Abstract
Unlike vitamin K antagonists (VKAs), the new oral anticoagulants (NOACs)—direct thrombin inhibitor, dabigatran, and direct activated factor X inhibitors, rivaroxaban, and apixaban—do not require routine INR monitoring. Compared to VKAs, they possess relatively rapid onset of action and short halflives, but vary in relative degrees of renal excretion as well as interaction with p-glycoprotein membrane transporters and liver cytochrome P450 metabolic enzymes. Recent completed phase III trials comparing NOACs with VKAs for stroke prevention in atrial fibrillation (AF)—the RE-LY, ROCKET AF, and ARISTOTLE trials—demonstrated at least noninferior efficacy, largely driven by significant reductions in haemorrhagic stroke. Major and nonmajor clinically relevant bleeding rates were acceptable compared to VKAs. Of note, the NOACs caused significantly less intracranial haemorrhagic events compared to VKAs, the mechanisms of which are not completely clear. With convenient fixed-dose administration, the NOACs facilitate anticoagulant management in AF in the community, which has hitherto been grossly underutilised. Guidelines should evolve towards simplicity in anticipation of greater use of NOACs among primary care physicians. At the same time, the need for caution with their use in patients with severely impaired renal function should be emphasised.
Highlights
Atrial fibrillation (AF) increases the risk of embolic stroke
Heart failure episodes destabilise international normalised ratio (INR) and make tight INR control challenging [47], which may be one of the possible explanations that may account for the lower mean time in therapeutic range (TTR) in ROCKET atrial fibrillation (AF) (55%) compared to randomized evaluation of long-term anticoagulation therapy (RE-LY) (64%) and ARISTOTLE (62%) [13,14,15]
There was a significant difference in study drug discontinuation rates between dabigatran-(21%) and VKAtreated (17%) subjects in RE-LY, which may be explained by the open-label design, as well as higher rates of dyspepsia with dabigatran [13, 48]
Summary
Anticoagulation with vitamin K antagonists (VKAs), doseadjusted to achieve a target international normalised ratio (INR) range of 2.0-3.0, significantly reduces stroke risk metaanalysis revealed a significant stroke risk reduction of 64% (CI, 49% to 74%) compared to placebo [1]—with acceptable rates of bleeding complications [1, 2]; but is limited by inherent problems. These problems include a narrow drug therapeutic index, wide variations in metabolism, and numerous food and drug interactions [3]. Combination therapy with aspirin and clopidogrel in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVEA) trial was better than aspirin alone for prevention of vascular events but was associated with increased bleeding
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