Choosing between a NOAC or a vitamin K antagonist: an approach based on risk stratification

This editorial refers to ‘A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial’†, by C.L. Fanola et al., on page 888. For many years vitamin K antagonists (VKAs) formed the cornerstone of thrombo-embolic prophylaxis in patients with atrial fibrillation. The introduction of non-vitamin K anticoagulants (NOACs) provided agents with comparative efficacy and reduced bleeding. Since NOACs obviated dosage titration, periodic laboratory testing, and dietary restrictions that are necessary with VKAs,1 it was assumed that they would rapidly replace these agents. However, the supplanting of VKAs by NOACs went more slowly than anticipated. Likely causes for the slower uptake were the absence of an intermational normalized ratio (INR) equivalent to judge therapeutic effect, the lack of a reversal agent until recently, and, perhaps most importantly, increased cost. The question emerged, therefore, as to whether patient subsets could be identified in whom NOACs were either markedly valuable or of little comparative benefit compared with VKAs. In this issue of the journal. Fanola and colleagues provide the first potential approach to selecting those patients who will receive the greatest benefit from NOACs.2 Anticoagulants are a class of agents that represent a ‘double-edged sword’; they have antithrombotic efficacy while exposing the patient to the risk of bleeding. While a number of scores exist to assess the relative risk of stroke/systemic embolus or bleeding, the scores are imperfect and often identify patients who are at risk for both events.3,4 Fanola etal. adopted the increasingly utilized approach of analysing the net clinical outcome (NCO) of NOACs vs. VKAs computed as the total of disabling stroke, life-threatening bleed, and all-cause death. From the outcomes of a group of 2898 VKA-naïve patients from the ENGAGE AF-TIMI 48 trial comparing VKA with edoxaban, the investigators utilized a sophisticated analytical protocol to derive and then validate 17 integer risk values. Based upon these values, they divided patients into cohorts of low, intermediate, and high risk, with risks of 3.5, 9.9, and 20.8%, respectively. Interestingly, the low-risk group comprised >50% of the derivation group. Importantly, when compared with treatment with a VKA in the VKA-naïve patients in the study, they found that NCO was significantly lower with edoxaban in the intermediate-and high-risk groups, but not in the low-risk group. Thus, these data hold the potential to provide a method by which physicians who desire to use a VKA in patients with atrial fibrillation may determine if and how much benefit in NCO they may forego compared with administering NOACs. As an early attempt to risk-stratify patients for NOAC benefit, it is not surprising that the study has a number of limitations. This is a retrospective analysis using data that applies to only a single NOAC and may not be applicable to others. The risk scores were derived only from patients who were VKA naïve, in patients with CHADS2 score of ≥2, and in only a very small number of black patients. Unfortunately, no data are available for the substantial number of patients currently taking a VKA. The statistical analysis is complex, and it is not clear how easily such an approach could be introduced to the clinical setting. As a composite outcome, the NCO includes events of different severity; life-threatening bleeds are obviously of different magnitude than death. Clearly, similar studies, preferably prospective trials, will be required in different populations and with different agents before this approach can be widely applied clinically. An ageing population carries with it an increasing incidence of non-valvular atrial fibrillation, and therefore the need for anticoagulant therapy. While the use of NOACs is extremely attractive for reasons enumerated above, these agents are not without drawbacks, perhaps the most practical and impactful being cost. Every day physicians, healthcare organizations, and payers must decide whether the benefits of NOACs are worth the cost for individuals and groups of patients. The data from Fanola etal. suggest that it might be possible to risk-stratify patients so as to answer this question. Extrapolated to their most provocative potential conclusion, the data suggest that, as compared with NOACs, VKA therapy may be administered to a substantial percentage of patients at low risk without an adverse effect upon the net clinical outcome. These initial data cannot establish the role of risk stratification in making therapeutic decisions regarding anticoagulants in atrial fibrillation. However, they represent an important first step to an approach that has considerable promise to provide such guidance. Conflict of interest: none declared.