Table 2 Pharmacological characteristics of warfarin and DOACs.

Commercial name (licenser)

COUMADIN^® (Bristol-Myers-Squibb)

PRADAXA^® (Boehringer Ingelheim Pharma GmbH & Co. KG)

XARELTO^® (Bayer Pharma AG)

ELIQUIS^® (Bristol-Myers-Squibb and Pfizer)

LIXIANA^® or SAVAYSA^® (Daiichi Sankyo)

Empirical Formula

C₁₉H₁₆O₄

C₃₅H₄₅N₇O₈S (mesylate salt)

C₁₉H₁₈ClN₃O₅S

C₂₅H₂₅N₅O₄

C₂₄H₃₀ClN₇O₄S•C₇H₈O₃S•H₂O

Molecular weight (g/mol)

308.33

723.86

435.89

459.5

738.27

Prodrug

No

Yes

No

No

No

Mechanism of action

Reduced synthesis of prothrombin and other vitamin K-dependent factors

Direct inhibition of thrombin

Direct inhibition of Factor Xa

Direct inhibition of Factor Xa

Direct inhibition of Factor Xa

Indication

• Prevention and treatment of thromboembolic complications associated with AF and/or cardiac valve replacement.

• Prevention and treatment of DVT and PE

• Reduce risk of recurrent DVT and PE

• Reduce risk of death, recurrent MI, and thromboembolic events after MI.

• Prevention of thromboembolic complications in NVAF

• Treatment of DVT and PE

• Prevention of DVT and PE

• Reduce risk of recurrent DVT and PE

• Prevention of thromboembolic complications in NVAF

• Treatment of DVT and PE

• Prevention of DVT and PE

• Reduce risk of recurrent DVT and PE

• Prevention of thromboembolic complications in NVAF

• Treatment of DVT and PE

• Prevention of DVT and PE

• Reduce risk of recurrent DVT and PE

• Prevention of thromboembolic complications in NVAF

• Treatment of DVT and PE

Oral dosing (frequency)

Variable dose adjusted based on INR (Once per day)

Fixed dose (Once or twice per day, dependent on indication)

Fixed dose (Once or twice per day, dependent on indication)

Fixed dose (Twice per day)

Fixed dose (Once per day)

Dosage strengths available

0.5 mg, 1 mg, 3 mg, 5 mg

75 mg, 110 mg, 150 mg

10 mg, 15 mg, 20 mg

2.5 mg, 5 mg

15 mg, 30 mg, 60 mg

Dose-dependent pharmacokinetics (linear PK)

Yes

Yes

Yes

Yes

Yes

Bioavailability (%)

98

3–7

≥80 (Optimal drug absorption is achieved when taken with food)

50

62

Peak onset (h)

72–120

0.5–2 (aged 18–45 years)

2–4 (aged ≥65 years)

2–4

1–3

1–2

Plasma half-life (h)

20–60

7–9 (single dose)

14–17 (multiple doses, aged 18–45 years)

12–14 (multiple doses, aged ≥65 years)

7–11 (aged 20–45 years)

11–13 (aged ≥60 years)

8–15

10–14

Protein binding (%)

99%

35%

92–95%

87%

40–59%

Volume of distribution (L)

Yes

50–70

50

21–23

>300

P-gp substrate

Yes

Yes

Yes

Yes

Yes

Metabolism

Oxidation (mainly via CYP2C9 with minor contributions from CYP1A2, 2C8, 2C18, 2C19, 3A4)

Conjugation

Oxidation via CYP3A4/5, 2J2 (major pathway) and hydrolysis

Oxidation (mainly via CYP3A4/5 with minor contributions from CYP1A2, 2J2, 2C8, 2C9, 2C19) and conjugation

Hydrolysis via CES1 (major pathway) and oxidation via CYP3A4

Renal excretion of unchanged drug (%)

0

77^a

4^b

36

27

50

Food and alcohol interaction

Yes

No

No

No

No

Dose monitoring

PT/INR

Not required

Useful tests

• aPTT: approximate measurement of drug effect

• dTT: quantitative plasma drug level

• ECT: quantitative plasma drug level

Not required

Useful tests

• PT: approximate measurement of drug effect

• Chromogenic anti-Factor-Xa assay: quantitative plasma drug level

Not required

Useful tests

• PT: approximate measurement of drug effect

• Chromogenic anti-Factor-Xa assay: quantitative plasma drug level

Not required

Useful tests

• PT: approximate measurement of drug effect

• Chromogenic anti-Factor-Xa assay: quantitative plasma drug level

Antidote

• Rapid reversal with fresh-frozen plasma or PCC

• Slow reversal with vitamin K

• Rapid reversal with idarucizamab

• Aripazine (ongoing phase II trial)

• Adexanet-α (ongoing phase IV trial)

• Aripazine (ongoing phase II trial)

• Adexanet-α (ongoing phase IV trial)

• Aripazine (ongoing phase II trial)

• Adexanet-α (ongoing phase IV trial)

• Aripazine (ongoing phase II trial)

References

[242]

75, 79, 115, 136, 138, 139, 243,244,245,246,247]

[82, 117, 142, 248,249,250,251,252,253,254,255,256,257]

[80, 116, 140, 141, 256,257,258,259,260,261,262,263,264]

76, 81, 140, 141, 256, 257, 265,266,267,268,269]