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NOACs: Overview


NOACs: an overview in atrial fibrillation


Development of non-VKA anticoagulants that are either superior or non-inferior to warfarin in terms of efficacy and safety as documented in large, well-designed, randomised, controlled trials is leading to a major change in this field


A John Camm MD Irina Savel MD PhD St George’s University of London, London, UK


Although vitamin K antagonists (VKAs) are very effective medications for thrombo-prophylaxis in patients with atrial fibrillation (AF) at risk of stroke, the associated risk of haemorrhage, particularly intracerebral haemorrhage, has significantly limited their clinical utilisation. They were used sparingly in the late 1980s and did not become much used until after the completion of randomised controlled clinical trials in the early 1990s. Meta-analysis of the efficacy of VKAs showed an impressive 64% reduction in stroke and a 26% reduction in all-cause mortality.1


Despite


these results, both doctors and patients continued to fear adverse bleeding events and at least 40% of patients in need of anticoagulant therapy remained without it. Instead, aspirin was used for stroke prevention in AF because doctors and patients thought that was it safe and, to some extent, effective.2


However, early


meta-analyses failed to document any significant efficacy3,4


and more recent


studies confirmed lack of efficacy of aspirin compared with anticoagulants and demonstrated conclusively that bleeding risks associated with aspirin were not significantly different to those seen with appropriately managed anticoagulant treatment.5,6


Dual


antiplatelet therapy with aspirin and clopidogrel has been advocated in patients unable to take oral anticoagulants, but proven inferior to dose-adjusted warfarin.7 Early this century, reports appeared


The NOAC drugs


There are now four NOACs (Table 1) that are relatively widely available; a factor Factor IIa inhibitor (dabigatran), and three factor Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban).8


about new anticoagulant drugs that were aimed at specific targets in the coagulation cascade, directly inhibiting either factor Factor IIa (thrombin) or Xa. These drugs were purposefully ‘designed’ to have no food–drug interactions and few drug–drug interactions and a relatively short elimination half-life when compared with VKAs. These drugs were initially known as new oral anticoagulants or NOACs. The terminology has now changed because these medicines are no longer new or novel, instead they are known as non-VKA oral anticoagulants (NOACs) or direct oral anticoagulants (DOACs).


The drugs have some similar


pharmacokinetic properties such as rapid anticoagulation (time to Cmax


= 1–4


hours), fast offset of action (short elimination half-lives of 12–16 hours) which is ‘right on the cusp’ of whether the drugs should be administered once (edoxaban and rivaroxaban) or twice (apixaban or dabigatran) a day, and dependency of the P-glycoprotein pump (p-GP) for mucosal transport of the drug (p-GP inhibitors such as verapamil, dronedarone and amiodarone increase the concentration of these anticoagulants). However, there are also some major differences. Dabigatran and, to a more limited extent, edoxaban are dependent on renal excretion, whereas apixaban and rivaroxaban are more reliant on hepatic metabolism (for example, via the CYP450 3A4 enzyme system). Dabigatran is a prodrug (dabigatran etexilate) and its


www.hospitalpharmacyeurope.com Target


Bioavailability (%) GI tolerability


Table 1: Features of non-VKA oral anticoagulants* Dabigatran IIa (thrombin) 3–7


80 (with food)


Intake with food recommended? Hours to Cmax


Half-life (h)


Renal clearance (%) Transporters


CYP-metabolism (%)


Protein binding (%) Dosing regimen


Xa 50


Mandatory No 2–4


5–13 33


P-gp 32%


92–95 QD


Rivaroxaban Apixaban Edoxaban Xa


Xa 62


Dyspepsia 5–10% No problem No problem No problem No 1–3


12–17 80


P-gp None


35 BD


CYP: cytochrome P450; P-gp: P-glycoprotein ; * SPCs; **absorbed dose


3–4 12 27


P-gp <32%


87 BD


No 1–2


10–14 50** P-gp


Minimal; <10%


40–59 QD


19


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