Table 4

Key pharmacological parameters and bleeding management recommendations for approved NOACs

Pharmacodynamics▸ Dabigatran is a specific inhibitor of thrombin, leading to longer coagulation times in standard clinical tests, including thrombin time (TT), activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT)17▸ Rivaroxaban is a selective inhibitor of FXa, demonstrating a dose-dependent prolongation of PT, the aPTT and the heparin clotting assay (HepTest®)18▸ Apixaban is a specific inhibitor or FXa, which leads to prolongations of the prothrombin time (PT), the INR and aPTT19▸ Edoxaban is a selective inhibitor of FXa, resulting in the inhibition of free FXa, prothrombinase activity, and the inhibition of thrombin-induced platelet aggregation21
Pharmacokinetics (PK)
  • ▸ Dabigatran, and its active conjugates have similar PK profiles17

  • ▸ The PK of dabigatran are dose-dependent from 10 mg to 400 mg, with a half-life of 12–17 h in healthy subjects17

▸ The elimination half-life of rivaroxaban ranges from 5 to 9 h in healthy subjects18
  • ▸ After oral administration, apixaban has a half-life of ∼12 h

  • ▸ The PK of apixaban are log-linear, with proportional increases in exposure for oral doses (up to 10 mg)19

  • ▸ After oral administration, the half-life of edoxaban is ∼10–14 h21

  • ▸ In healthy subjects, edoxaban demonstrates approximately dose-proportional PK for doses from 15 to 150 mg, and from 60 to 120 mg following single and repeat doses, respectively21

  • ▸ The dabigatran etexilate pro-drug is a substrate of the P-glycoprotein (P-gp) efflux transporter in the gut. Dabigatran's bioavailability after oral dosing is 3–7%17

  • ▸ While the presence of food does not alter the overall bioavailability dabigatran, it does alter the time to Cmax (1 h under fasting conditions, while dosing with a high-fat meal can delay the Cmax by ∼2 h)17

  • ▸ The bioavailability of rivaroxaban is dose-dependent: at the 10 mg dose, 80–100% of the drug is bioavailable (and unaffected by food)18

  • ▸ At the 20 mg dose, the bioavailability is ∼66%, and absorption is impacted by food (mean area under the curve and Cmax increase by 39% and 76%, respectively)18

  • ▸ Apixaban has a bioavailability of ∼50% at doses up to 10 mg

  • ▸ Food consumption has no known impact on the bioavailability or PK of apixaban19

  • ▸ Apixaban demonstrates proportional increases in bioavailability for doses up to 10 mg, and the Cmax is seen ∼3–4 h after an oral dose19

  • ▸ The absolute bioavailability of edoxaban is 62%21

  • ▸ After oral dosing, peak plasma concentrations are measured within 1–2 h21

  • ▸ Consumption of food does not impact the overall systemic exposure to edoxaban21

  • ▸ Approximately 35% of dabigatran is bound to human plasma proteins17

  • ▸ In healthy subjects, the apparent volume of distribution is 50–70 L17

  • ▸ Approximately 92–95% of rivaroxaban is bound to human plasma proteins18

  • ▸ In healthy subjects, the apparent volume of distribution at steady state is approximately 50 L18

  • ▸ Approximately 87% of absorbed apixaban is bound to plasma proteins19

  • ▸ The apparent volume of distribution of apixaban at steady state is ∼21 L19

  • ▸ By in vitro assay, plasma protein binding of edoxaban is approximately 55%21

  • ▸ At steady state, the volume of distribution of edoxaban is 107 L21

  • ▸ After intravenous dosing, the primary route of elimination for dabigatran is renal clearance, (∼80% of total)17

  • ▸ Following oral dosing of dabigatran, only ∼7% is recovered from the urine, with ∼86% found in the faeces17

  • ▸ After an oral dose, ∼33% of the absorbed drug is excreted unchanged in the urine

  • ▸ The remainder of the absorbed dose, ∼66%, is converted to inactive metabolites and excreted in the urine and faeces

  • ▸ Excretion is by both the faeces and the urine (∼27% of total clearance), with both biliary and direct intestinal excretion contributions

  • ▸ Apixaban has a total clearance of ∼3.3 L/h

  • ▸ The primary route of elimination is for unmodified edoxaban to be excreted in the urine, for ∼50% of the total clearance (22 L/h)21

  • ▸ The remaining fraction of edoxaban is excreted via metabolism and biliary/intestinal route21

Specific emergency reversal/bleeding management options
  • ▸ No specific agent currently available

  • ▸ Idarucizumab, an investigational fully humanised antibody fragment under study as a specific reversal agent78

  • ▸ Idarucizumab has received Breakthrough Therapy designation from the FDA71

  • ▸ No specific agent currently available

  • ▸ Andexanet alfa is a recombinant, modified factor Xa molecule that is being developed as a direct reversal agent for FXa inhibitors79

  • ▸ Andexanet alfa has received Breakthrough Therapy designation from the FDA79

  • ▸ No specific agent currently available

  • ▸ Andexanet alfa is a recombinant, modified factor Xa molecule that is being developed as a direct reversal agent for FXa inhibitors79

  • ▸ Andexanet alfa has received Breakthrough Therapy designation from the FDA79

  • ▸ A specific reversal agent for edoxaban is not available21

  • ▸ There is no established way to reverse the anticoagulant effects of edoxaban, which can be expected to persist for approximately 24 h after the last dose21

Supportive strategies for reversal of anticoagulation
  • ▸ Withhold dabigatran for two or more half-lives

  • ▸ Coagulation factor concentrates, such as II, IX, or X, or aPCCs, for example, FEIBA or rFVIIa may be administered17

  • ▸ If a prolonged anticoagulant effect is anticipated, dialysis can be considered17

  • ▸ Administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used17

  • ▸ It is important to note that these agents/strategies have not been adequately evaluated in randomised clinical trials17

  • ▸ Withhold rivaroxaban for two or more half-lives

  • ▸ Rivaroxaban is highly protein bound, therefore dialysis is of limited utility for removal of the drug18

  • ▸ The anticoagulant effect of rivaroxaban is not expected to be influenced by either protamine sulphate or vitamin K18

  • ▸ Modest reversal of the prolongation in the PTT has been reported in healthy volunteers following administration of PCCs18

  • ▸ Note: The use of either aPCC or rFVIIa has not been adequately evaluated in randomised clinical trials18

  • ▸ Withhold apixaban for two or more half-lives

  • ▸ Dialysis is of limited utility due to high plasma protein binding of apixaban19

  • ▸ Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of apixaban19

  • ▸ Partial reversal of PTT prolongation has been seen after administration of PCCs in healthy volunteers19

  • ▸ Note: The use of other procoagulant reversal agents such as aPCC or rFVIIa has not been adequately evaluated in randomised clinical trials19

  • ▸ After overdose or accidental ingestion, doses of activated charcoal, provided at 2 and 6 h post ingestion may reduce the amount of drug absorbed into the blood19

  • ▸ Standard laboratory testing procedures cannot reliably assess the anticoagulant effect of edoxaban21

  • ▸ Haemodialysis cannot be relied on to significantly reduce plasma levels of edoxaban21

  • ▸ General agents such as tranexamic acid, vitamin K and protamine sulphate, vitamin K will not effectively reverse the anticoagulation effect of edoxaban21

  • aPCC, activated prothrombin complex concentrates; aPTT, activated partial thromboplastin time; FDA, US Food and Drug Administration; FEIBA, factor VIII inhibitor bypassing activity; INR, international normalised ratio; NOACs, non-warfarin oral anticoagulants; PCCs, prothrombin complex concentrates; PT, prothrombin time; rFVIIa, recombinant factor VIIa.