Should patients on vitamin K antagonists be treated differently?

Relative to warfarin, non-vitamin K oral anticoagulants (NOACs) are at least as good at preventing stroke or systemic embolism, cause less haemorrhagic stroke, and result in modestly lower mortality. Thus, the European Society of Cardiology has recommended NOACs in place of vitamin K antagonists (VKAs) in most patients with atrial fibrillation (class IIa, level of evidence A). According to one report, the use of NOACs in the USA has increased to . 60% of prescriptions for patients being initiated on oral anticoagulation. However, patients already treated with VKAs are usually not switched to NOACs. The low rates of switching from VKAs to NOACs relate to multiple factors including patient preference, medication cost, and clinical factors such as severe renal impairment. There is a common perception that a patient who is stable on a VKA will derive less benefit from a NOAC than a “VKA-naı̈ve”, patient who has not been previously treated with a VKA. The question remains whether or not this perception is supported by evidence. Not only does prior use of a VKA influence decisions to use a NOAC, but so does the degree of International Normalized Ratio (INR) control on a VKA, as measured by the time in therapeutic range (TTR). The prevailing opinion is that switching to a NOAC is less beneficial for patients on a VKA with a high TTR. In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) trial, patients who were at centres with higher average TTR did better on warfarin than on clopidogrel and aspirin, which was not the case for patients at centres with low TTR. While this finding seemed logical from a clinical perspective, this “subgroup” was defined by post-randomization features and was confounded by other factors, and thus should be interpreted with caution. In aggregate, when analyses according to TTR were done in the four large trials comparing NOACs with warfarin, stroke rates were lower at centres with high TTR in the warfarin group— but also in the NOAC group, showing that TTR is reflecting more thanqualityofVKA treatment. Overall, therewas modestly less treatment benefit with NOACs vs. warfarin in the centres with high TTR, although the lower rate of haemorrhagic stroke with NOAC vs. warfarin was consistent regardless of TTR. Therefore, despite some uncertainty related to the limitations of the analyses, it appears that the benefits of NOACs, while somewhat less, are generally consistent regardless of INR control at the level of the centre. The issue of INR control is also relevant to the discussion of prior VKA treatment, since patients with a history of VKA treatment have modestly higher TTR values than patients that are VKA naı̈ve in the clinical trials (Table 1). –8 In this issue of the journal, O’Donoghue et al. describe the results of the Edoxaban versus Warfarin in VKA experienced and naı̈ve patients from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 trial (ENGAGE AF) according to prior VKA use. The ENGAGE AF trial randomized 21 105 patients to warfarin, high-dose edoxaban, or low-dose edoxaban. Patients treated with a VKA for . 60 days prior to enrolment in the trial were considered VKA experienced, and 94% of these patients were on a VKA at the time of randomization. Patients with a history of VKA use had higher stroke risk profiles than patients without prior VKA use, with more patients with age ≥ 75 years (42% vs. 38%), prior stroke or transient ischaemic attack (29% vs. 27%), diabetes mellitus (38% vs. 33%), and CHADS2 score . 3 (23% vs. 22%). There were other differences as well. Patients in certain geographic regions, such as North America and Western Europe, were much more likely to be VKA experienced, whereas VKA-naı̈ve patients had a higher rate of aspirin use (42% vs. 21%) at baseline and at 1-year follow-up (27% vs, 19%). The median TTR was higher for VKA-experienced patients (71% vs. 65%, P , 0.001), a difference that persisted over the 3-year course of the trial. Within ENGAGE AF, the effect of edoxaban vs. warfarin differed according to prior VKA use. The reduction of stroke or systemic embolism with each dose of edoxaban vs. warfarin was greater in