Healio
Healio
September 13, 2011
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Risk Stratification for Stroke in Patients with Atrial Fibrillation

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Stroke is the leading cause of morbidity and mortality associated with atrial fibrillation. Patients with AF have a 5-fold higher stroke risk than those without AF, which amounts to about a 5% per year risk of symptomatic stroke.1,2 When accounting for all ischemic events, including transient ischemic attacks (TIA) and silent strokes, the risk exceeds 7% per year. Estimates place the proportion of all strokes caused by AF at 15%.3

Strokes in the setting of AF are often more severe than strokes due to other causes.4 Patients with AF experiencing strokes are more likely to have cortical deficit, aphasia, severe limb weakness and diminished alertness. These patients are likely to be bedridden on admission and have longer in-hospital stays with a lower rate of discharge to their own home.5 Stroke associated with AF is nearly twice as likely to be fatal as non-AF–related stroke.6

The risk of thromboembolic events in patients with AF increases regardless of whether the AF is intermittent or sustained. The risk of embolization appears to be similar in patients with paroxysmal AF as compared with persistent and permanent AF,7-9 particularly in the presence of stroke risk factors.10 Among patients with paroxysmal AF, up to 90% of recurrences may not be sensed by the patient.11 Furthermore, up to 17% of patients will experience asymptomatic episodes lasting more than 48 hours.12 Acute or paroxysmal AF for as little as 72 hours is associated with embolic events.7 Transesophageal echocardiographic (TEE) studies have shown that 15% of patients with AF of less than 72-hours duration have evidence of left atrial thrombus.13 Thus, patients with paroxysmal AF should be assessed for stroke risk and managed in a similar manner as those with sustained (persistent/permanent) AF.14

Stroke Risk Factors

Stroke risk in patients with AF is influenced by the presence or absence of several clinical factors.15,16 Increasing age raises AF-associated stroke incidence significantly.17,18 Large population studies from the Danish National Registry of Patients evaluated 27,202 men and women, ages 50 to 89, with a hospital diagnosis of AF and no prior diagnosis of stroke.18 The rates of subsequent stroke (percent per patient per year) were 1.3% in patients ages 50 to 59 years, 2.2% in those ages 60 to 69 years, 4.2% for those ages 70 to 79 years, and 5.1% for those ages 80 to 89 years.

Risk of systemic embolization in patients with valvular heart disease and AF is substantially higher than in patients with nonvalvular AF, especially for those with mitral valve disease, and particularly mitral valve stenosis.1,19 Patients with AF and rheumatic mitral valve disease or prosthetic heart valves are considered to be at very high risk for clinical embolization.

Aside from mitral valve disease, other findings on transthoracic echocardiography may be considered risk factors for thromboembolic events in patients with AF. A meta-analysis of 1,066 patients from the BAATAF, SPINAF and SPAF I AF trials, which incorporated into their risk-stratification scheme echocardiography, found that left ventricular (LV) systolic dysfunction was an independent risk factor for stroke in patients with AF.20 The relative risk of stroke was 2.5 for those with moderate to severe LV dysfunction compared with patients with mildly abnormal or normal LV function. Although the SPAF investigators did find that left atrial dimension diameter >2.5 cm/m2 was an independent predictor of thromboembolism, left atrial dimension was not a predictor of stroke in the pooled multivariate analysis.20-21

Several other risk factors for stratification in patients with nonvalvular AF have been derived from five randomized stroke-prevention trials.22-26 Data from these trials were pooled by the Atrial Fibrillation Investigators (AFI) to develop a stronger risk-stratification scheme.2 In addition to age, independent risk factors were a history of stroke or TIA, diabetes mellitus and systemic hypertension.

CHADS2

The most commonly used algorithm for stroke-risk stratification of patients with AF is the CHADS2 scoring system, derived from the AFI and SPAF III models, which assigns points for risk factors (Table 1).27,28,29 Similar to older risk-stratification schemes, the CHADS2 score arbitrarily divides the risk of thromboembolism into low, moderate and high.27 A CHADS2 score of 0 is stratified as low risk, a score of 1 or 2 as moderated risk, and a score of 3 or more as high risk (Table 2).

Table 1. Stroke Risk in AF: CHADS2 Scoring System

Gage BF, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation JAMA. 2001;285:2864-2870.

Click here for a larger view of this image.

Stroke Risk in Patients With Nonvalvular AF NotTreated With Anticoagulation According to the CHADS2 Score

*The adjusted stroke rate was derived from multivariate analysis assuming no aspirin usage.
Gage BF, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation JAMA. 2001;285:2864-2870.

Click here for a larger view of this image.

Validation studies have found the CHADS2 score superior to the AFI and SPAF models.27,30 Although well validated and clinically useful, CHADS2 has a number of limitations. Most importantly, the algorithm classifies a large proportion of patients as being at intermediate risk and does not incorporate many other potential thromboembolic risk factors that have been shown to modulate risk.31

The 2006 ACC/AHA/ESC guidelines for managing patients with AF listed additional, less well-validated factors that may potentially modulate risk: female sex, age 65 to 74 years, history of coronary artery disease, and thyrotoxicosis.1 More recently, stronger evidence has accumulated that at least some of these additional risk factors should be considered in assessing thromboembolic risk.31,32

CHA2DS2-VASc

Additional stroke-risk factors have been expressed in the CHA2DS2-VASc score (vascular disease, age 65 to 74 years, sex category), proposed to complement the CHADS2.32 This system assigns 2 points for a history of stroke or TIA or age 75 years or older, and 1 point each for the other categories. Vascular disease encompasses myocardial infarction, complex aortic plaque and peripheral arterial disease.

CHA2DS2-VASc scores of 0, 1 and 2 or more correspond to low, intermediate and high risk, respectively.32 In the original validation study from the Euro-Heart survey, CHA2DS2-VASc was better than CHADS2 at identifying the patients at truly low risk, and it categorized only a small proportion into the intermediate risk category.32

Importantly, in the 2011 focused update of the ACC/AHA/HRS guidelines, the CHA2DS2-VASc risk-scoring algorithm was not included and was not specifically recommended for risk stratification.33,34 The writers found insufficient evidence that the CHA2DS2-VASc score is superior to the CHADS2 score in improving clinical outcomes and influencing clinical decisions regarding choice of antithrombotic therapy.

More recent studies that have attempted to validate the CHA2DS2-VASc approach and compare it with CHADS2 in cohorts of real-world patients suggest that CHA2DS2-VASc may identify those at truly low risk and minimize classification of subjects as intermediate or moderate risk.35-37 The European Society of Cardiology guidelines, published in 2010, recommended use of the CHA2DS2-VASc score to further refine risk stratification if the CHADS2 score is < 2.38

Therapy and Stroke Risk

Appropriate antithrombotic therapy in patients with AF should be selected on the basis of the assessed risk of thromboembolism and bleeding.1,33,34 Decisions should be individualized considering the relative risks and benefits. Patients with rheumatic mitral valve stenosis or prosthetic (mechanical) heart valves should receive oral anticoagulation with warfarin unless there is an overwhelming, compelling contraindication. Patients deemed to be at high risk for stroke based on the risk-stratification algorithms should receive anticoagulant therapy.

High-risk patients should be treated with either adjusted-dose warfarin with the INR maintained at 2.0 to 3.0 or the newer direct thrombin inhibitor dabigatran (150 mg twice per day). Patients with moderate or intermediate risk (1 moderate risk factor or CHADS2 score of 1) may be treated with aspirin or anticoagulation therapy (warfarin or dabigatran). Even in moderate-risk patients, anticoagulation therapy is likely to be superior to aspirin in prevention of thromboembolism. However, therapeutic decisions in individual cases should be based on an assessment of the risk of bleeding complications, patient preferences and possibly consideration of the other less well-validated risk factors discussed above.

Finally, guidelines recommend that patients determined to be at low risk for thromboembolic events be treated with aspirin (81 mg to 325 mg daily) as an alternative to anticoagulation therapy.1 However, data to support the efficacy of aspirin to prevent stroke in AF (especially in low-risk patients) are controversial. Some experts recommend that young patients with no risk factors for stroke receive no antithrombotic therapy.

The 2011 ACC/AHA/HRS focused update of the guidelines addressed the role of dabigatran and combination antiplatelet therapy as alternatives to oral anticoagulation with warfarin.33,34 Use of dabigatran in patients with AF at moderate to high risk of stroke is supported by data from the RELY trial.39 Dabigatran (150 mg twice daily) was superior to warfarin for prevention of stroke or systemic embolism with a similar risk of major bleeding. Dabigatran was given a class I recommendation as being useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance < 15 mL/min), or advanced liver disease.34

The ACTIVE-W trial compared clopidogrel plus aspirin with warfarin for prevention of vascular events in AF patients.40 Warfarin therapy was found to be superior for prevention of vascular events in AF patients. Clopidogrel plus aspirin was associated with similar bleeding risk to warfarin. Thus, in patients with AF and risk factors for stroke, anticoagulation therapy is preferable to antiplatelet therapy in the absence of absolute contraindications.

The ACTIVE-A trial examined whether clopidogrel plus aspirin would reduce the risk of vascular events in AF patients considered unsuitable for warfarin therapy. The combination therapy was found to reduce the risk of major vascular events, especially stroke. However, combination antiplatelet therapy was associated with an increased risk of major bleeding compared with aspirin alone.41

Thus, the net clinical benefit of combination antiplatelet therapy in patients considered unsuitable for warfarin therapy remains uncertain and decisions must be individualized. The ACC/AHA/HRS focused update indicates that clopidogrel plus aspirin might be considered in patients considered unsuitable for warfarin therapy.34

Conclusions

Stroke is the most devastating and feared complication of AF. However, stroke risk in patients with AF is heterogeneous and modulated by comorbidities. Antithrombotic therapies must be individualized considering risks, benefits, patient preferences and adherence. Although validated algorithms are available to risk stratify patients with AF for stroke, commonly used schemes have modest predictive value and continue to categorize many patients as intermediate risk with unclear antithrombotic therapy recommendations. The newer CHA2DS2-VASc scheme may better discriminate those at truly low risk. Newer oral anticoagulants that have better (or similar) efficacy, lower (or similar) bleeding risk without dietary and monitoring limitations may simplify decision making, increase use of oral anticoagulation and prevent strokes.

References

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