomitant use with rifampin

Avoid concomitant use with P-gp inhibitors in patients with severe renal impairment (CrCl 15–30 mL/min)

No dose reduction is recommended in patients taking concomitant P-gp inhibitors

Hepatic impairment

Large intersubject variability but no evident consistent change in exposure or PD in patients with moderate hepatic impairment

Avoid use in moderate and severe hepatic impairment or with any hepatic disease associated with coagulopathy

No dose adjustment necessary in patients with mild hepatic impairment

Use of edoxaban in patients with moderate or severe hepatic impairment is not recommended as these patients may have intrinsic coagulation abnormalities. No dose reduction is required in patients with mild hepatic impairment

No dosing recommendations available for patients with moderate hepatic impairment because of lack of clinical experience with apixaban in these patients

Not recommended in patients with severe hepatic impairment

Renal elimination

80 % [69]

36 % [68]

27 % [29, 66]

50 % [57]

Renal impairment

Contraindicated in patients with CrCl <15 mL/min; reduce dosage to 75 mg bid if CrCl 15–30 mL/min

Avoid use in patients with CrCl <15 mL/min

Reduce dosage to 2.5 mg bid in patients with serum creatinine ≥1.5 mg/dL and either age ≥80 years or body weight ≤60 kg

Reduce edoxaban dose to 30 mg qd in patients with CrCl 15-50 mL/min. Not recommended in patients with CrCl<15 mL/min

5 mg bid in patients with ESRD maintained on hemodialysis. Reduce dose to 2.5 mg bid in patients with ESRD aged ≥80 years or body weight ≤60 kg

Reversal antidote

In progress; none approved for use

In progress; none approved for use

In progress; none approved for use

In progress; none approved for use

Tested reversal strategies^a

Dialysis [54]

PCC (Cofact) [50]

rFVIIa [51]

rFVIIa [56]

aPCC (FEIBA®) [55]

aPCC (FEIBA®) [53]

aPCC (FEIBA®) [51]

aPCC (FEIBA®) [56]

PER977 (when available) [76]

Andexanet alfa (when available) [52]

Activated charcoal [71]

PPSB-HT [56]

PER977 (when available) [76]

Andexanet alfa (when available) [49, 52]

PER977 (when available) [76]