Editor's Note: Commentary based on Chao TF, Liu CJ, Wang KL et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA₂DS₂-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65:635-42.

Background

Atrial fibrillation (AF) is a major cause of ischemic stroke, and anticoagulant therapy has been used as a strategy to reduce this risk.¹ The CHA₂DS₂-VASc score has been proposed as a risk stratification tool for ischemic stroke in patients with non-valvular AF and both the European Society of Cardiology (ESC) and the American College of Cardiology (ACC)/American Heart Association (AHA) AF guidelines recommend its use to identify patients most likely to benefit from antithrombotic therapy.^2-4 However, there are differences between these two guidelines regarding management of patients with an intermediate CHA₂DS₂-VASc score. Specifically, patients with a CHA₂DS₂-VASc score of 1 (excluding females with no additional risk factors) warrant anticoagulant treatment to prevent thromboembolism per the ESC guidelines. However, the ACC/AHA notes that the data are uncertain, and, hence, states that these patients may be managed with no antithrombotic therapy, aspirin alone, or an oral anticoagulant.

Methods

This study by Chao et al. retrospectively analyzed the National Health Insurance Research Database of the Taiwan National Health Research Institutes, which is a mandatory universal health insurance program that covers all Taiwanese residents.⁵ Between January 1996 and December 2011, all patients with AF ≥20 years of age were identified. Patients with prior use of antiplatelet or anticoagulant agents were excluded, as well as those with CHA₂DS₂-VASc scores >1 for males and >2 for females. The study endpoint was the occurrence of ischemic stroke.

Results

A total of 12,935 males and 7,900 females with a CHA₂DS₂-VASc score of 1 and 2, respectively, were included in the study, with ages between 65 and 74 years and hypertension being the most common risk factors. Over the study period, there was an annual risk of ischemic stroke of 2.75% per year for males and 2.55% per year for females. Compared to patients with a CHA₂DS₂-VASc risk score of 0 (for males) and 1 (for females), the hazard ratio risk of stroke was 2.385 for males and 2.251 for females. However, there was variability among the risk of stroke among the different risk factors. For males, the risk of ischemic stroke ranged between 1.96% per year for vascular disease and 3.50% per year for those with ages between 65 to 74 years. Similarly, for females the risk of ischemic stroke per year was lowest in those with hypertension, 1.91% per year, and highest in those between 65 to 74 years of age, 3.34% per year.

Commentary/Perspective

This study shows a substantial risk of ischemic stroke (2.55-2.75% annually) in patients with AF and one additional CHA₂DS₂-VASc risk factor compared to those with no additional risk factors. Compared to prior studies of patients with similar risk for stroke, the stroke rate appears to be higher in this study.^2,6-8 For example, in the derivation population and a subsequent large confirmatory study for the CHA₂DS₂-VASc risk score, the one-year rates of stroke for patients with a CHA₂DS₂-VASc score of 1 were 0.7% (after adjusting for aspirin use) and 2.01%, respectively.^2,8 Nonetheless, since the risk intracranial hemorrhage is approximately 50% lower (≤0.5% annually) with non-vitamin K oral anticoagulants (NOACs) compared to warfarin, the current study findings argue strongly for anticoagulation of patients with CHA₂DS₂-VASc scores of 1, particularly with a NOAC.⁹

Of note, several (but not all) prior studies combined males and females with a CHA₂DS₂-VASc score of 1; thus, women had no additional risk factors for stroke, since the CHA₂DS₂-VASc score assigns one point for female sex. In addition, prior studies included patients who received antiplatelet agents, which may confound the comparison, although these studies did attempt to adjust for antiplatelet use.^2,6,8 The study by Chao et al., therefore, supports recommendations by the ESC to administer oral anticoagulants to prevent ischemic stroke in patients with nonvalvular AF and a CHA₂DS₂-VASc risk of 1 (for males) and 2 (for females). Also, notably, there was variability in the risk of stroke depending on the individual risk factor, with ages 65 to 74 years old conferring the greatest risk, suggesting an even stronger indication for anticoagulant therapy in this older age group.

There are some notable limitations of this study, including not specifying whether all included patients had nonvalvular AF (as opposed to AF related to mitral stenosis), which would raise stroke risks even further. The analysis also did not account for anticoagulant or antiplatelet use after the study enrollment period which would potentially impact the ischemic stroke rate, but this likely does not change the overall direction of the conclusions. The study population is limited to patients from Taiwan, which may impact the generalizability of this study as well. However, since the proportion of ischemic versus hemorrhagic stroke is lower in East Asian patients compared to most of the rest of the developed world, the overall risk-benefit profile may be even more favorable in non-Asian populations.¹⁰ Additionally the study is limited by its design, which is based on the review of diagnosis codes of an administrative database. However, the authors do comment that this particular database has been shown to have high accuracy in the diagnosis of AF and ischemic stroke. Similarly, due to study design, the authors were also not able to determine whether the cause of ischemic stroke was actually AF. A prospective, blinded, randomized controlled study is needed to answer the question of how to manage patients with AF with an intermediate CHA₂DS₂-VASc risk to understand the risk of major bleeding events as well as the reduction in stroke risk with anticoagulant use. Additional analysis of other emerging risk factors such as left atrial structure is also needed.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8.
2. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72.
3. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.
4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-104.
5. Chao TF, Liu CJ, Wang KL, et al. Should atrial fibrillation patients with 1 additional risk factor of the CHA₂DS₂-VASc score (beyond sex) receive oral anticoagulation? J Am Coll Cardiol 2015;65:635-42.
6. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA₂DS₂-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost 2012;107:1172-9.
7. Coppens M, Eikelboom JW, Hart RG, et al. The CHA₂DS₂-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy. Eur Heart J 2013;34:170-6.
8. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011;342:d124.
9. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-62.
10. Hori M, Connolly SJ, Zhu J, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke 2013;44:1891-6.

Keywords: Academies and Institutes, American Heart Association, Anticoagulants, Aspirin, Atrial Fibrillation, Female, Fibrinolytic Agents, Humans, Hypertension, Insurance, Health, Intracranial Hemorrhages, Male, Mitral Valve Stenosis, National Health Programs, Odds Ratio, Platelet Aggregation Inhibitors, Prospective Studies, Retrospective Studies, Risk, Risk Factors, Stroke, Taiwan, United States, Vitamin K, Warfarin, Thromboembolism

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