Practical advice on safe and effective use of non-vitamin K antagonist oral anticoagulants

This editorial refers to ‘New oral anticoagulants: a practical guide for physicians’ by R. Hinojar et al., on page 134 The most important public health goal in stroke prevention for patients with atrial fibrillation (AF) is to treat a larger proportion of patients with risk factors for stroke with oral anticoagulation. It has been estimated that of the 20 million patients with AF worldwide, only about half are treated with oral anticoagulation, resulting in hundreds of thousands of preventable strokes per year.1 The specific reasons for not using anticoagulation are poorly defined, but inability to reliably monitor INR or to keep patients in a target International Normalized Ratio (INR) range are important contributing factors.2 Physician and patient concerns over risks of bleeding (including intracranial haemorrhage) and of falling are also common reasons to not use oral anticoagulation.3 There are now three non-vitamin K antagonist oral anticoagulants (NOACs) approved by the EMA and FDA (dabigatran, rivaroxaban, and apixaban) and a fourth (edoxaban) approved by the FDA. As a class, NOACs share three major advantages over vitamin K antagonists (VKAs): ease of use, lower risk of intracranial haemorrhage, and modestly lower mortality.4 Thus, the European Society of Cardiology has recommended NOACs in preference to VKAs in most patients with AF (class IIa, level of evidence A).5 The hope has been that NOACs would enable the treatment of the population not suitable for VKA therapy resulting in a substantial increase in the proportion of anticoagulated patients. This has not yet happened, which is in part related to challenges in the use of NOACs and complexity in differences between them. To use NOACs safely, providers must be familiar with practical issues in their use. To this end, Hinojar et al.6 in this issue of the European Heart Journal — Cardiovascular Pharmacotherapy provide important advice on use of NOACs for various patient subpopulations and clinical situations. Their review builds on the state-of-the-art manuscript by Heidbuchel et al.7 from 2013. Topics of management of bleeding on NOACs and dosing around procedures are well covered. Which drug should be used for which patient? Hinojar et al. provide some sensible general considerations. We agree that dabigatran 150 mg twice a day has the largest reduction in ischaemic stroke, rivaroxaban and edoxaban have the advantage of once daily dosing and well-established dose reduction for renal insufficiency, and apixaban has the best safety profile. One drug that should not be used as an effective treatment to prevent stroke in AF is aspirin, and the misperception that it is safe and effective is another contributor to underuse of oral anticoagulation.8 Apixaban, which is far more effective at preventing ischaemic stroke than aspirin, has comparable rates of major bleeding and intracranial haemorrhage.2 Patients with stage 4 or 5 chronic kidney disease (creatinine clearance <30 mL/min) were excluded from clinical trials of NOACs and thus should be treated with VKA.5 The single most common reason to favour VKA is cost, which limits access to NOACs for many patients around the world. How do we measure the anticoagulant effect of NOACs, and when should we? Hinojar et al. review the effects of the NOACs on coagulation parameters. The article does not address an important debate about whether outcomes might be improved in selected patients if NOAC dosing is determined with knowledge of plasma concentrations, given the evidence of a relationship between drug concentration and risk of bleeding and thrombosis.9 The combination of less-effective prevention of ischaemic stroke (vs. warfarin) and low plasma concentrations of edoxaban for patients with creatinine clearance >95 mL/min led the FDA to place a ‘boxed warning’ in the edoxaban label due to ‘reduced efficacy’ for this population. This was a controversial decision since it was based on a post hoc subgroup finding with the associated limitations. The clearer practical issue is with reduced renal function: dose adjustment (or dose choice) of the NOACs is important for patients with creatinine clearance <50 mL/min. A related very important issue is underdosing of NOACs in general practice, where a large percentage of patients receives lower-dose NOACs than recommended based on the clinical trial evidence.10 The article emphasizes the fact that NOACs should not be used for patients with mechanical prosthetic heart valves, and that we lack evidence of effectiveness in patients with rheumatic mitral stenosis. What is less well appreciated is that NOACs are effective for patients with AF and most other valve abnormalities. For example, in the ROCKET-AF and ARISTOTLE trials, 14–26% of patients had significant valve abnormalities (most commonly mitral insufficiency), and these patients had similar protection against stroke as patients without valve abnormalities.11,12 Another opportunity to improve care of anticoagulated patients is to avoid aspirin, unless there is a compelling reason to use it, like recent acute coronary syndrome. In the RE-LY trial, 38% of patients on oral anticoagulation were also treated with an antiplatelet agent (aspirin or clopidogrel), and patients treated with antiplatelet agents had an increased risk of major bleeding (HR 1.60, 95% CI 1.42–1.82).13 In the ARISTOTLE trial, 25% of patients were treated with aspirin in addition to an oral anticoagulant, and about half of these had no history of vascular disease and thus, no apparent reason to be on the aspirin.14 Aspirin use was associated with a substantial increase in major bleeding.14 These findings have been corroborated in registries. Avoidance of unnecessary aspirin may be especially important with NOACs, as they result in more gastrointestinal bleeding than VKAs. In conclusion, the NOACs provide important advantages to VKAs therapy, including for many patients who are not suitable for VKA due to challenges in anticoagulation monitoring. To be used safely, there are a series of practical issues that must be addressed, as outlined by Hinojar et al. Important opportunities to improve care for the AF patient on a NOAC include selecting the right dose and limiting concomitant aspirin use. Conflict of interest: S.D.P. reports modest research grant support from Astra Zeneca, Gilead, and Boston Scientific; modest Advisory Board from Janssen Pharmaceuticals. C.B.G. reports research grants from Armetheon, Boehringer-Ingelheim, Bristol-MyersSquibb/Pfizer, Bayer, Daiichi Sankyo, Janssen, GlaxoSmithKline, Medtronic Foundation, and The Medicines Company; consultancy fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Gilead, GlaxoSmithKline, Hoffman-La Roche, Janssen, Lilly, and The Medicines Company. Full disclosures at https://www.dcri.org/about-us/conflict-of-interest.