Published online before print April 17, 2008, doi: 10.1161/STROKEAHA.107.501825
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(Stroke. 2008;39:1901.)
© 2008 American Heart Association, Inc.
Progress Reviews |
Comparison of 12 Risk Stratification Schemes to Predict Stroke in Patients With Nonvalvular Atrial Fibrillation
*See Appendix for Working Group participants and affiliations.
Correspondence to Robert G. Hart, MD, Department of Neurology, University of Texas Health Science Center, 7703 Floyd Curl Drive MC 7883, San Antonio, TX 78229-3900; E-mail Hartr{at}uthscsa.edu
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Abstract |
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Background and Purpose— More than a dozen schemes for stratifying stroke risk in patients with nonvalvular atrial fibrillation have been published. Differences among these schemes lead to inconsistent stroke risk estimates for many atrial fibrillation patients, resulting in confusion among clinicians and nonuniform use of anticoagulation.
Methods— Twelve published schemes stratifying stroke risk in patients with nonvalvular atrial fibrillation are analyzed, and observed stroke rates in independent test cohorts are compared with predicted risk status.
Results— Seven schemes were based directly on event-rate analyses, whereas 5 resulted from expert consensus. Four considered only clinical features, whereas 7 schemes included echocardiographic variables. The number of variables per scheme ranged from 4 to 8 (median, 6). The most frequently included features were previous stroke/TIA (100% of schemes), patient age (83%), hypertension (83%), and diabetes (83%), and 8 additional variables were included in 
1 schemes. Based on published test cohorts, all 8 tested schemes stratified stroke risk, but the absolute stroke rates varied widely. Observed rates for those categorized as low risk ranged from 0% to 2.3% per year and those categorized as high risk ranged from 2.5% to 7.9% per year. When applied to the same cohorts, the fractions of patients categorized by the different schemes as low risk varied from 9% to 49% and those categorized by the different schemes as high-risk varied from 11% to 77%.
Conclusions— There are substantial, clinically relevant differences among published schemes designed to stratify stroke risk in patients with atrial fibrillation. Additional research to identify an optimum scheme for primary prevention and subsequent standardization of recommendations may lead to more uniform selection of patients for anticoagulant prophylaxsis.
Key Words: atrial fibrillation • clinical prediction rules • risk factors • stroke
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Introduction |
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The absolute risk of stroke varies widely among patients with atrial fibrillation depending on patient age and other clinical features. Estimating stroke risk is a critical first step when balancing the potential benefits and risks of chronic antithrombotic therapy for stroke prevention. Multiple stroke risk stratification schemes for atrial fibrillation patients have been proposed based on various combinations of clinical and echocardiographic predictors.1 Although there is considerable overlap, differences alter the predicted risk status of hundreds of thousands of atrial fibrillation patients,2–4 contributing to the inconsistent use of anticoagulation.5
Here, we compare 12 published schemes that stratify stroke risk in patients with nonvalvular atrial fibrillation.6–17 The key features, the distribution of atrial fibrillation patients classified into different risk strata, and the stroke rates in test cohorts are analyzed for each scheme.
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Materials and Methods |
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Twelve stroke risk stratification schemes were selected for inclusion based on publication in peer-reviewed English language journals from 1994 to mid 2007, beginning with the landmark Atrial Fibrillation Investigators initial analysis.6 Schemes were identified through a computerized literature search using OVID software combining the key term "atrial fibrillation" with (separately) "risk factor" and "risk stratification." Recent review articles and a recent systematic review of independent predictors of stroke in atrial fibrillation patients1 were also canvassed. Schemes were included if they sought to predict all stroke, ischemic stroke, or a combination of stroke, systemic embolism, or TIA in patients with nonvalvular atrial fibrillation not receiving oral anticoagulation; schemes assessing stroke in patients receiving antiplatelet therapy were included. Included reports must have explicitly proposed risk strata using
1 clinical or echocardiographic features and must have linked the strata to recommendations for antithrombotic prophylaxis; those assessing stroke risk factors but without proposing a specific risk stratification scheme were not considered. For schemes generated by expert groups that were serially revised, only the most recent version was included. For example, only the most recent version of the American College of Cardiology/American Heart Association/European Society of Cardiology guideline was included,11 and an earlier iteration was not considered.18 The single exception was inclusion of both the 2001 version13 and the 2004 revision16 of the American College of Chest Physicians consensus statement because the earlier scheme has been tested in 2 independent cohorts. Studies reporting the performance of specific risk stratification schemes in independent populations of nonanticoagulated patients with atrial fibrillation (including those receiving antiplatelet agents) comprised the 11 test cohorts.2,12,15,17,19–26 The stratification schemes were applied to a stratified random sample of 1000 patients was selected from Stroke Prevention in Atrial Fibrillation III participants22,23 to compare the relative distribution of risk strata. This sample included 40% women and a 10% prevalence of previous stroke/TIA; 2 years were added to each participant’s age to increase the mean age of this cohort to 72 years, closer to that of a large outpatient atrial fibrillation population3,26 and pooled participants in clinical trials.14
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Results |
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Seven of the 12 schemes were based on event-rate analyses of stroke predictors in a derivation cohort,6–10,14,15 whereas the remainder originated from consensus of expert panels (Table 1).11–13,16,17 Two investigator groups published 2 schemes each. In one instance, this was because of addition of echocardiographic variables to a previously published clinical scheme,6,9 and in the other, analysis of a separate larger cohort given aspirin modified an earlier multivariate analysis of stroke predictors in the absence of antithrombotic therapy.7,10 Four schemes included only clinical features, whereas 7 schemes also considered transthoracic echocardiographic variables (Table 1). One scheme stratified risk among atrial fibrillation patients with recent stroke or TIA and included results of brain CT.8
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The schemes varied substantially in complexity: the number of variables ranged6,11,17 from 4 to 8, with a median of 6 (Table 2
). The most frequent elements were previous stroke/TIA (100%), age (83%), hypertension (83%), and diabetes (83%; Table 3). Heart failure (50%), left ventricular systolic dysfunction (50%), and systolic blood pressure (42%) were the next most frequent; coronary artery disease (33%) and female sex (25%) were included in a minority of schemes (Table 3). Schemes varied in whether they used age and systolic blood pressure as continuous or ordered categorical variables and, in the latter case, different age thresholds were used (eg, 65 vs 75 years).
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Stroke rates associated with specific risk strata were assessed in independent test cohorts for 8 of the schemes, whereas for the remaining 4 schemes no test cohorts were identified (Table 4). The characteristics of patients in the 11 test cohorts varied widely, from an elderly hospital discharge cohort (mean age, 81 years) with a 25% prevalence of previous stroke/TIA,12 to a younger outpatient-based cohort (mean age, 72 years), with a 8% prevalence of previous stroke/TIA.24,26 Two of the test cohorts were restricted to primary prevention.2,20 Mean observation duration ranged from 1.2 years12 to 5.3 years,21 with a median of 2.0 years. Two schemes7,12 were evaluated in 6 independent test cohorts,6,13–17 1 in 5, and the remaining 5 in 1 or 2. In some test cohorts, echocardiographic assessment of left ventricular function was not available and clinical heart failure was substituted; in other test cohorts, a history of hypertension was substituted for measured systolic blood pressure >160 mm Hg12,15,20,26 compromising assessment.7
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In the test cohorts all of the schemes predicted rank order of stroke risk (Table 4
). Stroke rates in patients categorized as being at low risk ranged from 0% to 2.3% per year.15,17 For example, patients classified as being at low risk based on the CHADS2 scheme12 had observed stroke rates ranging from 0.5% per year (95% CI, 0.3 to 0.8)26 to 1.9% per year (95% CI, 1.2 to 3.0),12 although TIAs were combined with stroke outcomes in the latter study. Patients classified as being at high risk had observed stroke rates varying from 2.5% per year26 to 7.9% per year.23
Comparisons of different schemes in a common test cohort are limited to a handful of studies (supplemental Table I, available online at http://stroke.ahajournals.org)2,12,15,17,20,26,28 and sometimes are compromised by substitution of some features for others (eg, heart failure for left ventricular systolic dysfunction; history of hypertension for systolic blood pressure >160 mm Hg). When compared in this fashion, the proportions of patients categorized as being at low risk varied between schemes from 12% (stroke rate 0.1% per year) to 37% (stroke rate 0.9% per year) and those as being at high risk varied between schemes from 16% (stroke rate 4.0% per year) to 80% (stroke rate 2.5% per year).26
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In the representative cohort of atrial fibrillation patients, the mean age was 72 years, 40% were women, and prevalences of hypertension, diabetes, heart failure, systolic blood pressure >160 mm Hg, coronary artery disease, and previous stroke/TIA were 56%, 15%, 29%, 12%, 24%, and 10%, respectively. Applying each scheme to the representative cohort (Figure), the fraction of patients categorized as being at low risk ranged from 7% to 42%. Assuming 2.8 million Americans with atrial fibrillation, application of different schemes would result in up to 980 000 more or fewer patients categorized as being at low risk.
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7 points. For Van Walraven et al, |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAppendixReferences |
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These 12 schemes for stratifying atrial fibrillation patients according to stroke risk reflect the spectrum of choices facing clinicians. Nearly all include previous stroke/TIA, age, hypertension, and diabetes as clinical predictors of stroke. However, the fraction of patients categorized as being at low risk and high risk varies 5- to 7-fold among schemes, and this contributes to inconsistent recommendations for anticoagulation for hundreds of thousands of patients with atrial fibrillation. "The widespread nonsystematic production of guidelines" [for anticoagulant treatment in atrial fibrillation] has led to considerable variation with implications for the quality of care and clinical decision making."29 Little has changed since this statement appeared a decade ago, and in the meantime additional schemes and guidelines have proliferated.
Authorities on clinical prediction rules advocate independent testing before their general clinical application.30–32 Several schemes have not been tested to characterize their predictive accuracy and hence cannot be compared, directly or indirectly, to others. The duration of follow-up in most derivation and validation cohorts averages 1 to 2 years, and the enduring predictive value of risk stratification schemes for longer periods is often unknown, requiring periodic reassessment of risk. The contribution of individual variables to risk stratification schemes has not been well-defined. For example, heart failure appeared in half the schemes, but this clinical feature has not been validated as an independent predictor of stroke in atrial fibrillation patients.1 Criteria used for diagnosis of heart failure have not been uniform in these studies, and the contribution of this variable to risk stratification is, therefore, unclear. The stroke risk attributable to hypertension in atrial fibrillation patients is likely to vary depending on its severity and treatment,33 confounding application of this prevalent risk factor. Previous stroke or TIA is the most powerful risk factor1 and, by itself, drives the successful identification of high-risk patients, regardless of the presence of other risk factors in all except 2 schemes.12,15 The predictive value of these schemes for primary prevention (ie, for patients without previous stroke or TIA) is a more important, albeit more difficult, problem.20
Stroke rates in recent clinical trials34–37 involving atrial fibrillation patients appear lower than in clinical trials completed 15 years ago.6 Better control of blood pressure may contribute to lower stroke rates among patients with a history of hypertension,38,39 because even modest blood pressure lowering has a substantial favorable impact on the risk of vascular events.33 Whether absolute stroke rates among those stratified as being at high risk by any scheme are lower now than they were 10 to 15 years ago is uncertain.38,40 In short, secular trends in stroke rates among atrial fibrillation patients may confound accurate risk prediction.
At the core of existing schemes are 4 features that have been independently and consistently associated with stroke in atrial fibrillation patients: previous stroke or TIA, hypertension, advanced age, and diabetes.1 Other risk factors included in several schemes (eg, coronary artery disease, heart failure, female sex) have not been validated as consistent independent predictors of stroke in atrial fibrillation patients.1,19,25 Additional possible independent predictors that are not included in current schemes (eg, estrogen replacement therapy associated with higher stroke risk, regular alcohol consumption with reduced stroke risk) have been identified,10 but these have not been sufficiently investigated to justify application in clinical practice. The additional discriminatory power of biomarkers of thrombosis and inflammation are an area of active research.17
Comparison of the predictive power of available schemes with subsequent stroke in a single cohort of atrial fibrillation patients of adequate size and with a full range of variables is not currently available, and the optimal risk stratification scheme cannot be determined from existing data. The proportion of patients categorized as being at low, moderate, or high risk by a scheme will vary depending on the composition of the patient cohort to which it is applied, ie, the proportions of primary versus secondary prevention cases, proportions of elderly patients with multiple risk factors versus younger individuals with few risk factors, and the availability of echocardiographic data. Considering the inherent difficulty in distinguishing patients with stroke risk of 1% per year versus 4% per year (a determining difference regarding recommendations to anticoagulate in most guidelines), it is surprising, perhaps, that the existing schemes appear able to do so, albeit with differing results at the individual patient level.
We surveyed a scattered and complex literature on stroke risk stratification for patients with atrial fibrillation to bring its strengths and limitations into focus. We do not address the threshold of absolute stroke risk for which anticoagulation is warranted, because this depends on additional considerations, including estimated bleeding risk during anticoagulation,41 access to quality anticoagulation monitoring, and patient preferences and values.42 Several million people with atrial fibrillation now receive chronic anticoagulation to prevent stroke. Additional research to identify more discriminating and accurate risk models around which standard recommendations could be developed would encourage more uniform use of antithrombotic agents and would likely lead to better patient outcomes.
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Appendix |
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Stroke Risk in Atrial Fibrillation Work Group
Robert G. Hart, MD (San Antonio, TX, USA); Lesly A. Pearce, MS (Minot, ND, USA); Jonathan L. Halperin, MD (New York, NY, USA); Elaine M. Hylek, MD, MPH (Boston, MA, USA); Gregory W. Albers, MD (Palo Alto, CA, USA); David C. Anderson, MD (Minneapolis, MN); Stuart J. Connolly, MD (Hamilton, ON, Canada); Gary H. Friday, MD (Bryn Mawr, PA, USA); Brian F. Gage, MD (St. Louis, MO, USA); Alan S. Go, MD (Oakland, CA, USA); Larry B. Goldstein, MD (Durham, NC, USA); Gary Gronseth, MD (Kansas City, KN, USA); Gregory Y.H. Lip, MD (Birmingham, UK); David G. Sherman, MD (San Antonio, TX, USA); Daniel E. Singer, MD (Boston, MA, USA); Carl van Walraven, MD, MSc (Ottawa, ON, Canada).
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Acknowledgments |
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Disclosures
Dr Hart has served on data monitoring committees of clinical trials involving patients with atrial fibrillation sponsored by Astellas Pharmaceuticals, Sanofi-Aventis Pharmaceuticals, and Biotroniks, Inc.
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Footnotes |
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Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
Received August 22, 2007; revision received October 10, 2007; accepted October 19, 2007.
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References |
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