DS 2. 72,452 subjects who had an ATRIA score of 0 to 5 (low risk).

Transcription

1 [ 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 Score A Nationwide Cohort Study Gregory Y. H. Lip, MD ; Peter Brønnum Nielsen, PhD ; Flemming Skjøth, PhD ; Deirdre A. Lane, PhD ; Lars Hvilsted Rasmussen, MD, PhD ; and Torben Bjerregaard Larsen, MD, PhD 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 [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 per 100 person-years, when subdivided by 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 (95% CI, ) to (95% CI, ) when the DS2 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 per 100 person-years. Thus, the stroke risk stratification scheme recommended in the ESC guidelines (based on the score) would be best at identifying the truly low risk subjects with AF who do not need any antithrombotic therapy. CHEST 2014; 146(5): Manuscript received March 4, 2014; revision accepted May 22, 2014; originally published Online First June 19, ABBREVIATIONS: AF 5 atrial fibrillation; ATRIA 5 Anticoagulation and Risk Factors in Atrial Fibrillation; CHA 5 congestive heart failure, hypertension, age 75 years, diabetes, previous stroke; - VASc 5 congestive heart failure, hypertension, age 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category; egfr 5 estimated glomerular filtration rate; ESC 5 European Society of Cardiology; ESRD 5 end-stage renal disease; ICD-10 5 International Classification of Diseases, 10th edition; NOAC 5 non-vitamin K antagonist; OAC 5 oral anticoagulation; R 2 CHADS2 5 renal dysfunction, congestive heart failure, hypertension, age 75 years, diabetes, previous stroke; ROCKET-AF 5 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 5 vitamin K antagonist journal.publications.chestnet.org 1337

2 At r i a l 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 al 8 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 AFFILIATIONS: 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. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Gregory Y. H. Lip, MD, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, B18 7QH, England; g.y.h.lip@bham.ac.uk 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest 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 (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 CHA (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 CHA and DS2 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 CHA 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 CHA score (0). However, a CHA score 5 0 has been shown to be poor at identifying low-risk patients, and in one study stroke/thromboembolism rates in patients with a CHA score 5 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 score 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 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 Original Research [ 146 # 5 CHEST NOVEMBER 2014 ]

3 Materials and Methods 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 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 Th is 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 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 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. Comparison of the ATRIA Score With the 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 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 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 score. For TABLE 1 ] Assignment of Points for Each Risk Factor in the ATRIA Score and Score ATRIA Risk Factor Prior Stroke No Prior Stroke Age 85 y y y 7 3 1, 65 y Female sex Diabetes CHF 1 1 CHF or LVD 1 Hypertension Proteinuria 1 1 egfr, 45 or ESRD 1 1 Vascular disease 1 Prior stroke/thromboembolism/transient ischemic attack 2 Total ATRIA 5 Anticoagulation and Risk Factors in Atrial Fibrillation; 5 congestive heart failure, hypertension, age 75 years, diabetes, previous stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category; CHF 5 defined as chronic heart failure (in ATRIA score) or congestive heart failure, left ventricular dysfunction, or recent decompensated heart failure (as per definition used in European Society of Cardiology guidelines); egfr 5 estimated glomerular filteration rate; ESRD 5 end-stage renal disease; LVD 5 left ventricular dysfunction. journal.publications.chestnet.org 1339

4 1-year follow-up, Kaplan-Meier estimates were used to present the proportion free of stroke/thromboembolism for each score group. Cox proportional hazard analyses were constructed to inspect the risk related to an increase in the 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 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). Results 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 score) in patients with an ATRIA score 0 to 5 are illustrated in Figure 2. The overall stroke/thromboembolic event rate for the low-risk ATRIA category (score 5 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 per 100 person-years at 1-year follow-up when subdivided by scores ( Fig 2, Table 2 ). A low-risk category based on the ESC guidelines (ie, score 5 0 for men or a score 5 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, score 5 0 for men or a score 5 1 for women) as the reference, at 1-year follow-up the hazard ratios adjusted for year of inclusion and antiplatelet treatment associated with scores 1 (men), 2, 3, 4, 5, and. 5 (five patients with a 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 (95% CI, ) to (95% CI, ) when the 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 and for ATRIA and, respectively. Investigating the components related to renal function in the ATRIA score among the subgroup of patients with a 2 (ie, high risk; n 5 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, ) and 1.30 (95% CI, ), respectively. The C statistics were unaffected and still significantly different in favor of the score (full data not shown). Figure 1 Selection of study population. AF 5 atrial fibrillation; ATRIA 5 Anticoagulation and Risk Factors in Atrial Fibrillation; VKA 5 vitamin K antagonist. Discussion 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 score) can further refine stroke risk stratification. Indeed, the lowrisk category defined by the ESC guidelines could clearly 1340 Original Research [ 146 # 5 CHEST NOVEMBER 2014 ]

5 TABLE 2 ] Baseline Characteristics for Patients With AF by ATRIA Score, Vitamin K Antagonist-Untreated at Baseline Total (N 5 154,147) ATRIA Score 0-5 Low Risk (n 5 72,452 [47.0%]) ATRIA Score 6 Intermediate Risk (n 5 23,138 [15.0%]) ATRIA Score 7-15 High Risk (n 5 58,557 [38.0%]) Age, mean (SD), y (11.8) (5.69) (8.03) CHF 3,117 (4.3) 1,833 (7.9) 12,572 (21.5) Hypertension 10,724 (14.8) 3,251 (14.1) 17,819 (30.4) Age 85 y 0 4,522 (19.5) 28,945 (49.4) Age y 8,809 (12.2) 16,554 (71.5) 23,574 (40.3) Age y 29,749 (41.1) 2,062 (8.9) 4,259 (7.3) Age, 65 y 33,894 (46.8) 0 1,779 (3.0) Diabetes mellitus 5,731 (7.9) 2,161 (9.3) 10,206 (17.4) Stroke (previous) ,297 (31.2) Vascular disease 8,822 (12.2) 3,909 (16.9) 11,965 (20.4) Sex category (female) 23,715 (32.7) 10,992 (47.5) 41,524 (70.9) Aspirin 20,514 (28.3) 9,258 (40.0) 30,459 (52.0) Clopidogrel 1,608 (2.2) 569 (2.5) 2,661 (4.5) Dipyridamole 2,115 (2.9) 926 (4.0) 6,825 (11.7) score 0 (female 5 1) 20,851 (28.8) (non-female) 12,756 (17.6) ,137 (33.3) 3,612 (15.6) 643 (1.1) 3 11,217 (15.4) 13,574 (58.7) 11,065 (18.9) 4 2,809 (3.9) 4,458 (19.3) 21,338 (36.4) (0.8) 1,219 (5.3) 14,445 (24.7) a (0.2) 275 (1.2) 11,066 (18.9) Among the patients with a low-risk ATRIA score (score 0-5), of the n patients with a score. 5, the additional risk factors in each ATRIA score value are summarized as follows: (1) ATRIA score 2: n 5 3 patients with LVD 1 SE/TIA 1 vascular disease; (2) ATRIA score 3: n 5 4 patients with SE/TIA 1 vascular disease, and n 5 7 patients with LVD 1 SE/TIA 1 vascular disease; (3) ATRIA score 4: n 5 11 with LVD 1 SE/TIA 1 vascular disease; and (4) ATRIA score 5: n 5 71 with SE/TIA 1 vascular disease, n 5 5 with LVD 1 SE/TIA, and n 5 33 with LVD 1 SE/TIA 1 vascular disease. Thus, for example, the three patients with ATRIA score 2 would earn 4 additional points on the score by having the additional risk factors not within the original specification of the ATRIA score. AF 5 atrial fibrillation; SE/TIA 5 systemic thromboembolism and/or transient ischemic attack. See Table 1 legend for expansion of other abbreviations. a Five patients with a score of 7, none with a higher score. 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 per 100 personyears. Furthermore, in patients categorized with an ATRIA score 0 to 5, the additional risk factors included in 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 CHA ; and 0.04%, 0.55%, and 2.52% with. 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 per 100 person-years. One reason that some patients with a low-risk ATRIA score (0-5) can have a score of 5 reflects the definitions of the scores used, with 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, 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 DS2 also includes ischemic stroke, systemic thromboembolism, journal.publications.chestnet.org 1341

6 TABLE 3 ] Event Rate of Stroke/Thromboembolism per 100 Person-Years in Patients With AF 1-y Follow-up 13-y Follow-up ATRIA Score 0-5 (Low Risk) Person-Years Events Stroke Rate (95% CI) Person-Years Events Stroke Rate (95% CI) , ( ) 89, ( ) 5 1 7, ( ) 30, ( ) , ( ) 58,717 1, ( ) 5 3 6, ( ) 23, ( ) 5 4 1, ( ) 5, ( ) ( ) ( ) ( ) ( ) Total 47,090 1, ,347 3,891 See Table 1 legend for expansion of abbreviations. 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 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 ) would help. 5,9 Indeed, the 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 CHA score (hence, the R 2 CHA score) improved the net reclassification index compared with the CHA and 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 CHA 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 CHA and 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 CHA and/or scores. In a recent analysis of thromboembolic events following catheter ablation of AF, the score further differentiated thromboembolic risk in patients with CHA and R 2 CHA scores of 0 or 1 and had the best predictive value for thromboembolism in patients with AF recurrences (C index, 0.894; P vs CHA, P vs R 2 CHADS2 ).27 None - theless, 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 1342 Original Research [ 146 # 5 CHEST NOVEMBER 2014 ]

7 Figure 2 A, B, Kaplan-Meier estimate of the proportion free of stroke/ thromboembolism (with competing risk of death taking into account) according to VASc score in patients with an ATRIA score 0 to 5 using (A) 1 y of follow-up and (B) 5 y of follow-up. VASc 5 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. 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 CHA 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 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 journal.publications.chestnet.org 1343

8 TABLE 4 ] Risk of Stroke/Thromboembolism in Patients With AF Adjusted for Antiplatelet Treatment and Year of Inclusion ATRIA Score 0-5 (Low Risk) Low risk using ESC guidelines (ie, 5 0, or if female, score 5 1) Adjusted Analyses 1-y Follow-up (Adjusted) 13-y Follow-up (Adjusted) Hazard Ratio 95% CI Hazard Ratio 95% CI Reference Reference 5 1 (nonfemale) ESC 5 European Society of Cardiology. See Table 1 legend for expansion of abbreviations. 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 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 Original Research [ 146 # 5 CHEST NOVEMBER 2014 ]

9 Acknowledgments 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. References 1. Hart RG, Pearce LA, Aguilar MI. Metaanalysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med ; 146 (12): Pisters R, Lane DA, Marin F, Camm AJ, Lip GY. Stroke and thromboembolism in atrial fibrillation. Circ J ;76(10): Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why? Eur Heart J ;34(14): Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med ;123(7): e4. 5. Lip GY. Recommendations for thromboprophylaxis in the 2012 focused update of the ESC guidelines on atrial fibrillation: a commentary. J Thromb Haemost ;11(4): Lip GY, Camm AJ, Hylek EM, Halperin JL, Weitz JI. Non-vitamin k antagonist oral anticoagulants: an appeal for consensus on terminology. Chest ;145(5): 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 ; 111 (5): Eckman MH, Singer DE, Rosand J, Greenberg SM. Moving the tipping point: the decision to anticoagulate patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes ;4(1): Camm AJ, Lip GY, De Caterina R, et al ; ESC Committee for Practice Guidelines- CPG ; Document Reviewers 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 ;14(10): 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 ;137(2): 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 ;342:d 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 ;2(3):e Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2 score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost ;107(6): Chao TF, Lin YJ, Tsao HM, et al. CHADS(2) and CHA(2)DS(2) scores in the prediction of clinical outcomes in patients with atrial fibrillation after catheter ablation. J Am Coll Cardiol ;58(23): Coppens M, Eikelboom JW, Hart RG, et al. The CHA2DS2 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 ;34(3): 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 ;39(suppl 7 ): Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health ;39(suppl 7 ): Kildemoes HW, Sørensen HT, Hallas J. The Danish national prescription registry. Scand J Public Health ;39(suppl 7 ): 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 ;131(12): Newson RB. Comparing the predictive powers of survival models using Harrell's C or Somers' D. Stata J ;10(3): 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 ;5(2): 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 ;127(2): 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 ;61(6): 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 ;61(20): Roldán V, Marín F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2 stroke stratification risk scores for atrial fibrillation? Thromb Haemost ;109(5): 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 ;34(46): Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2, and journal.publications.chestnet.org 1345

10 R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol ;6(5): 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 ;285(22): 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 ;11: Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med ;367(7): 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 ;106(4): 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 ;125(19): Original Research [ 146 # 5 CHEST NOVEMBER 2014 ]