Patients with atrial fibrillation (AF) are at increased risk of stroke and thromboembolism (TE), and oral anticoagulation (OAC) reduces stroke (by 64%), ischemic stroke (by 67%), and all-cause mortality (by 26%) compared to placebo/control.¹ However, the risk of stroke in AF is not homogeneous, depending on the presence of various stroke risk factors. These risk factors have been used to formulate stroke risk stratification schemes, the most common of which are the CHADS₂ and CHA₂DS₂-VASc scores. The latter is now recommended in international guidelines.^2,3

While simple, the limitations of the CHADS₂ score are recognized,^4,5 and even patients with a CHADS₂ score = 0 (supposedly "low-risk" in older guidelines) can have a stroke rate as high as 3.2% per year.⁶ The newer CHA₂DS₂-VASc score is more inclusive of common stroke risk factors and is particularly good at identifying "truly low-risk" patients,^7-9 so that patients with a CHA₂DS₂-VASc score of 0 in males (or 1 in females) have an annual stroke rate of 1% or less. In one cohort of lone AF patients followed over 12 years, only the CHA₂DS₂-VASc score (and not CHADS₂) was predictive of the absence of ischemic stroke.¹⁰

Thus, rather than a didactic use of scores to artificially categorize patients into treatment groups, the European and National Institute for Health and Care Excellence (NICE) guidelines recommend a risk factor-based approach to thromboprophylaxis, so that the first step is to identify low-risk patients (i.e., CHA₂DS₂-VASc score = 0 in males or 1 in females) who do not need any antithrombotic therapy (Step 1). The subsequent step (Step 2) is to offer effective stroke prevention to those with ≥1 additional stroke risk factors.

A recent debate has arisen whether a CHA₂DS₂-VASc score = 1 has lower event rates than previously thought, with a recent Swedish publication¹¹ showing that CHA₂DS₂-VASc score = 1 patients had an ischemic stroke event rate <1% per year. The devil is in the detail of the methodology; for example, if transient ischemic attacks (TIAs) and TE events are excluded, the absolute event rates look lower – despite TIAs and TEs identifying a high-risk cohort. Also, the study cohort is confined to subjects in whom warfarin was never used, so there is selection for lower-risk patients given that those in whom warfarin is started during follow-up are likely to be higher-risk (so-called "conditioning for the future"), thus leading to artificially low event rates. Finally, the artificial "blanking periods" in that study can be debated since stroke risk and the decision to treat with OAC is made at the outset, and not just after, for example, four weeks.

In contrast, other recent papers show that even patients with one additional stroke risk factor (that is, CHA₂DS₂-VASc score = 1 in males, 2 in females) have a high risk of stroke, TE, and/or death.¹² Chao et al.¹³ recently reported that among 12,935 male AF patients with a CHA₂DS₂-VASc score of 1, the annual stroke rate was 2.75%; as expected, different risk factors within the CHA₂DS₂-VASc risk factors conferred different absolute rates, whereby ischemic stroke ranged from 1.96% per year for men with vascular disease to 3.50% per year for those age 65 to 74 years. For the 7,900 females with AF and a CHA₂DS₂-VASc score of 2, the annual stroke rate was 2.55%, with ischemic stroke risk ranging from 1.91% per year for women with hypertension to 3.34% per year for those between the ages of 65 to 74 years.

These data are further supported by the Danish nationwide cohort data,¹² which show that the presence of one additional risk factor (CHA₂DS₂-VASc = 1 for males, or 2 for females) increased overall ischemic stroke rate to 1.55 per 100 person-years, representing a significant 3.01-fold increase, compared to truly low-risk patients (CHA₂DS₂-VASc = 0 for males, 1 for females) who had ischemic stroke rates of 0.43 per 100 person-years at one year. Even in the patients with one risk factor, there were reductions in stroke and death with warfarin versus no treatment and with warfarin versus aspirin, but there was no increase in bleeding with warfarin versus aspirin.

Consistent data for high event rates even with one stroke risk factor have been reported in other AF cohorts, as recently summarized by Nielsen and Chao.¹⁴ However, we also recognize that stroke risk scores have to balance simplicity and practicality, for use in everyday clinical practice – without the need for complex weighted formulae, often derived from multivariate analyses of highly selected trial cohorts.

Should patients with AF and 1 additional stroke risk factor (CHA₂DS₂-VASc Score of 1 in males, 2 in females) receive anticoagulation? As the majority of the published data show, a single risk factor confers real risk, and this can be serious from stroke, TE, and/or death. As mentioned, OAC reduces strokes, TE, and/or death in AF. It is also important to appreciate that we are not dealing with a patient population that has a static risk profile, given the elderly age, multiple comorbidities, and frequent hospitalizations associated with AF. The net clinical benefit balancing stroke reduction against serious bleeding is also positive with ≥1 stroke risk factors.^15,16 Finally, AF patients strongly value stroke avoidance much more than bleeding, and to avoid one stroke they are even prepared to sustain four major bleeds.¹⁷ Thus, we must speak more to our patients, and not simply assume that bleeding considerations outweigh stroke prevention for them¹⁸ Clearly, some decisions need to be individualized, notwithstanding that some patients are at very high risk of bleeding (for example, those with prior intracranial bleeding), but these patients are also at high risk of stroke and death, if not adequately treated.¹⁹

As highlighted by Nielsen and Chao,¹⁴ clinicians should honestly ask themselves – is it really worth taking the risk of not offering stroke prevention (that is, OAC) to our patients, especially since AF patients are at higher risk of fatal and severely disabling strokes? Surely we can do better for our AF patients and remember that even a single additional stroke risk factor confers real risk.

References

1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.
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-e76.
3. Camm A, Lip G, 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 Hear J 2012;33:2719-47.
4. Keogh C, Wallace E, Dillon C, Dimitrov BD, Fahey T. Validation of the CHADS₂ clinical prediction rule to predict ischaemic stroke. A systematic review and meta-analysis. Thromb Haemost 2011;106:528-38.
5. Zhu W, Xiong Q, Hong K. Meta-Analysis of CHADS₂ versus CHA₂DS₂-VASc for predicting stroke and thromboembolism in atrial fibrillation patients independent of anticoagulation. Tex Heart Inst J 2015;42:6-15.
6. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GYH. 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. Lip GYH, Nielsen PB, Skjøth F, Rasmussen LH, Larsen TB. Atrial fibrillation patients categorised as "not for anticoagulation" with the 2014 Canadian Cardiovascular Society algorithm are not "low risk." Can J Cardiol 2015;31:24-8.
8. Chao T-F, Liu C-J, Wang K-L, et al. Using the CHA₂DS₂-VASc score for refining stroke risk stratification in "low-risk" Asian patients with atrial fibrillation. J Am Coll Cardiol 2014;64:1658-65.
9. Chen J-Y, Zhang A-D, Lu H-Y, Guo J, Wang F-F, Li Z-C. CHADS2 versus CHA₂DS₂-VASc score in assessing the stroke and thromboembolism risk stratification in patients with atrial fibrillation: a systematic review and meta-analysis. J Geriatr Cardiol 2013;10:258-66.
10. Potpara TS, Polovina MM, Licina MM, Marinkovic JM, Prostran MS, Lip GYH. Reliable identification of "truly low" thromboembolic risk in patients initially diagnosed with "lone" atrial fibrillation the belgrade atrial fibrillation study. Circ Arrhythm Electrophysiol 2012;5:319-26.
11. 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.
12. Lip GYH, Skjøth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA₂DS₂-VASc score. J Am Coll Cardiol 2015 March 5. [Epub ahead of print].
13. Chao T-F, Liu C-J, Wang K-L, 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.
14. Nielsen PB, Chao T. The risks of risk scores for stroke risk assessment in atrial fibrillation. Thromb Haemost 2015 March 11. [Epub ahead of print]
15. Friberg L, Rosenqvist M, Lip GYH. Net clinical benefit of warfarin in patients with atrial fibrillation: A report from the swedish atrial fibrillation cohort study. Circulation 2012;125:2298-307.
16. Olesen JB, Lip GYH, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a "real world" nationwide cohort study. Thromb Haemost 2011;106:739-49.
17. Lahaye S, Regpala S, Lacombe S, et al. Evaluation of patients' attitudes towards stroke prevention and bleeding risk in atrial fibrillation. Thromb Haemost 2013;111:465-73.
18. Lane DA, Lip GYH. Patient's values and preferences for stroke prevention in atrial fibrillation: balancing stroke and bleeding risk with oral anticoagulation. Thromb Haemost 2014;111:381-3.
19. Nielsen PB, Larsen TB, Gorst-Rasmussen A, Skjøth F, Rasmussen LH, Lip GYH. Intracranial haemorrhage and subsequent ischemic stroke in patients with atrial fibrillation: A nationwide cohort study. CHEST 2014 Nov 20. [Epub ahead of print]

Keywords: Aged, Aspirin, Atrial Fibrillation, Cohort Studies, Comorbidity, Fibrinolytic Agents, Follow-Up Studies, Hospitalization, Hypertension, Intracranial Hemorrhages, Ischemic Attack, Transient, Multivariate Analysis, Risk Factors, Stroke, Warfarin, Thromboembolism, Anticoagulants

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