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Original Research: Cardiovascular Disease |

The Value of the European Society of Cardiology Guidelines for Refining Stroke Risk Stratification in Patients With Atrial Fibrillation Categorized as Low Risk Using the Anticoagulation and Risk Factors in Atrial Fibrillation Stroke ScoreStroke Risk in Atrial Fibrillation: A Nationwide Cohort Study FREE TO VIEW

Gregory Y. H. Lip, MD; Peter Brønnum Nielsen, PhD; Flemming Skjøth, PhD; Deirdre A. Lane, PhD; Lars Hvilsted Rasmussen, MD, PhD; Torben Bjerregaard Larsen, MD, PhD
Author and Funding Information

From the University of Birmingham Centre for Cardiovascular Sciences (Drs Lip and Lane), City Hospital, Birmingham, England; the Aalborg Thrombosis Research Unit (Drs Lip, Nielsen, Skjøth, Rasmussen, and Larsen), Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark; and the Department of Cardiology (Drs Skjøth, Rasmussen, and Larsen), Aalborg AF Study Group, Aalborg University Hospital, Aalborg, Denmark.

CORRESPONDENCE TO: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, England; e-mail: g.y.h.lip@bham.ac.uk


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(5):1337-1346. doi:10.1378/chest.14-0533
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BACKGROUND:  Our objective was to determine stroke and thromboembolism event rates in patients with atrial fibrillation (AF) classified as “low risk” using the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) score and to ascertain event rates in this group in relation to the stroke risk assessment advocated in the 2012 European Society of Cardiology (ESC) guidelines (based on the CHA2DS2-VASc [congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category] score). We tested the hypothesis that the stroke risk assessment scheme advocated in the ESC guidelines would be able to further refine stroke risk stratification in the low-risk category defined by the ATRIA score.

METHODS:  In our cohort of 207,543 incident patients with AF from 1999 to 2012, we identified 72,452 subjects who had an ATRIA score of 0 to 5 (low risk).

RESULTS:  Even among these patients categorized as low risk using the ATRIA score, the 1-year stroke/thromboembolic event rate ranged from 1.13 to 36.94 per 100 person-years, when subdivided by CHA2DS2-VASc scores. In patients with an ATRIA score 0 to 5, C statistics at 1 year follow-up in the Cox regression model were significantly improved from 0.626 (95% CI, 0.612-0.640) to 0.665 (95% CI, 0.651-0.679) when the CHA2DS2-VASc score was used for categorizing stroke risk instead of the ATRIA score (P < .001).

CONCLUSIONS:  Patients categorized as low risk using an ATRIA score 0 to 5 are not necessarily low risk, with 1-year event rates as high as 36.94 per 100 person-years. Thus, the stroke risk stratification scheme recommended in the ESC guidelines (based on the CHA2DS2-VASc score) would be best at identifying the “truly low risk” subjects with AF who do not need any antithrombotic therapy.

Figures in this Article

Atrial fibrillation (AF) confers an increased risk of stroke, and the use of oral anticoagulation (OAC) with the vitamin K antagonists (VKAs) (eg, warfarin) reduces stroke by 64% and all-cause mortality by 26% compared with placebo/control.1 Although antithrombotic therapy reduces stroke, the downside is an increase in bleeding, particularly intracranial hemorrhage.

The risk of stroke is not homogeneous. Various stroke risk factors have been identified and clustered into stroke risk stratification schemes, which have been particularly developed to identify high-risk patients who could be targeted for OAC treatment, especially with an “inconvenient” drug, warfarin, which also conferred a risk of serious bleeding.2,3 Nonetheless, stroke risk in AF is a continuum, with the division into low-, moderate-, and high-risk strata being artificial; despite the intended focus on the definition of high-risk patients, numerous studies have shown that these high-risk patients are undertreated with OAC.4 In 2010, the European Society of Cardiology (ESC) guidelines deemphasized the artificial low/moderate/high-risk categorization and recommended a risk factor-based approach, given that any stroke risk factor confers a risk, and if AF is present, the patient could be at risk for a fatal or disabling stroke.5

In addition, the availability of the non-VKAs (NOACs) (previously referred to as new or novel oral anticoagulants) has changed the landscape of stroke prevention in AF, given that these drugs offered efficacy, safety, and convenience compared with VKAs.6,7 Indeed, Eckman et al8 proposed that the threshold for treatment using a NOAC could be a stroke rate of 0.9%/y compared with the threshold for warfarin, which was 1.7%/y. In 2012, the focused update of the ESC guidelines strongly advocated a clinical practice shift so that the initial decision step was the identification of truly low-risk patients with AF, who did not need any antithrombotic therapy. Subsequent to this initial step, patients with AF and one or more stroke risk factors can be offered effective stroke prevention, which is OAC—whether given as well-controlled VKA or one of the NOACs.9 The 2012 focused update recommended use of the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score,10 which was good at identification of low-risk patients, and was as good as—and possibly better than—older scores, such as the CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke) score, in identifying the high-risk patients who subsequently developed stroke and thromboembolism.11

In 2013, the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) investigators developed the ATRIA stroke risk score,12 which performed better than the existing CHADS2 and CHA2DS2-VASc stroke risk scores, showing improvement in predicting events (with a positive net reclassification improvement), although the C indexes were only marginally different. It was noted that the ATRIA score was based on the CHADS2 risk factors and additionally included female sex, proteinuria, and low estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD), with different weighting for primary and secondary prevention cohorts (Table 1). This score categorized patients into low (0-5 points), moderate (6 points), and high (7-15 points) risk strata, and in the original validation paper classified a similar proportion into the low-risk strata as the CHADS2 score (0). However, a CHADS2 score = 0 has been shown to be poor at identifying low-risk patients, and in one study stroke/thromboembolism rates in patients with a CHADS2 score = 0 range between 0.8% to 3.2% (with the upper boundary of the 95% CI as high as 6.4%) per year when substratified by the CHA2DS2-VASc score.1315

Table Graphic Jump Location
TABLE 1 ]  Assignment of Points for Each Risk Factor in the ATRIA Score and CHA2DS2-VASc Score

ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation; CHA2DS2-VASc = congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category; CHF = defined as chronic heart failure (in ATRIA score) or congestive heart failure, left ventricular dysfunction, or recent decompensated heart failure (as per CHA2DS2-VASc definition used in European Society of Cardiology guidelines); eGFR = estimated glomerular filteration rate; ESRD = end-stage renal disease; LVD = left ventricular dysfunction.

Our objective was to determine stroke and thromboembolism event rates in real-world patients with AF classified as low risk using the ATRIA score and to ascertain event rates in these groups in relation to the stroke risk assessment advocated in the 2012 ESC guidelines (which is based on the CHA2DS2-VASc score). Given the current emphasis to initially identify low-risk patients as the first management step for stroke prevention in AF, we tested the hypothesis that the stroke risk assessment scheme advocated in the ESC guidelines would be able to further refine stroke risk stratification in the low-risk category defined by the ATRIA score. We tested this hypothesis in a large nationwide cohort study from Denmark.

Registry Data

The nationwide cohort for this study was established by linking data from two registers on the civil registration system on individual level using the unique personal registration number provided to all Danish citizens.16 The Danish National Patient Register holds extensive data on > 99% of all hospital admissions in Denmark since 1977.17 Data include date of admission and discharge diagnosis and are coded according to the International Classification of Diseases, 10th edition (ICD-10) since 1994 (e-Appendix 1). We used the Danish National Prescription Registry to establish accurate information on prescribed medicine in Denmark.18 This registry contains date of purchase, package size, and type of drugs coded according to the international Anatomic Therapeutic Chemical classification system. We linked the Danish National Patient Register with the Danish National Prescription Registry to calculate both the ATRIA score and the CHA2DS2-VASc score.

Study Population and Outcome

We identified all patients with an incident hospital diagnosis of nonvalvular AF (index date) in the study period from 1999 to the end of 2012 (Fig 1). Nonvalvular AF was defined as presence of AF (ICD-10: I48) and baseline absence of mitral stenosis or mechanical heart valves (ICD-10: I05 or Z952-Z954). This entails a period prior to 1999 to establish a baseline of claimed prescriptions and comorbidities (used in calculating both the ATRIA score and the CHA2DS2-VASc score). We used only person-time off VKA treatment (warfarin or phenprocoumon) in the analysis. Patients with a prescription of a VKA prior to the index date were excluded, and VKA on-treatment was defined if a prescription of a VKA was claimed in the 14-day period after the AF diagnosis. Patients only contributed with person-time in the analysis until prescription of said VKA (if any) was claimed in the follow-up period. The cohort was controlled for emigration, and emigrants with AF were excluded if a hospital diagnosis of AF was registered prior to the onset of the study. Otherwise, person-time for emigrants was censored at date of emigration. The main outcome of stroke/thromboembolism was defined as a combined end point of stroke, systemic embolism, and transient ischemic attack (ICD-10: I63; I64, G45; I74). Person-time was censored if patients died or if a prescription of a VKA was claimed during follow-up.

Figure Jump LinkFigure 1 –  Selection of study population. AF = atrial fibrillation; ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation; VKA = vitamin K antagonist.Grahic Jump Location
Comparison of the ATRIA Score With the CHA2DS2-VASc Score

To calculate the ATRIA score, we extracted the following risk factors: age, female sex, diabetes, chronic heart failure, hypertension, proteinuria, and renal impairment (defined as an eGFR < 45 or ESRD). As discussed previously, there is different weighting for primary and secondary prevention patients (defined in ATRIA as ischemic stroke, not including systemic embolism or transient ischemic attack), and the ATRIA score was collapsed into low (0-5 points), moderate (6 points), and high (7-15 points) risk categories. The definitions are in alignment with the original definitions used in the ATRIA cohort and the ATRIA score specifications.12,19

Calculation of stroke risk based on the ESC 2012 guidelines (ie, the CHA2DS2-VASc score) included data on chronic heart failure/left ventricular dysfunction/recent decompensated heart failure, hypertension, age, diabetes, female sex, vascular disease, and presence of previous stroke/thromboembolism/transient ischemic attack. Table 1 lists the value attributed to each risk factor for both scoring systems. We further substratified those defined as low risk (ie, score 0-5) using the ATRIA score by the CHA2DS2-VASc score.

Statistical Analysis

We performed two separate analyses: a 1-year follow-up and a full follow-up (up to 13 years). Event rates of stroke/thromboembolism per 100 person-years were calculated for the CHA2DS2-VASc score. For 1-year follow-up, Kaplan-Meier estimates were used to present the proportion free of stroke/thromboembolism for each CHA2DS2-VASc score group. Cox proportional hazard analyses were constructed to inspect the risk related to an increase in the CHA2DS2-VASc score; this was done for both a crude ratio and a ratio adjusted for year of inclusion and baseline antiplatelet treatment. By using C statistics, we investigated if inclusion of the CHA2DS2-VASc score added significant discrimination abilities to the Cox regression models.20

A two-sided P value < .05 was considered statistically significant. All analyses were performed with SAS statistical software, version 9.3 (SAS Institute Inc) and Stata statistical software, version 12.1 (StataCorp LP).

In our cohort of 205,743 incident patients with AF from 1999 to 2012, we identified 72,452 subjects who had an ATRIA score of 0 to 5 (Fig 1, Table 2). Event rates for stroke and thromboembolism per 100 person-years in patients not treated with warfarin are shown in Table 3; Kaplan-Meier estimates of the probability of remaining free of stroke/thromboembolism according to the ESC guidelines scheme (and CHA2DS2-VASc score) in patients with an ATRIA score 0 to 5 are illustrated in Figure 2.

Table Graphic Jump Location
TABLE 2 ]  Baseline Characteristics for Patients With AF by ATRIA Score, Vitamin K Antagonist-Untreated at Baseline

Among the patients with a low-risk ATRIA score (score 0-5), of the n = 134 patients with a CHA2DS2-VASc score > 5, the additional CHA2DS2-VASc risk factors in each ATRIA score value are summarized as follows: (1) ATRIA score 2: n = 3 patients with LVD + SE/TIA + vascular disease; (2) ATRIA score 3: n = 4 patients with SE/TIA + vascular disease, and n = 7 patients with LVD + SE/TIA + vascular disease; (3) ATRIA score 4: n = 11 with LVD + SE/TIA + vascular disease; and (4) ATRIA score 5: n = 71 with SE/TIA + vascular disease, n = 5 with LVD + SE/TIA, and n = 33 with LVD + SE/TIA + vascular disease. Thus, for example, the three patients with ATRIA score 2 would earn 4 additional points on the CHA2DS2-VASc score by having the additional risk factors not within the original specification of the ATRIA score. AF = atrial fibrillation; SE/TIA = systemic thromboembolism and/or transient ischemic attack. See Table 1 legend for expansion of other abbreviations.

a 

Five patients with a CHA2DS2-VASc score of 7, none with a higher score.

Table Graphic Jump Location
TABLE 3 ]  Event Rate of Stroke/Thromboembolism per 100 Person-Years in Patients With AF

See Table 1 legend for expansion of abbreviations.

Figure Jump LinkFigure 2 –  A, B, Kaplan-Meier estimate of the proportion free of stroke/thromboembolism (with competing risk of death taking into account) according to CHA2DS2VASc score in patients with an ATRIA score 0 to 5 using (A) 1 y of follow-up and (B) 5 y of follow-up. CHA2DS2VASc = congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

The overall stroke/thromboembolic event rate for the low-risk ATRIA category (score = 0-5) was 3.22 per 100 person-years at 1-year follow-up and 1.87 per 100 person-years at 13-year follow-up. Even among patients categorized as low risk using the ATRIA score, there was a graded increase in the stroke/thromboembolic rate ranging from 1.13 to 36.94 per 100 person-years at 1-year follow-up when subdivided by CHA2DS2-VASc scores (Fig 2, Table 2). A low-risk category based on the ESC guidelines (ie, CHA2DS2-VASc score = 0 for men or a score = 1 for women) would identify a truly low-risk cohort, with annual event rates at 1- and 13-year follow-up of 1.13 and 0.78, respectively, per 100 person-years.

In patients with ATRIA score 0 to 5, using the ESC guideline-defined low-risk patients (ie, CHA2DS2-VASc score = 0 for men or a score = 1 for women) as the reference, at 1-year follow-up the hazard ratios adjusted for year of inclusion and antiplatelet treatment associated with CHA2DS2-VASc scores 1 (men), 2, 3, 4, 5, and > 5 (five patients with a CHA2DS2-VASc of seven, none higher) were 2.37, 3.07, 4.03, 6.84, 14.13, and 25.24, respectively (Table 4). In patients with ATRIA score 0 to 5, C statistics at 1-year follow-up in the Cox regression model were significantly improved from 0.626 (95% CI, 0.612-0.640) to 0.665 (95% CI, 0.651-0.679) when the CHA2DS2-VASc score was used for stroke risk categorization instead of the ATRIA score (P < .001). In patients with an ATRIA score 0 to 5, C statistics in the Cox regression model adjusted for year of inclusion and antiplatelet therapy at full follow-up were 0.636 and 0.658 for ATRIA and CHA2DS2-VASc, respectively.

Table Graphic Jump Location
TABLE 4 ]  Risk of Stroke/Thromboembolism in Patients With AF Adjusted for Antiplatelet Treatment and Year of Inclusion

ESC = European Society of Cardiology. See Table 1 legend for expansion of abbreviations.

Investigating the components related to renal function in the ATRIA score among the subgroup of patients with a CHA2DS2-VASc ≥ 2 (ie, high risk; n = 32,462) demonstrates 0.05% with proteinuria and 3.49% with an eGFR < 45 or ESRD. Also, in the same subgroup, 9.76% had previous vascular disease.

Sensitivity Analysis

As a sensitivity analysis, we performed the analysis with our cohort using ATRIA score 0 to 3 as low risk, leaving us with 42,538 patients. The stroke/thromboembolism rates for 1-year and full follow-up were still high, that is, 2.31 (95% CI, 2.14-2.49) and 1.30 (95% CI, 1.24-1.36), respectively. The C statistics were unaffected and still significantly different in favor of the CHA2DS2-VASc score (full data not shown).

In this study, we have shown that even in patients categorized as low risk using an ATRIA score 0 to 5, the stroke risk stratification scheme recommended in the ESC guidelines (based on the CHA2DS2-VASc score) can further refine stroke risk stratification. Indeed, the low-risk category defined by the ESC guidelines could clearly identify truly low-risk subjects with AF, whereas those defined using an ATRIA score (0-5) are not at low risk, with 1-year event rates as high as 36.94 per 100 person-years. Furthermore, in patients categorized with an ATRIA score 0 to 5, the additional risk factors included in CHA2DS2-VASc significantly improved the predictive value of the Cox regression analysis compared with ATRIA score alone.

In the original validation article of the ATRIA score,12 the overall annual stroke rates for low-, moderate-, and high-risk groups were 0.63%, 1.91%, and 3.89%, respectively, using the ATRIA score; compared with 0.88%, 2.96%, and 5.97% with CHADS2; and 0.04%, 0.55%, and 2.52% with CHA2DS2-VASc. In the present analysis, when applied to a real-world nationwide cohort, our principal finding is that that those categorized as low risk using the ATRIA score are not low risk, given a potential stroke rate at 1 year as high as 36.94 per 100 person-years. One reason that some patients with a low-risk ATRIA score (0-5) can have a CHA2DS2-VASc score of ≥ 5 reflects the definitions of the scores used, with CHA2DS2-VASc being more inclusive of common stroke risk factors. For example, in the ATRIA score article, chronic heart failure is only a subset of the (broader) “C” definition for CHA2DS2-VASc, which also includes moderate to severe left ventricular dysfunction and recent decompensated heart failure, as used in the 2012 ESC guidelines (the latter being the basis for this analysis). Likewise, the “S” criterion in CHA2DS2-VASc also includes ischemic stroke, systemic thromboembolism, and transient ischemic attack, whereas in the ATRIA score, stroke is only defined on the basis of prior ischemic stroke. Hence, it is possible to obtain up to (say) four more points in CHA2DS2-VASc compared with the ATRIA score in a particular patient. Our data support the approach in the ESC guidelines that advocates a clinical practice shift toward the initial identification of truly low-risk patients, and a simple, practical, and user-friendly clinical score (based on CHA2DS2-VASc) would help.5,9

Indeed, the CHA2DS2-VASc score has been shown to reliably predict low-risk patients and had the best predictive value for the absence of thromboembolism in a long-term cohort of initially “lone AF”’ patients.21 Various proposals to refine stroke risk stratification, with particular emphasis on identifying high-risk patients with AF using biomarkers (whether urine or blood based, or imaging using cardiac or cerebral imaging modalities) have been proposed, which may offer additional precision at the cost of reduced practicality and ease of use.3,5

Although proteinuria and renal impairment may be risk factors for stroke in AF, a recurrent debate is whether their presence independently adds predictive value to existing stroke risk scores. In an ancillary analysis from the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), the presence of renal dysfunction (given 2 points) added to the CHADS2 score (hence, the R2CHADS2 score) improved the net reclassification index compared with the CHADS2 and CHA2DS2-VASc scores, although there were only minimal difference in C indexes.22 However, ROCKET-AF was a selected trial-based anticoagulated AF population that excluded patients with severe renal impairment, and the broad range of stroke risk was not studied (as ROCKET-AF excluded patients with CHADS2 score 0-1).23 Ideally, the added predictive value of a risk factor should also be tested in a non-anticoagulated cohort.

Additional studies from real-world cohorts with a broader range of stroke risk and renal function have concluded that although renal impairment in patients with AF represented a high-risk population, this did not independently add to the predictive or discriminant value of the CHADS2 and CHA2DS2-VASc scores.24,25 Broadly similar observations were noted from one clinical trial-based anticoagulated AF cohort.26 This is perhaps unsurprising, as determinants of renal impairment include heart failure, age, diabetes, vascular disease, and hypertension, which are components of the CHADS2 and/or CHA2DS2-VASc scores. In a recent analysis of thromboembolic events following catheter ablation of AF, the CHA2DS2-VASc score further differentiated thromboembolic risk in patients with CHADS2 and R2CHADS2 scores of 0 or 1 and had the best predictive value for thromboembolism in patients with AF recurrences (C index, 0.894; P = .022 vs CHADS2, P = .031 vs R2CHADS2).27 Nonetheless, the C statistics for the two scores in this study were modest for the low-risk category (approximately 0.65), although for a comparative prediction analysis, the broad range of stroke risk (ie, whole population) should be studied. In the original ATRIA article, the C statistics were between 0.73 and 0.70 for the two scores, notwithstanding the relatively selected ATRIA population (and the score derivation cohort from the 1990s)19 compared with our more contemporary real-world Danish nationwide cohort study. Future research may focus on some additional (bio)marker that might provide better prediction (and higher C statistics) than either clinically based score and permit improved definition of those at low risk to not warrant anticoagulation.3

Limitations

This analysis is limited by its observational cohort design, as with similar real-world cohort data. In Danish registries, the positive predictive value of the AF diagnosis is very high (99%), but this analysis of hospitalized patients with AF may have focused on an increased risk status in these patients for stroke and thromboembolism. Nonetheless, many validation cohorts of stroke risk scores (including the CHADS2 score28) have been based on hospital-based cohorts, and the applicability to community-based (and often asymptomatic and “uncomplicated”) AF cohorts is less uncertain. Also, the risk score assignment was made on our strata from baseline, which is then unaffected/not updated for the following years. During the first year, the CHA2DS2-VASc score is accurately estimated, but as time passes it perhaps becomes somewhat less accurate (especially as age is a powerful driver of stroke risk).

We have used proteinuria and renal impairment coding to calculate the ATRIA score. The validation of moderate/severe renal impairment is high from the Danish register,29 and these patients with AF and renal impairment have been shown to have a high risk of stroke, death, myocardial infarction, and bleeding.30 However, the sensitivity and specificity of the ICD-10 codes for proteinuria remain to be investigated. Thus, it is possible that such analyses may have inadvertent bias common to observational studies because of reporting and recording errors. The difficulties and the accuracy of diagnosing thromboembolic events, especially minor stroke and transient ischemic attack or systemic thromboembolism, are apparent.

Some patients could be taking aspirin, which is available as over-the-counter medication. We have adjusted for known aspirin use among patients with AF not receiving anticoagulation therapy. However, the stroke/thromboembolic event rates may be slightly attenuated by some aspirin use, but there is probably only a small effect of aspirin on stroke given the (nonsignificant) stroke reduction by 19% compared with control/placebo in the historical trials.1 In real-world cohorts, including Danish registries, aspirin does not decrease stroke risk and demonstrates no positive net clinical benefit when balancing stroke against serious bleeding.31,32

In conclusion, patients categorized as low risk using an ATRIA score 0 to 5 are not low risk, with 1-year event rates as high as 37%. Thus, the stroke risk stratification scheme recommended in the ESC guidelines (based on the CHA2DS2-VASc score) can further refine the ATRIA stroke risk stratification and is best at identifying truly low-risk subjects with AF, who do not need any antithrombotic therapy.

Author contributions: G. Y. H. L. and T. B. L. are guarantors of the study. G. Y. H. L. contributed to the original hypothesis and study conception, data interpretation, and manuscript drafting/revisions; and P. B. N. and F. S. contributed to data collection and analysis; and G. Y. H. L., P. B. N., F. S., D. A. L., L. H. R., and T. B. L. contributed to interpretation of results, revising the manuscript critically for important intellectual content, and all approved the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lip has served as a consultant for Bayer AG; Astellas Pharma; Merck & Co, Inc; AstraZeneca; Sanofi; BMS/Pfizer Inc; Daiichi-Sankyo Company Limited; Medtronic, Inc; BIOTRONIK SE & Co KG; Portola Pharmaceuticals, Inc; and Boehringer Ingelheim GmbH and has been on the speakers bureau for Bayer AG; BMS/Pfizer Inc; Boehringer Ingelheim GmbH; Medtronic, Inc; Daiichi-Sankyo Company Limited; and Sanofi Aventis US LLC. Dr Lane has received investigator-initiated educational grants from Bayer HealthCare AG and Boehringer Ingelheim GmbH and served as a speaker for Boehringer Ingelheim GmbH, Bayer HealthCare AG, and BMS/Pfizer Inc. In addition, Dr Lane is on the Steering Committee of a Phase IV apixaban study (AEGEAN). Dr Rasmussen has been on the speaker bureaus for Bayer AG, BMS/Pfizer Inc, Janssen Pharmaceuticals, Inc, Takeda Pharmaceutical Company Limited, Roche Diagnostics, and Boehringer Ingelheim GmbH. Dr Larsen has served as an investigator for Janssen Scientific Affairs, LLC, and Boehringer Ingelheim GmbH. He has also been on the speaker bureaus for Bayer AG, BMS/Pfizer Inc, Janssen Pharmaceuticals, Inc, Takeda Pharmaceutical Company Limited, Roche Diagnostics, and Boehringer Ingelheim GmbH. Drs Nielsen and Skjøth have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.

AF

atrial fibrillation

ATRIA

Anticoagulation and Risk Factors in Atrial Fibrillation

CHADS2

congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke

CHA2DS2-VASc

congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category

eGFR

estimated glomerular filtration rate

ESC

European Society of Cardiology

ESRD

end-stage renal disease

ICD-10

International Classification of Diseases, 10th edition

NOAC

non-vitamin K antagonist

OAC

oral anticoagulation

R2CHADS2

renal dysfunction, congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke

ROCKET-AF

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation

VKA

vitamin K antagonist

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Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. 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(2):263-272. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Singer DE, Chang Y, Borowsky LH, et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc. 2013;2(3):e000250. [CrossRef] [PubMed]
 
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(6):1172-1179. [CrossRef] [PubMed]
 
Chao TF, Lin YJ, Tsao HM, et al. CHADS(2) and CHA(2)DS(2)-VASc scores in the prediction of clinical outcomes in patients with atrial fibrillation after catheter ablation. J Am Coll Cardiol. 2011;58(23):2380-2385. [CrossRef] [PubMed]
 
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(3):170-176. [CrossRef] [PubMed]
 
Thygesen LC, Daasnes C, Thaulow I, Brønnum-Hansen H. Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving. Scand J Public Health. 2011;39(suppl 7):12-16. [CrossRef] [PubMed]
 
Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health. 2011;39(suppl 7):30-33. [CrossRef] [PubMed]
 
Kildemoes HW, Sørensen HT, Hallas J. The Danish national prescription registry. Scand J Public Health. 2011;39(suppl 7):38-41. [CrossRef] [PubMed]
 
Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med. 1999;131(12):927-934. [CrossRef] [PubMed]
 
Newson RB. Comparing the predictive powers of survival models using Harrell's C or Somers' D. Stata J. 2010;10(3):339-358.
 
Potpara TS, Polovina MM, Licina MM, Marinkovic JM, Prostran MS, Lip GY. 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(2):319-326. [CrossRef] [PubMed]
 
Piccini JP, Stevens SR, Chang Y, et al; ROCKET AF Steering Committee and Investigators. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation. 2013;127(2):224-232. [CrossRef] [PubMed]
 
Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: Analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol. 2013;61(6):651-658. [CrossRef] [PubMed]
 
Banerjee A, Fauchier L, Vourc’h P, et al. Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. J Am Coll Cardiol. 2013;61(20):2079-2087. [CrossRef] [PubMed]
 
Roldán V, Marín F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost. 2013;109(5):956-960. [CrossRef] [PubMed]
 
Apostolakis S, Guo Y, Lane DA, Buller H, Lip GY. Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial. Eur Heart J. 2013;34(46):3572-3579. [CrossRef] [PubMed]
 
Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol. 2013;6(5):868-874. [CrossRef] [PubMed]
 
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870. [CrossRef] [PubMed]
 
Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sørensen HT. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol. 2011;11:83. [CrossRef] [PubMed]
 
Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625-635. [CrossRef] [PubMed]
 
Olesen JB, Lip GY, 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(4):739-749. [CrossRef] [PubMed]
 
Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation. 2012;125(19):2298-2307. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Selection of study population. AF = atrial fibrillation; ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation; VKA = vitamin K antagonist.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, Kaplan-Meier estimate of the proportion free of stroke/thromboembolism (with competing risk of death taking into account) according to CHA2DS2VASc score in patients with an ATRIA score 0 to 5 using (A) 1 y of follow-up and (B) 5 y of follow-up. CHA2DS2VASc = congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Assignment of Points for Each Risk Factor in the ATRIA Score and CHA2DS2-VASc Score

ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation; CHA2DS2-VASc = congestive heart failure, hypertension, age ≥ 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category; CHF = defined as chronic heart failure (in ATRIA score) or congestive heart failure, left ventricular dysfunction, or recent decompensated heart failure (as per CHA2DS2-VASc definition used in European Society of Cardiology guidelines); eGFR = estimated glomerular filteration rate; ESRD = end-stage renal disease; LVD = left ventricular dysfunction.

Table Graphic Jump Location
TABLE 2 ]  Baseline Characteristics for Patients With AF by ATRIA Score, Vitamin K Antagonist-Untreated at Baseline

Among the patients with a low-risk ATRIA score (score 0-5), of the n = 134 patients with a CHA2DS2-VASc score > 5, the additional CHA2DS2-VASc risk factors in each ATRIA score value are summarized as follows: (1) ATRIA score 2: n = 3 patients with LVD + SE/TIA + vascular disease; (2) ATRIA score 3: n = 4 patients with SE/TIA + vascular disease, and n = 7 patients with LVD + SE/TIA + vascular disease; (3) ATRIA score 4: n = 11 with LVD + SE/TIA + vascular disease; and (4) ATRIA score 5: n = 71 with SE/TIA + vascular disease, n = 5 with LVD + SE/TIA, and n = 33 with LVD + SE/TIA + vascular disease. Thus, for example, the three patients with ATRIA score 2 would earn 4 additional points on the CHA2DS2-VASc score by having the additional risk factors not within the original specification of the ATRIA score. AF = atrial fibrillation; SE/TIA = systemic thromboembolism and/or transient ischemic attack. See Table 1 legend for expansion of other abbreviations.

a 

Five patients with a CHA2DS2-VASc score of 7, none with a higher score.

Table Graphic Jump Location
TABLE 3 ]  Event Rate of Stroke/Thromboembolism per 100 Person-Years in Patients With AF

See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 4 ]  Risk of Stroke/Thromboembolism in Patients With AF Adjusted for Antiplatelet Treatment and Year of Inclusion

ESC = European Society of Cardiology. See Table 1 legend for expansion of abbreviations.

References

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(12):857-867. [CrossRef] [PubMed]
 
Pisters R, Lane DA, Marin F, Camm AJ, Lip GY. Stroke and thromboembolism in atrial fibrillation. Circ J. 2012;76(10):2289-2304. [CrossRef] [PubMed]
 
Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why? Eur Heart J. 2013;34(14):1041-1049. [CrossRef] [PubMed]
 
Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(7):638-645.e4. [CrossRef] [PubMed]
 
Lip GY. Recommendations for thromboprophylaxis in the 2012 focused update of the ESC guidelines on atrial fibrillation: a commentary. J Thromb Haemost. 2013;11(4):615-626. [CrossRef] [PubMed]
 
Lip GY, Camm AJ, Hylek EM, Halperin JL, Weitz JI. Non-vitamin k antagonist oral anticoagulants: an appeal for consensus on terminology. Chest. 2014;145(5):1177-1178. [CrossRef] [PubMed]
 
Husted S, De Caterina R, Andreotti F, et al; ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel. Thromb Haemost. 2014;111(5):781-782. [CrossRef] [PubMed]
 
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(1):14-21. [CrossRef] [PubMed]
 
Camm AJ, Lip GY, De Caterina R, et al; ESC Committee for Practice Guidelines-CPG; Document Reviewers. 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(10):1385-1413. [CrossRef] [PubMed]
 
Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. 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(2):263-272. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Singer DE, Chang Y, Borowsky LH, et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc. 2013;2(3):e000250. [CrossRef] [PubMed]
 
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(6):1172-1179. [CrossRef] [PubMed]
 
Chao TF, Lin YJ, Tsao HM, et al. CHADS(2) and CHA(2)DS(2)-VASc scores in the prediction of clinical outcomes in patients with atrial fibrillation after catheter ablation. J Am Coll Cardiol. 2011;58(23):2380-2385. [CrossRef] [PubMed]
 
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(3):170-176. [CrossRef] [PubMed]
 
Thygesen LC, Daasnes C, Thaulow I, Brønnum-Hansen H. Introduction to Danish (nationwide) registers on health and social issues: structure, access, legislation, and archiving. Scand J Public Health. 2011;39(suppl 7):12-16. [CrossRef] [PubMed]
 
Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health. 2011;39(suppl 7):30-33. [CrossRef] [PubMed]
 
Kildemoes HW, Sørensen HT, Hallas J. The Danish national prescription registry. Scand J Public Health. 2011;39(suppl 7):38-41. [CrossRef] [PubMed]
 
Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med. 1999;131(12):927-934. [CrossRef] [PubMed]
 
Newson RB. Comparing the predictive powers of survival models using Harrell's C or Somers' D. Stata J. 2010;10(3):339-358.
 
Potpara TS, Polovina MM, Licina MM, Marinkovic JM, Prostran MS, Lip GY. 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(2):319-326. [CrossRef] [PubMed]
 
Piccini JP, Stevens SR, Chang Y, et al; ROCKET AF Steering Committee and Investigators. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation. 2013;127(2):224-232. [CrossRef] [PubMed]
 
Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: Analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol. 2013;61(6):651-658. [CrossRef] [PubMed]
 
Banerjee A, Fauchier L, Vourc’h P, et al. Renal impairment and ischemic stroke risk assessment in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. J Am Coll Cardiol. 2013;61(20):2079-2087. [CrossRef] [PubMed]
 
Roldán V, Marín F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost. 2013;109(5):956-960. [CrossRef] [PubMed]
 
Apostolakis S, Guo Y, Lane DA, Buller H, Lip GY. Renal function and outcomes in anticoagulated patients with non-valvular atrial fibrillation: the AMADEUS trial. Eur Heart J. 2013;34(46):3572-3579. [CrossRef] [PubMed]
 
Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol. 2013;6(5):868-874. [CrossRef] [PubMed]
 
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870. [CrossRef] [PubMed]
 
Thygesen SK, Christiansen CF, Christensen S, Lash TL, Sørensen HT. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol. 2011;11:83. [CrossRef] [PubMed]
 
Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med. 2012;367(7):625-635. [CrossRef] [PubMed]
 
Olesen JB, Lip GY, 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(4):739-749. [CrossRef] [PubMed]
 
Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation. 2012;125(19):2298-2307. [CrossRef] [PubMed]
 
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