Rivaroxaban is a selective, short-lived and direct inhibitor of factor Xa. It has a bioavailability of almost 100 % if administered with food and its peak plasma concentrations occur within 2–4 h after oral administration [23, 24]. The half-life of the drug is 5–9 h in young patients and about 11–13 h in the elderly population [25]. Rivaroxaban is predominantly excreted through the kidneys: about 36 % of the drug is excreted unchanged and 30 % is excreted as inactive metabolites; the remaining drug is eliminated in faeces. Rivaroxaban is metabolised via the CYP450 system, primarily through CYP3A4 and CYP2J2 [26]. Therefore, known CYP3A4 inhibitors such as azoles or inducers such as phenytoin will affect its metabolism [26, 27]. Unlike warfarin, rivaroxaban does not require initial bridging with LMWH, and also does not require routine anticoagulation monitoring.

Dabigatran is the only oral direct thrombin inhibitor currently licensed in the UK. It is a selective, short-lived inhibitor of both free and clot bound thrombin. Time to peak plasma concentration after oral intake is 0.5–2 h. Maximum anticoagulant effects are achieved within 1–2 h depending upon food intake with maximum effect in 2 h. Dabigatran etexilate is the prodrug which is converted to the active compound dabigatran by non-specific esterases in plasma and liver [28]. Renal excretion of unchanged drug is the predominant elimination pathway, with about 80 % of drug being excreted unchanged in the urine [29]. Dabigatran is not metabolised, induced or inhibited by CYP450 enzyme system. It has a low protein binding (35 %) and is potentially dialyzable. However, because of its large volume of distribution, there is usually a rebound in the drug level; therefore, dialysis as a means of removing the drug from the body is impractical [29, 30]. For management of active bleeding, supportive care and activated charcoal may be given if the patient is seen within 2 h of ingestion of dabigatran.

Apixaban is a selective, reversible and direct inhibitor of factor Xa. Food does not interfere significantly with its absorption. Its half-life is 8–15 h. Time to reach maximum plasma concentration is 3–4 h. It is metabolised by the CYP3A4 in the CYP450 system. Apixaban is approximately 87 % protein bound and is therefore difficult to dialyze [31]. Renal excretion of the active drug is 25 %. Slower excretion is expected in the setting of chronic kidney disease (CKD). Although there has been concern regarding cumulative toxicity in renal insufficiency, however, it has been used successfully with no major increase in bleeding complications in CKD stage III patients [32]. Apixaban seems to have a favourable pharmacokinetic and pharmacodynamic profile compared to the other NOACs. It is minimally excreted through kidneys and has a short half-life. Meta-analysis and indirect comparisons for the safety and efficacy of the three anticoagulants showed apixaban safer than others secondary to less major bleeds [33, 34]

Although the NOACs have significantly fewer drug-drug interactions, compared to VKAs, drugs that strongly affect the CYP3A4 enzyme and/or P-glycoprotein can alter the plasma concentration of the NOACs and may lead to clinically significant changes in the anticoagulant effect [27]. CYP3A4 is a member of the hepatic cytochrome P450 enzyme and is responsible for oxidative metabolism of both apixaban and rivaroxaban [35]. Dabigatran etexilate, the prodrug, is metabolised by esterases in the plasma and liver without significant involvement of CYP3A4 [20, 26, 36]. Rivaroxaban and apixaban, substrates of CYP3A4, can act as both inducers and inhibitors leading to potentially increased toxicity or decreased efficacy [35].

P-glycoprotein, an ATP-dependent efflux transporter, mediates drug absorption and excretion. P-glycoprotein is present in many normal human tissues, most notably the luminal membrane of enterocytes and the apical membrane of both hepatocytes and renal tubular cells [36]. P-glycoprotein is responsible for the efflux of drugs into the biliary canaliculi and renal tubules, decreasing net absorption via increased excretion of drug into the bile and urine [24]. Dabigatran etexilate, rivaroxaban and apixaban (substrates of P-glycoprotein) are susceptible to strong inhibitors or inducers of this transporter.

Commonly prescribed drugs in critical care may interact with the NOACs and are summarised in Table 12.3.