Editor's Note: Commentary based on Friberg L, Skeppholm M, Terént A. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA₂DS₂-VASc score of 1. J Am Coll Cardiol 2015;65;225-32.

Background

Both U.S. and European guidelines recommend using the CHA₂DS₂-VASc scoring system as a risk stratification tool to guide decisions regarding the use of oral anticoagulants (OACs) in patients with atrial fibrillation (AF).^1,2 However, reports vary widely on the stroke risk among patients with a CHA₂DS₂-VASc score of 1, and whether these patients benefit from oral anticoagulation remains unclear.

Methods

Using the Swedish National Patient Register and the national stroke register (Riks-Stroke), Friberg et al. performed a retrospective study of all patients with non-valvular AF with no exposure to OACs³ to estimate the stroke risk in patients with CHA₂DS₂-VASc scores of 1. Stroke outcomes were stratified by gender and by CHA₂DS₂-VASc score, and data are presented for both strict (ischemic stroke only) and broader (ischemic stroke, thromboembolism including pulmonary embolism [PE], and transient ischemic attack [TIA], all of which have been used as outcomes in prior studies^4,5) outcome definitions.

Results

A total of 140,420 patients were included in the analysis. Stroke outcomes are reported for both the Riks-Stroke register and the National Patient Register, with the former slightly lower in all cases. Using National Patient Register data, the annualized ischemic stroke rate was 3.6%. Expanding the outcome definition, as described above, increased the event rate substantially – inclusion of thromboembolic events increased the event rate to 4.5% (a 25% relative increase) and inclusion of thromboembolic events or TIA increased the event rate to 5.2% (a 44% relative increase).

Among patients with a CHA₂DS₂-VASc score of 1, the annualized event rate ranged from 0.5% to 0.9%, depending on the outcome definition used. The corresponding rate was 0.3% in the Riks-Stroke registry. Ischemic stroke risk for women was 0.1-0.2% annually, while the risk for men ranged from 0.5% (Riks-Stroke) to 0.7% (National Patient Register). The annual rate of the more inclusive endpoint among men was 1.3%.

Of patients on warfarin at study baseline (a group excluded from primary analysis), patients with CHA₂DS₂-VASc score of 1 had the second highest rate of anticoagulation (~40%); higher-risk patients had much lower rates of anticoagulation.

Conclusion

This study found low rates of ischemic stroke in patients with a CHA₂DS₂-VASc score of 1 and suggests that such patients are unlikely to benefit from systemic anticoagulation.

Commentary/Perspective

While high-risk patients unquestionably benefit from anticoagulation, the decision of whether or not to anticoagulate lower-risk patients is a challenging one. It is telling that professional societies differ in their recommendations regarding patients with CHA₂DS₂-VASc score of 1, with European guidelines suggesting use of an OAC and American guidelines suggesting individualized therapy, which may include OAC, aspirin, or no antithrombotic therapy.^1,2 This study provides the largest analysis to date of stroke risk in low-risk patients with AF and suggests that the stroke risk in this population is lower than several previous studies have shown.⁴ In a Danish registry study, for instance, the annual event rate for patients with a CHA₂DS₂-VASc score of 1 was 2.0%,⁴ while in a recent cohort from Taiwan, Chao et al. found an annual event rate of 2.75% among men with a CHA₂DS₂-VASc score of 1 (as compared to 0.5-0.7% in this study).⁶

Different thresholds have been suggested for the level of annual stroke risk at which there is a net benefit of OAC treatment in AF, with one recent paper citing figures ranging from 0.9% to 1.7%,⁷ depending on which OAC was used as the comparator. In this study, annualized risk of stroke among patients with CHA₂DS₂-VASc score of 1 fell below either of these cutoffs, thereby calling into question the appropriateness of anticoagulation in such a population. At the same time, the study also highlights a seeming misapplication of anticoagulation, as this very population had higher rates of warfarin usage than patients with much higher risk.

An additional key issue raised by this paper pertains to choice of clinical endpoints in anticoagulation decision-making. It may be noted that this study showed an event rate of 1.3% in men with CHA₂DS₂-VASc score of 1 using the more expansive outcome definition. However, the authors argue that inclusion of outcomes such as PE^4,5,8 and TIA^8,9 is problematic, as the former is not directly related to embolic risk from AF, and the latter presents significant challenges for consistent diagnosis and validation.

This paper has several important limitations. First, the primary analysis included, by design, only those patients in whom a decision had been made not to anticoagulate, indicating the potential for a significant inclusion bias towards patients at lower risk for thromboembolic events. Additionally, no data are provided on the use of antiplatelet agents, which are known to modify stroke risk, albeit to a lesser degree than OACs. Generalizability may be limited, as all patients were drawn from Sweden and patients in other regions have shown high rates of thromboembolism.⁶ Finally, this was a retrospective study and was, therefore, limited to ICD-10 coding for establishing diagnoses, allowing for the possibility of misclassification. A randomized, double-blind trial would be necessary to definitively establish the risk/benefit ratio of anticoagulation in patients with a CHA₂DS₂-VASc score of 1.

References

1. 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. Europace 2012;14:1385-413.
2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.
3. Friberg L, Skeppholm M, Terent A. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA₂DS₂-VASc score of 1. J Am Coll Cardiol 2015;65:225-32.
4. 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.
5. 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.
6. 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.
7. Eckman MH, Singer DE, Rosand J, Greenberg SM. Moving the tipping point: the decision to anticoagulate patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2011;4:14-21.
8. Guo Y, Apostolakis S, Blann AD, et al. Validation of contemporary stroke and bleeding risk stratification scores in non-anticoagulated Chinese patients with atrial fibrillation. Int J Cardiol 2013;168:904-9.
9. Poli D, Lip GY, Antonucci E, Grifoni E, Lane D. Stroke risk stratification in a "real-world" elderly anticoagulated atrial fibrillation population. J Cardiovasc Electrophysiol 2011;22:25-30.

Keywords: Anticoagulants, Aspirin, Atrial Fibrillation, Double-Blind Method, Fibrinolytic Agents, International Classification of Diseases, Ischemic Attack, Transient, Odds Ratio, Platelet Aggregation Inhibitors, Pulmonary Embolism, Registries, Retrospective Studies, Risk, Stroke, Sweden, Taiwan, Thromboembolism, Warfarin

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