Canadian Journal of Cardiology 30 (2014) 405e412
Clinical Research
R2CHADS2 Score and Thromboembolic Events After Catheter Ablation of Atrial Fibrillation in Comparison With the CHA2DS2-VASc Score Tze-Fan Chao, MD,a,b Yenn-Jiang Lin, MD,a,b Shih-Lin Chang, MD,a,b Li-Wei Lo, MD,a,b Yu-Feng Hu, MD,a,b Ta-Chuan Tuan, MD,a,b Jo-Nan Liao, MD,a,b Fa-Po Chung, MD,a,b Ming-Hsiung Hsieh, MD,c and Shih-Ann Chen, MDa,b a b c
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
Division of Cardiology, Department of Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan
See editorial by Kornej and Lip, pages 385-387 of this issue. ABSTRACT
RESUM E
Background: A new risk model, the R2CHADS2 (Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack) score, was proposed to be a powerful scoring scheme in predicting stroke or systemic embolism in atrial fibrillation (AF). The goal of the present study is to validate the usefulness of the R2CHADS2 score among patients with AF after catheter ablation. We also aimed to compare the accuracy of the CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age [ 75 y], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 y], Sex [Female]) and R2CHADS2 scores for risk stratification of thromboembolic (TE) events after ablation procedures. Methods: We enrolled a total of 526 patients with AF who underwent catheter ablation. The clinical end point was the occurrence of TE events (ischemic stroke, transient ischemic attack, or other systemic embolisms) during the postablation follow-up. Results: During a follow-up of 37.5 21.3 months, 14 patients (2.7%) experienced TE events. The R2CHADS2 score was an independent
Introduction : Un nouveau modèle de risque, le score R2CHADS2 (Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, nal, l’insuffisStroke/Transient Ischemic Attack, soit la dysfonction re ance cardiaque congestive, l’hypertension, l’âge, le diabète, l’accident re bral et l’ische mie ce re brale transitoire) a e te propose vasculaire ce dire l’accident vasculaire comme grille de scores efficace pour pre re bral ou l’embolie syste mique lors de fibrillation auriculaire (FA). Le ce sente e tude est de valider l’utilite du score R2CHADS2 chez but de la pre ter. Nous avons les patients ayant une FA après l’ablation par cathe galement pour but de comparer la pre cision des scores CHA2DS2-VASc e (Congestive Heart Failure, Hypertension, Age [ 75 y], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 y], Sex [Female], soit l’insuffisance cardiaque congestive, l’hypertension, l’âge re bral et l’ische mie [ 75 ans], le diabète, l’accident vasculaire ce re brale transitoire, la maladie vasculaire, l’âge [65-74 ans], le sexe ce minin]) et R2CHADS2 quant à la stratification du risque [fe ve nements thromboemboliques (ET) après les proce de s d’ablation. d’e
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and its incidence is projected to rise continuously over the next few decades.1,2 Besides medical treatment, catheter ablation of AF has become more and more popular and provides an effective therapy for patients with drugrefractory AF. Several recent studies showed that patients
undergoing AF ablation have a significantly lower risk of stroke compared with patients with AF who do not undergo ablation.3-5 However, the data regarding the predictors of thromboembolic (TE) events after AF ablation are limited. Recently, the CHA2DS2-VASc score (Congestive Heart Failure, Hypertension, Age [ 75 y], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 y], Sex [Female]) has been recommended as a guide for antithrombotic therapies in patients with AF and was also demonstrated to be a significant predictor of adverse events in patients receiving catheter ablation.6,7 In addition, a new risk model, designated the R2CHADS2 (Renal Dysfunction, Congestive Heart Failure, Hypertension, Age 75 years, Diabetes, Stroke/Transient Ischemic Attack) score, that incorporates the
Received for publication October 10, 2013. Accepted January 9, 2014. Corresponding author: Dr Shih-Ann Chen, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. Tel.: 886-2-2875-7156; fax: 886-2-28735656. E-mail: [email protected] See page 411 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2014.01.005
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predictor of TE events in the multivariate analysis. Patients with an R2CHADS2 score of > 2 had a higher event rate compared with those with a score of 0 or 1 (0.5% vs 7.7%). The areas under the receiver operating characteristic (ROC) curves of CHA2DS2-VASc and R2CHADS2 scores in predicting TE events were 0.832 and 0.872, respectively. The difference between these 2 curves did not reach statistical significance (P ¼ 0.338). In addition, the R2CHADS2 score did not improve net stroke risk reclassification over the CHA2DS2-VASc score (net reclassification improvement, 0.9%; P ¼ 0.948). Conclusions: The R2CHADS2 and CHA2DS2-VASc scores could be used to predict TE events for patients with AF undergoing catheter ablation. The predictive accuracy of both scores were similar in this relatively small cohort undergoing ablation.
thodes : Nous avons inscrit un total de 526 patients atteints de FA Me ter. Le critère de jugement clinique qui ont subi une ablation par cathe tait la survenue d’ET (accident vasculaire ce re bral ische mique, e mie ce re brale transitoire ou autres embolies syste miques) durant ische le suivi après l’ablation. sultats : Durant un suivi de 37,5 21,3 mois, 14 patients (2,7 %) Re te un pre dicteur inde pendant ont subi des ET. Le score R2CHADS2 a e e. Les patients ayant un score R2CHADS2 d’ET dans l’analyse multivarie ve nement plus e leve comparativement à ceux > 2 ont eu un taux d’e ayant un score de 0 ou de 1 (0,5 % vs 7,7 %). Les surfaces sous les ristiques d’efficacite du re cepteur (ROC : receiver courbes caracte operating characteristic) des scores CHA2DS2-VASc et R2CHADS2 pour dire les ET ont respectivement e te de 0,832 et de 0,872. La pre rence entre ces 2 courbes n’a pas suffisamment e te marque e diffe pour être statistiquement significative (P ¼ 0,338). De plus, le score liore la reclassification nette du risque d’acciR2CHADS2 n’a pas ame re bral par rapport au score CHA2DS2-VASc (Net dent vasculaire ce Reclassification Improvement, 0,9 %; P ¼ 0,948). Conclusions : Les scores R2CHADS2 et CHA2DS2-VASc pourraient être s pour pre dire les ET des patients souffrant de FA qui subissent utilise ter. Dans cette cohorte relativement limite e une ablation par cathe cision pre dictive des deux scores a e te ayant subi une ablation, la pre similaire.
components of the CHADS2 score and awards 2 points for renal dysfunction, was proposed to be a powerful scoring scheme in predicting stroke or systemic embolism in AF.8 However, whether the R2CHADS2 score is useful for risk stratification in patients with AF after catheter ablation has not been explored. The goal of the present study was to investigate the association of the R2CHADS2 score and TE events after AF ablation. We also aimed to compare the accuracy of the CHA2DS2-VASc and R2CHADS2 scores in identifying patients at risk of TE events after catheter ablation.
Catheter ablation of AF
Methods A total of 526 patients with symptomatic drug-refractory AF who underwent radiofrequency catheter ablation from 20042009 were enrolled in the study. We excluded those who received long-term oral anticoagulant therapy (OAT) because 1 of our goals was to investigate whether the R2CHADS2 score could be helpful for determining a long-term strategy for oral anticoagulation therapy. It would be more appropriate to study this issue in patients not receiving long-term OAT. The CHA2DS2-VASc score was calculated for every patient based on a point system in which 2 points were assigned for a history of a stroke or transient ischemic attack (TIA) or age 75 years. One point was assigned for age between 65 and 74 years, a history of hypertension, diabetes, recent cardiac failure, vascular disease (myocardial infarction, complex aortic plaque, or peripheral artery disease), and female sex.9 The estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of the Diet in Renal Disease Study equation: eGFR (mL/min/1.73m2) ¼ 186.3 (serum creatinine [mg/ dL])1.154 (age [years])0.203 (0.742 if a woman).10 The R2CHADS2 score was derived by incorporating the components of the CHADS2 score and awarding 2 points for renal dysfunction, defined as an eGFR < 60 mL/min/1.73m2.8
Each patient underwent an electrophysiological study and catheter ablation in the fasting nonsedated state after written informed consent was obtained. The details have been described previously.11,12 In brief, after completing the left atrial geometry, continuous circumferential lesions were created encircling the right and left pulmonary vein (PV) ostia guided by the Ensite NavX system (St. Jude Medical, Austin, TX) using either a conventional 4-mmetip or irrigated-tip catheter. The intention was to place the radiofrequency lesions at least 1-2 cm away from the angiographically defined ostia. Successful circumferential PV isolation was demonstrated by the absence of any PV activity or dissociated PV activity. The need for additional linear ablation was assessed based on AF inducibility.13 If nonparoxysmal AF did not stop after the PV isolation and linear ablation, an additional complex fractionated electrographically guided substrate ablation was performed sequentially, based on the complex fractionated electrographic maps. Complex fractionated electrographic ablation was confined to the continuous complex fractionated electrograms (> 5 seconds) in the left atrium and proximal coronary sinus.14,15 The end point of complex fractionated electrographic site ablation was to obtain a prolongation of cycle length, eliminate complex fractionated electrograms, or abolish local fractionated potentials (bipolar voltage < 0.05 mV). After sinus rhythm was restored from AF by procedural AF termination or electrical cardioversion, we applied mapping and ablation only to spontaneously initiating focal atrial tachycardias and non-PV ectopy that initiated AF. If any nonPV ectopy initiating AF from the superior vena cava was identified, isolation of the superior vena cava was guided by circular catheter recordings from the superior vena cavaeatrial junction.
Chao et al. R2CHADS2 Score and Thromboembolic Events
Definitions of clinical end points and follow-up After receiving catheter ablation, the patients were followed every 1-3 months at our cardiology clinic or by the referring physicians. The strategy for use of OAT after ablation has been described in our previous publication.6 During the follow-up, patients were carefully examined, and 24-hour Holter monitoring or cardiac event recording, or both, were performed for 1 week. AF recurrence was defined as an episode lasting longer than 1 minute 2 months after ablation (blanking period). The clinical end point was the occurrence of TE events (ischemic stroke, TIA, or other systemic embolism). The diagnosis of ischemic stroke/TIA should be confirmed by a neurologist, and imaging studies of the brain, including computed tomographic scans or magnetic resonance images, were obtained for each patient to exclude the presence of intracranial hemorrhage. In the present study, more than 70% of the study population underwent follow-up regularly at the cardiology clinics, and the rest of the patients were completely assessed by telephone consultations. Once patients reported the occurrence of TE events in the telephone consultations, individualized medical records regarding the symptoms, findings of imaging studies, and the final diagnosis of the events were acquired and reviewed to ascertain the cause. Since Taiwan is a small island and more than 99% of the population is covered by the national health insurance program, it was easy for patients to seek medical advice and convenient for doctors to access patients’ medical records. Statistical analysis Differences between continuous values were assessed using an unpaired 2-tailed t test for normally distributed continuous variables, the Mann-Whitney test for skewed variables, and the c2 test for nominal variables. Event rates between groups with different scores were compared by the c2 test for linear trends. The risk of TE events was assessed using the Cox regression analysis. We assessed the predictive accuracy of the CHA2DS2-VASc and R2CHADS2 scores using the receiver operating characteristic (ROC) curve. The areas under the ROC curves of these 2 scoring systems were compared using deLong’s method. In addition, the net reclassification index comparing the R2CHADS2 score with the CHA2DS2-VASc score was calculated. Statistical significance was set at P < 0.05.
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Table 1. Baseline patient characteristics Study population (n ¼ 526)
Variable Age, y Age 65 y Age 75 y Sex (male) Medical history, % Hypertension Diabetes mellitus Congestive heart failure Coronary artery disease Previous stroke/TIA Previous vascular disease Renal dysfunction (eGFR < 60 mL/min/1.73m2) Body mass index, kg/m2 Long-term use of antiplatelet agents Left atrial diameter, mm LVEF, % AF type (paroxysmal AF) Recurrence rate after ablation CHA2DS2-VASc score, median (IQR) R2CHADS2 score, median (IQR)
53.7 12.2 18.1% 3.8% 72.6% 45.4% 12.4% 8.0% 26.8% 4.6% 1.3% 15.2% 25.2 3.5 57.8% 39.2 7.1 58.7 8.0 78.3% 27.8% 1 (0-2) 1 (0-2)
AF, atrial fibrillation; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); eGFR, estimated glomerular filtration rate; IQR, interquartile range; LVEF, left ventricular ejection fraction; R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; TIA, transient ischemic attack.
and other systemic embolism in 1 patient. Among the 9 patients with ischemic stroke, 3 had heart failure, 6 had hypertension, 2 had diabetes mellitus, 2 had previous stroke or TIA, and 5 had an eGFR < 60 mL/min/1.73m2. The significant predictors of TE events based on the univariate Cox regression analysis are shown in Table 2. The CHA2DS2VASc and R2CHADS2 scores remained independent predictors of TE events in the multivariate model (Tables 3 and 4). The association between the R2CHADS2 score and rate of TE events is shown in Fig 1. The TE event rate continuously increased from 0% for patients with a score of 0 to as high as 66.7% for those with a score of 6. At the cutoff value of 2 identified by the ROC curve, patients with a R2CHADS2 score of 2 had a significantly higher event rate compared with those with a score of 0 or 1 (0.5% vs 7.7%; P < 0.001) (Fig 2).
Results Baseline characteristics of study patients
Table 2. Univariate Cox regression analysis for predictors of thromboembolic events after catheter ablation
The baseline characteristics of the study population are shown in Table 1. The mean age of the patients was 53.7 12.2 years, and 72.6% of them were men. The median values (interquartile range) of both the CHA2DS2-VASc and R2CHADS2 scores were 1 (0-2). Hypertension was the most prevalent comorbidity and was noted in 45.4% of patients. The AF recurrence rate after multiple procedures was 27.8%.
Variable
R2CHADS2 scores and the risk of TE events During the mean follow-up of 37.5 21.3 months, there were 14 patients (2.7%) who experienced TE events, including ischemic stroke in 9 patients, TIAs in 4 patients,
AF type (nonparoxysmal) Recurrence after multiple ablations Left atrial diameter (mm) LVEF (%) CHA2DS2-VASc score R2CHADS2 score
Hazard ratio 4.199 4.798 1.069 0.926 2.206 2.376
95% CI
P value
1.462-12.058 0.008 1.608-14.319 0.005 1.028-1.111 0.001 0.879-0.976 0.004 1.646-2.955 < 0.001 1.813-3.116 < 0.001
AF, atrial fibrillation; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); CI, confidence interval; LVEF, left ventricular ejection fraction; R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
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Table 3. Multivariate Cox regression analysis for predictors of thromboembolic events after catheter ablation using the CHA2DS2VASc score Variable AF type (nonparoxysmal) Recurrence after multiple ablations Left atrial diameter (mm) LVEF (%) CHA2DS2-VASc score
Hazard ratio
95% CI
P value
2.590 2.272 0.995 0.981 1.963
0.758-8.848 0.683-7.558 0.948-1.045 0.926-1.038 1.415-2.724
0.129 0.181 0.845 0.504 < 0.001
Variables with P < 0.05 in Table 2 were adjusted with the CHA2DS2VASc score in the multivariate Cox regression analysis. AF, atrial fibrillation; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); CI, confidence interval; LVEF, left ventricular ejection fraction.
Comparisons between CHA2DS2-VASc and R2CHADS2 scores The area under the ROC curve of the CHA2DS2-VASc and R2CHADS2 scores in predicting TE events were 0.832 (95% confidence interval [CI], 0.730-0.934; P < 0.001) and 0.872 (95% CI, 0.792-0.951; P < 0.001), respectively. Although the area under the ROC curve of the R2CHADS2 score was slightly higher than that of the CHA2DS2-VASc score, the difference between these 2 curves (0.04) did not reach statistical significance (P ¼ 0.338) (Fig 3). In addition, the R2CHADS2 score did not improve net stroke risk reclassification over the CHA2DS2-VASc score (net reclassification improvement, 0.9%; 95% CI, 29.2%-27.3%; P ¼ 0.948). Discussion Main findings In this study, we investigated the association between the R2CHADS2 score and the risk of TE events after AF ablation. We also compared the accuracy of the R2CHADS2 and the CHA2DS2-VASc scores in predicting TE events after catheter ablation. The main findings were as follows: (1) The R2CHADS2 score could be used to predict TE events in patients with AF receiving catheter ablations and (2) The R2CHADS2 and CHA2DS2-VASc scores were equally accurate in predicting TE events after AF ablations assessed by ROC curves and the net reclassification index in this relatively small cohort. Table 4. Multivariate Cox regression analysis for predictors of thromboembolic events after catheter ablation using the R2CHADS2 score Variable AF type (nonparoxysmal) Recurrence after multiple ablations Left atrial diameter (mm) LVEF (%) R2CHADS2 score
Hazard ratio
95% CI
P value
2.414 2.827 0.989 0.967 2.414
0.677-8.604 0.845-9.457 0.939-1.042 0.914-1.022 1.756-3.318
0.174 0.092 0.676 0.234 < 0.001
Variables with P < 0.05 in Table 2 were adjusted with the R2CHADS2 score in the multivariate Cox regression analysis. AF, atrial fibrillation; CI, confidence interval; LVEF, left ventricular ejection fraction; R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
R2CHADS2, CHA2DS2-VASc scores and adverse events in patients with AF How to identify patients with AF at risk of TE events who should receive long-term OAT is an important issue. The CHA2DS2-VASc score, which extends the CHADS2 scheme by considering additional stroke risk factors (vascular diseases and female sex), was recommended by the European Society of Cardiology (ESC) to guide antithrombotic therapy for patients with AF.16 The usefulness of the CHA2DS2VASc score in predicting AF-related TE events has been validated in several subsequent studies.17-19 The CHA2DS2VASc score is particularly useful and valuable in identifying “truly low-risk” patients.20 In a nationwide cohort study from Denmark, Olesen et al. demonstrated that for patients categorized as “low risk,” using a CHADS2 score ¼ 0, the CHA2DS2-VASc score significantly improved the predictive value of the CHADS2 score alone and a CHA2DS2-VASc score ¼ 0 could clearly identify truly low-risk patients.21 However, the best scoring scheme for the prediction of TE events for patients with AF is still an open issue and drawing much attention. Piccini et al. demonstrated that renal dysfunction was an important risk factor for stroke and systemic embolism in patients with AF enrolled 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) trial,8,22 and the R2CHADS2 scoring system was derived accordingly.8 In addition, the authors of the previous study showed that the R2CHADS2 score could improve the net reclassification index by 6.2% compared with the CHA2DS2-VASc score and by 8.2% compared with the CHADS2 score. In contrast, Roldán et al. investigated a similar issue in 978 patients with AF from an outpatient anticoagulation clinic and concluded that although renal dysfunction would confer a poor overall prognosis, adding it to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.23 The diverse results of these previous studies may be partly explained by the essential differences between the “trial cohorts” and “real world,” and may imply that whether renal dysfunction could improve the accuracy of current scoring systems in predicting clinical outcomes for patients with AF remained uncertain. It should also be emphasized that the R2CHADS2 score was derived from the ROCKET-AF cohort,22 and therefore several limitations of such a derivation were present.24 First, ROCKET-AF was an anticoagulation trial, and to test the added value of a risk factor should ideally be made in a cohort not receiving anticoagulation. Second, the ROCKET-AF trial excluded patients with severe renal dysfunction. To test the value of adding renal impairment to the CHADS2 score, we should see the broad range of renal function in the study population. Third, the ROCKET-AF trial focused only on high-risk patients with a CHADS2 score 2. To test the improvement of adding a risk factor to the present scoring systems, we need to test in a broad range of patients with AF. Based on the limitations mentioned, the anticoagulated ROCKET AF cohort may not be representative of the general AF population in clinical practice.
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Figure 1. R2CHADS2 score and event rates. The thromboembolic event rate continuously increased when the scores became higher. R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
Validation of the R2CHADS2 score in patients with AF receiving catheter ablation In the present study, we validated the usefulness of the R2CHADS2 score for risk stratification in patients with AF receiving catheter ablation and compared its accuracy with the CHA2DS2-VASc score. Several previous studies have
demonstrated that patients who received catheter ablation had a better prognosis than those who did not undergo ablation procedures.3-5,25 Bunch et al. compared the long-term risk of death, dementia, and stroke in patients with AF treated with catheter ablation and patients with AF who did not receive ablation and non-AF patients.25 They found that patients with AF receiving ablation had a significantly lower risk of
Figure 2. Event-free survival curve for patients with different R2CHADS2 scores. A Kaplan-Meier survival analysis showed that an R2CHADS2 score of > 2 was associated with a higher event rate than a score of 0 or 1 (0.5% vs 7.7%, P < 0.001). R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
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schemes.26 Nevertheless, the CHA2DS2-VASc score can differentiate TE risk in the low-risk strata based on the R2CHADS2 score and may be superior in the subgroup with AF recurrence.26 Unlike this previous study, we included only patients not receiving OAT. Because the goals for developing scoring systems was to guide the use of oral anticoagulants, it may be better to validate the usefulness of these schemes in a cohort not receiving anticoagulation. However, the sample size of our study was smaller than that of the Leipzig Heart Center AF Ablation Registry, and therefore we were not able to perform further analysis for patients with a low R2CHADS2 score or specifically for those with AF recurrence. Clinical implications
Figure 3. Receiver operating characteristic (ROC) curves for the CHA2DS2-VASc and R2CHADS2 scores for predicting events. The areas under the ROC curves did not differ significantly between the CHA2DS2-VASc and R2CHADS2 scores for predicting thromboembolic events (difference between areas ¼ 0.04; P ¼ 0.338). CHA2DS2VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
adverse events in comparison with patients with AF not receiving ablation, despite the fact that 35.6% of patients with AF receiving ablation experienced AF recurrence. In a more recent study, the same group further showed that the stroke risk reduction conferred by catheter ablation was consistent across all CHADS2 profiles and ages.5 Similarly, we also demonstrated that there was a potential increased survival rate in patients with AF with rhythm control achieved by an ablation strategy, irrespective of the state of recurrence.4 The results of these observational studies may suggest that catheter ablation can modify the risk of adverse events presented by AF and may therefore change its natural course. Therefore, the scoring system in predicting adverse events that was derived from patients with AF who did not undergo ablation should be further validated to confirm its usefulness in those who received catheter ablation. The results of the present study suggested that the R2CHADS2 score could be used to predict TE events after AF ablation. Compared with the CHA2DS2-VASc score, which has already been validated in patients undergoing AF ablation,6 the area under the ROC curve was not statistically different between the R2CHADS2 and CHA2DS2-VASc scores. In addition, these 2 scoring systems did not differ from each other regarding the predictive accuracy assessed by the net reclassification index. In a recent study that analyzed the accuracy of the R2CHADS2 and CHA2DS2-VASc scores in predicting TE events using the Leipzig Heart Center AF Ablation Registry, Kornej et al. also found that the area under the ROC curve was similar between these 2 scoring
Similar to the CHA2DS2-VASc score, the R2CHADS2 score could predict the occurrence of TE events among patients with AF receiving catheter ablation. However, renal impairment is an important factor associated with the occurrence of bleeding events,27 even for those with mild kidney disease.28 In the study performed by Manzano-Fernández et al., patients with AF with mild renal dysfunction (eGFR ¼ 60-89 mL/min/1.73m2) receiving antithrombotic treatment had a more than 2-fold higher risk of major bleeding compared with patients with normal renal function.28 Therefore, adding renal dysfunction, a significant risk factor for bleeding, to a scoring scheme that aims to estimate the risk of TE events and guide antithrombotic therapy may be inappropriate. Because the results of the present study did not show significant differences between the R2CHADS2 and the CHA2DS2-VASc scores regarding their accuracy in predicting TE events after AF ablation, the CHA2DS2-VASc score is a preferred scoring system for risk stratification because it has been validated in a broad range of patients with AF. Study limitations There were several limitations of the present study. First, there were only 14 patients with TE events during the followup period. Therefore, there may be concern about the overfitness of the multivariate Cox regression model used to evaluate the usefulness of the R2CHADS2 score in predicting TE events. However, the problem of a small number of events in the regression model should be a type 2 error,29 which is not the case in this study. Second, although the diagnoses of 9 patients with ischemic strokes and 4 patients with TIAs were all confirmed by neurologists and imaging studies of the brain, it was still possible that these ischemic events were caused by thrombosis of the cerebral artery rather than AF-related thromboembolism. In addition, the telephone interviews may have missed some stroke events. Third, although the predictive accuracy of the R2CHADS2 and CHA2DS2-VASc scores was similar when assessed by ROC curves and the net reclassification index, we cannot exclude the possibility that the number of events was too small to demonstrate statistically significant differences. Finally, R2CHADS2 and CHA2DS2VASc scores may change over time, and thus the baseline values may not be appropriately representative of the risk of TE events during the follow-up period. However, it is a common limitation that was frequently present in previous studies. The relationship between the “dynamic” changes of
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risk scores and TE events has not been well investigated before, and it is an important issue that deserves more investigation. Based on the limitations mentioned, the results of the present study with its small sample size should be interpreted carefully. A further large-scale prospective trial is necessary to confirm the findings presented here.
10. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70.
Conclusions In summary, the R2CHADS2 and CHA2DS2-VASc scores could be used to predict TE events for patients with AF receiving catheter ablation. The predictive accuracy of both scores was similar in this relatively small cohort undergoing ablation.
12. Chao TF, Tsao HM, Lin YJ, et al. Clinical outcome of catheter ablation in patients with nonparoxysmal atrial fibrillation: results of 3-year followup. Circ Arrhythm Electrophysiol 2012;5:514-20.
Funding Sources This work was supported in part by grants from the National Science Council (NSC98-2410-H-010-003-MY2), and Taipei Veterans General Hospital (V99C1-140, V99A-153, V100D-002-3, and V101D-001-2). Disclosures The authors have no conflicts of interest to disclose. References 1. Potpara TS, Lip GY. Lone atrial fibrillation: what is known and what is to come. Int J Clin Pract 2011;65:446-57.
11. Chao TF, Ambrose K, Tsao HM, et al. Relationship between the CHADS(2) score and risk of very late recurrences after catheter ablation of paroxysmal atrial fibrillation. Heart Rhythm 2012;9:1185-91.
13. Chang SL, Tai CT, Lin YJ, et al. The efficacy of inducibility and circumferential ablation with pulmonary vein isolation in patients with paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2007;18: 607-11. 14. Lin YJ, Tai CT, Kao T, et al. Consistency of complex fractionated atrial electrograms during atrial fibrillation. Heart Rhythm 2008;5:406-12. 15. Lin YJ, Tai CT, Chang SL, et al. Efficacy of additional ablation of complex fractionated atrial electrograms for catheter ablation of nonparoxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2009;20: 607-15. 16. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369-429. 17. 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.
2. Ahmad Y, Lip GY, Lane DA. Recent developments in understanding epidemiology and risk determinants of atrial fibrillation as a cause of stroke. Can J Cardiol 2013;29:S4-13.
18. Abu-Assi E, Otero-Ravina F, Allut Vidal G, et al. Comparison of the reliability and validity of four contemporary risk stratification schemes to predict thromboembolism in non-anticoagulated patients with atrial fibrillation. Int J Cardiol 2013;166:205-9.
3. Hunter RJ, McCready J, Diab I, et al. Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death. Heart 2012;98:48-53.
19. Chao TF, Liu CJ, Chen SJ, et al. Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1? Stroke 2012;43:2551-5.
4. Lin YJ, Chao TF, Tsao HM, et al. Successful catheter ablation reduces the risk of cardiovascular events in atrial fibrillation patients with CHA2DS2-VASc risk score of 1 and higher. Europace 2013;15:676-84.
20. Ha A, Healey JS. The evolving role of stroke prediction schemes for patients with atrial fibrillation. Can J Cardiol 2013;29:1173-80.
5. Bunch TJ, May HT, Bair TL, et al. Atrial fibrillation ablation patients have long-term stroke rates similar to patients without atrial fibrillation regardless of CHADS2 score. Heart Rhythm 2013;10:1272-7.
21. 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;107:1172-9.
6. 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;58:2380-5.
22. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban vs warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
7. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719-47.
23. Roldán V, Marin F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013;109:956-60.
8. Piccini JP, Stevens SR, Chang Y, et al. 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;127:224-32.
24. Apostolakis S, Lane DA, Banerjee A. Letter by Apostolakis et al regarding article, “renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R2CHADS2 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;128:e171.
9. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. 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;137:263-72.
25. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:839-45.
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26. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of TE events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013;6: 868-74.
28. Manzano-Fernández S, Cambronero F, Caro-Martinez C, et al. Mild kidney disease as a risk factor for major bleeding in patients with atrial fibrillation undergoing percutaneous coronary stenting. Thromb Haemost 2012;107:51-8.
27. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-35.
29. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol 2007;165:710-8.
Clinical Research
R2CHADS2 Score and Thromboembolic Events After Catheter Ablation of Atrial Fibrillation in Comparison With the CHA2DS2-VASc Score Tze-Fan Chao, MD,a,b Yenn-Jiang Lin, MD,a,b Shih-Lin Chang, MD,a,b Li-Wei Lo, MD,a,b Yu-Feng Hu, MD,a,b Ta-Chuan Tuan, MD,a,b Jo-Nan Liao, MD,a,b Fa-Po Chung, MD,a,b Ming-Hsiung Hsieh, MD,c and Shih-Ann Chen, MDa,b a b c
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
Division of Cardiology, Department of Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan
See editorial by Kornej and Lip, pages 385-387 of this issue. ABSTRACT
RESUM E
Background: A new risk model, the R2CHADS2 (Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack) score, was proposed to be a powerful scoring scheme in predicting stroke or systemic embolism in atrial fibrillation (AF). The goal of the present study is to validate the usefulness of the R2CHADS2 score among patients with AF after catheter ablation. We also aimed to compare the accuracy of the CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age [ 75 y], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 y], Sex [Female]) and R2CHADS2 scores for risk stratification of thromboembolic (TE) events after ablation procedures. Methods: We enrolled a total of 526 patients with AF who underwent catheter ablation. The clinical end point was the occurrence of TE events (ischemic stroke, transient ischemic attack, or other systemic embolisms) during the postablation follow-up. Results: During a follow-up of 37.5 21.3 months, 14 patients (2.7%) experienced TE events. The R2CHADS2 score was an independent
Introduction : Un nouveau modèle de risque, le score R2CHADS2 (Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, nal, l’insuffisStroke/Transient Ischemic Attack, soit la dysfonction re ance cardiaque congestive, l’hypertension, l’âge, le diabète, l’accident re bral et l’ische mie ce re brale transitoire) a e te propose vasculaire ce dire l’accident vasculaire comme grille de scores efficace pour pre re bral ou l’embolie syste mique lors de fibrillation auriculaire (FA). Le ce sente e tude est de valider l’utilite du score R2CHADS2 chez but de la pre ter. Nous avons les patients ayant une FA après l’ablation par cathe galement pour but de comparer la pre cision des scores CHA2DS2-VASc e (Congestive Heart Failure, Hypertension, Age [ 75 y], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 y], Sex [Female], soit l’insuffisance cardiaque congestive, l’hypertension, l’âge re bral et l’ische mie [ 75 ans], le diabète, l’accident vasculaire ce re brale transitoire, la maladie vasculaire, l’âge [65-74 ans], le sexe ce minin]) et R2CHADS2 quant à la stratification du risque [fe ve nements thromboemboliques (ET) après les proce de s d’ablation. d’e
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and its incidence is projected to rise continuously over the next few decades.1,2 Besides medical treatment, catheter ablation of AF has become more and more popular and provides an effective therapy for patients with drugrefractory AF. Several recent studies showed that patients
undergoing AF ablation have a significantly lower risk of stroke compared with patients with AF who do not undergo ablation.3-5 However, the data regarding the predictors of thromboembolic (TE) events after AF ablation are limited. Recently, the CHA2DS2-VASc score (Congestive Heart Failure, Hypertension, Age [ 75 y], Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age [65-74 y], Sex [Female]) has been recommended as a guide for antithrombotic therapies in patients with AF and was also demonstrated to be a significant predictor of adverse events in patients receiving catheter ablation.6,7 In addition, a new risk model, designated the R2CHADS2 (Renal Dysfunction, Congestive Heart Failure, Hypertension, Age 75 years, Diabetes, Stroke/Transient Ischemic Attack) score, that incorporates the
Received for publication October 10, 2013. Accepted January 9, 2014. Corresponding author: Dr Shih-Ann Chen, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. Tel.: 886-2-2875-7156; fax: 886-2-28735656. E-mail: [email protected] See page 411 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2014.01.005
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predictor of TE events in the multivariate analysis. Patients with an R2CHADS2 score of > 2 had a higher event rate compared with those with a score of 0 or 1 (0.5% vs 7.7%). The areas under the receiver operating characteristic (ROC) curves of CHA2DS2-VASc and R2CHADS2 scores in predicting TE events were 0.832 and 0.872, respectively. The difference between these 2 curves did not reach statistical significance (P ¼ 0.338). In addition, the R2CHADS2 score did not improve net stroke risk reclassification over the CHA2DS2-VASc score (net reclassification improvement, 0.9%; P ¼ 0.948). Conclusions: The R2CHADS2 and CHA2DS2-VASc scores could be used to predict TE events for patients with AF undergoing catheter ablation. The predictive accuracy of both scores were similar in this relatively small cohort undergoing ablation.
thodes : Nous avons inscrit un total de 526 patients atteints de FA Me ter. Le critère de jugement clinique qui ont subi une ablation par cathe tait la survenue d’ET (accident vasculaire ce re bral ische mique, e mie ce re brale transitoire ou autres embolies syste miques) durant ische le suivi après l’ablation. sultats : Durant un suivi de 37,5 21,3 mois, 14 patients (2,7 %) Re te un pre dicteur inde pendant ont subi des ET. Le score R2CHADS2 a e e. Les patients ayant un score R2CHADS2 d’ET dans l’analyse multivarie ve nement plus e leve comparativement à ceux > 2 ont eu un taux d’e ayant un score de 0 ou de 1 (0,5 % vs 7,7 %). Les surfaces sous les ristiques d’efficacite du re cepteur (ROC : receiver courbes caracte operating characteristic) des scores CHA2DS2-VASc et R2CHADS2 pour dire les ET ont respectivement e te de 0,832 et de 0,872. La pre rence entre ces 2 courbes n’a pas suffisamment e te marque e diffe pour être statistiquement significative (P ¼ 0,338). De plus, le score liore la reclassification nette du risque d’acciR2CHADS2 n’a pas ame re bral par rapport au score CHA2DS2-VASc (Net dent vasculaire ce Reclassification Improvement, 0,9 %; P ¼ 0,948). Conclusions : Les scores R2CHADS2 et CHA2DS2-VASc pourraient être s pour pre dire les ET des patients souffrant de FA qui subissent utilise ter. Dans cette cohorte relativement limite e une ablation par cathe cision pre dictive des deux scores a e te ayant subi une ablation, la pre similaire.
components of the CHADS2 score and awards 2 points for renal dysfunction, was proposed to be a powerful scoring scheme in predicting stroke or systemic embolism in AF.8 However, whether the R2CHADS2 score is useful for risk stratification in patients with AF after catheter ablation has not been explored. The goal of the present study was to investigate the association of the R2CHADS2 score and TE events after AF ablation. We also aimed to compare the accuracy of the CHA2DS2-VASc and R2CHADS2 scores in identifying patients at risk of TE events after catheter ablation.
Catheter ablation of AF
Methods A total of 526 patients with symptomatic drug-refractory AF who underwent radiofrequency catheter ablation from 20042009 were enrolled in the study. We excluded those who received long-term oral anticoagulant therapy (OAT) because 1 of our goals was to investigate whether the R2CHADS2 score could be helpful for determining a long-term strategy for oral anticoagulation therapy. It would be more appropriate to study this issue in patients not receiving long-term OAT. The CHA2DS2-VASc score was calculated for every patient based on a point system in which 2 points were assigned for a history of a stroke or transient ischemic attack (TIA) or age 75 years. One point was assigned for age between 65 and 74 years, a history of hypertension, diabetes, recent cardiac failure, vascular disease (myocardial infarction, complex aortic plaque, or peripheral artery disease), and female sex.9 The estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of the Diet in Renal Disease Study equation: eGFR (mL/min/1.73m2) ¼ 186.3 (serum creatinine [mg/ dL])1.154 (age [years])0.203 (0.742 if a woman).10 The R2CHADS2 score was derived by incorporating the components of the CHADS2 score and awarding 2 points for renal dysfunction, defined as an eGFR < 60 mL/min/1.73m2.8
Each patient underwent an electrophysiological study and catheter ablation in the fasting nonsedated state after written informed consent was obtained. The details have been described previously.11,12 In brief, after completing the left atrial geometry, continuous circumferential lesions were created encircling the right and left pulmonary vein (PV) ostia guided by the Ensite NavX system (St. Jude Medical, Austin, TX) using either a conventional 4-mmetip or irrigated-tip catheter. The intention was to place the radiofrequency lesions at least 1-2 cm away from the angiographically defined ostia. Successful circumferential PV isolation was demonstrated by the absence of any PV activity or dissociated PV activity. The need for additional linear ablation was assessed based on AF inducibility.13 If nonparoxysmal AF did not stop after the PV isolation and linear ablation, an additional complex fractionated electrographically guided substrate ablation was performed sequentially, based on the complex fractionated electrographic maps. Complex fractionated electrographic ablation was confined to the continuous complex fractionated electrograms (> 5 seconds) in the left atrium and proximal coronary sinus.14,15 The end point of complex fractionated electrographic site ablation was to obtain a prolongation of cycle length, eliminate complex fractionated electrograms, or abolish local fractionated potentials (bipolar voltage < 0.05 mV). After sinus rhythm was restored from AF by procedural AF termination or electrical cardioversion, we applied mapping and ablation only to spontaneously initiating focal atrial tachycardias and non-PV ectopy that initiated AF. If any nonPV ectopy initiating AF from the superior vena cava was identified, isolation of the superior vena cava was guided by circular catheter recordings from the superior vena cavaeatrial junction.
Chao et al. R2CHADS2 Score and Thromboembolic Events
Definitions of clinical end points and follow-up After receiving catheter ablation, the patients were followed every 1-3 months at our cardiology clinic or by the referring physicians. The strategy for use of OAT after ablation has been described in our previous publication.6 During the follow-up, patients were carefully examined, and 24-hour Holter monitoring or cardiac event recording, or both, were performed for 1 week. AF recurrence was defined as an episode lasting longer than 1 minute 2 months after ablation (blanking period). The clinical end point was the occurrence of TE events (ischemic stroke, TIA, or other systemic embolism). The diagnosis of ischemic stroke/TIA should be confirmed by a neurologist, and imaging studies of the brain, including computed tomographic scans or magnetic resonance images, were obtained for each patient to exclude the presence of intracranial hemorrhage. In the present study, more than 70% of the study population underwent follow-up regularly at the cardiology clinics, and the rest of the patients were completely assessed by telephone consultations. Once patients reported the occurrence of TE events in the telephone consultations, individualized medical records regarding the symptoms, findings of imaging studies, and the final diagnosis of the events were acquired and reviewed to ascertain the cause. Since Taiwan is a small island and more than 99% of the population is covered by the national health insurance program, it was easy for patients to seek medical advice and convenient for doctors to access patients’ medical records. Statistical analysis Differences between continuous values were assessed using an unpaired 2-tailed t test for normally distributed continuous variables, the Mann-Whitney test for skewed variables, and the c2 test for nominal variables. Event rates between groups with different scores were compared by the c2 test for linear trends. The risk of TE events was assessed using the Cox regression analysis. We assessed the predictive accuracy of the CHA2DS2-VASc and R2CHADS2 scores using the receiver operating characteristic (ROC) curve. The areas under the ROC curves of these 2 scoring systems were compared using deLong’s method. In addition, the net reclassification index comparing the R2CHADS2 score with the CHA2DS2-VASc score was calculated. Statistical significance was set at P < 0.05.
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Table 1. Baseline patient characteristics Study population (n ¼ 526)
Variable Age, y Age 65 y Age 75 y Sex (male) Medical history, % Hypertension Diabetes mellitus Congestive heart failure Coronary artery disease Previous stroke/TIA Previous vascular disease Renal dysfunction (eGFR < 60 mL/min/1.73m2) Body mass index, kg/m2 Long-term use of antiplatelet agents Left atrial diameter, mm LVEF, % AF type (paroxysmal AF) Recurrence rate after ablation CHA2DS2-VASc score, median (IQR) R2CHADS2 score, median (IQR)
53.7 12.2 18.1% 3.8% 72.6% 45.4% 12.4% 8.0% 26.8% 4.6% 1.3% 15.2% 25.2 3.5 57.8% 39.2 7.1 58.7 8.0 78.3% 27.8% 1 (0-2) 1 (0-2)
AF, atrial fibrillation; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); eGFR, estimated glomerular filtration rate; IQR, interquartile range; LVEF, left ventricular ejection fraction; R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; TIA, transient ischemic attack.
and other systemic embolism in 1 patient. Among the 9 patients with ischemic stroke, 3 had heart failure, 6 had hypertension, 2 had diabetes mellitus, 2 had previous stroke or TIA, and 5 had an eGFR < 60 mL/min/1.73m2. The significant predictors of TE events based on the univariate Cox regression analysis are shown in Table 2. The CHA2DS2VASc and R2CHADS2 scores remained independent predictors of TE events in the multivariate model (Tables 3 and 4). The association between the R2CHADS2 score and rate of TE events is shown in Fig 1. The TE event rate continuously increased from 0% for patients with a score of 0 to as high as 66.7% for those with a score of 6. At the cutoff value of 2 identified by the ROC curve, patients with a R2CHADS2 score of 2 had a significantly higher event rate compared with those with a score of 0 or 1 (0.5% vs 7.7%; P < 0.001) (Fig 2).
Results Baseline characteristics of study patients
Table 2. Univariate Cox regression analysis for predictors of thromboembolic events after catheter ablation
The baseline characteristics of the study population are shown in Table 1. The mean age of the patients was 53.7 12.2 years, and 72.6% of them were men. The median values (interquartile range) of both the CHA2DS2-VASc and R2CHADS2 scores were 1 (0-2). Hypertension was the most prevalent comorbidity and was noted in 45.4% of patients. The AF recurrence rate after multiple procedures was 27.8%.
Variable
R2CHADS2 scores and the risk of TE events During the mean follow-up of 37.5 21.3 months, there were 14 patients (2.7%) who experienced TE events, including ischemic stroke in 9 patients, TIAs in 4 patients,
AF type (nonparoxysmal) Recurrence after multiple ablations Left atrial diameter (mm) LVEF (%) CHA2DS2-VASc score R2CHADS2 score
Hazard ratio 4.199 4.798 1.069 0.926 2.206 2.376
95% CI
P value
1.462-12.058 0.008 1.608-14.319 0.005 1.028-1.111 0.001 0.879-0.976 0.004 1.646-2.955 < 0.001 1.813-3.116 < 0.001
AF, atrial fibrillation; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); CI, confidence interval; LVEF, left ventricular ejection fraction; R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
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Table 3. Multivariate Cox regression analysis for predictors of thromboembolic events after catheter ablation using the CHA2DS2VASc score Variable AF type (nonparoxysmal) Recurrence after multiple ablations Left atrial diameter (mm) LVEF (%) CHA2DS2-VASc score
Hazard ratio
95% CI
P value
2.590 2.272 0.995 0.981 1.963
0.758-8.848 0.683-7.558 0.948-1.045 0.926-1.038 1.415-2.724
0.129 0.181 0.845 0.504 < 0.001
Variables with P < 0.05 in Table 2 were adjusted with the CHA2DS2VASc score in the multivariate Cox regression analysis. AF, atrial fibrillation; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); CI, confidence interval; LVEF, left ventricular ejection fraction.
Comparisons between CHA2DS2-VASc and R2CHADS2 scores The area under the ROC curve of the CHA2DS2-VASc and R2CHADS2 scores in predicting TE events were 0.832 (95% confidence interval [CI], 0.730-0.934; P < 0.001) and 0.872 (95% CI, 0.792-0.951; P < 0.001), respectively. Although the area under the ROC curve of the R2CHADS2 score was slightly higher than that of the CHA2DS2-VASc score, the difference between these 2 curves (0.04) did not reach statistical significance (P ¼ 0.338) (Fig 3). In addition, the R2CHADS2 score did not improve net stroke risk reclassification over the CHA2DS2-VASc score (net reclassification improvement, 0.9%; 95% CI, 29.2%-27.3%; P ¼ 0.948). Discussion Main findings In this study, we investigated the association between the R2CHADS2 score and the risk of TE events after AF ablation. We also compared the accuracy of the R2CHADS2 and the CHA2DS2-VASc scores in predicting TE events after catheter ablation. The main findings were as follows: (1) The R2CHADS2 score could be used to predict TE events in patients with AF receiving catheter ablations and (2) The R2CHADS2 and CHA2DS2-VASc scores were equally accurate in predicting TE events after AF ablations assessed by ROC curves and the net reclassification index in this relatively small cohort. Table 4. Multivariate Cox regression analysis for predictors of thromboembolic events after catheter ablation using the R2CHADS2 score Variable AF type (nonparoxysmal) Recurrence after multiple ablations Left atrial diameter (mm) LVEF (%) R2CHADS2 score
Hazard ratio
95% CI
P value
2.414 2.827 0.989 0.967 2.414
0.677-8.604 0.845-9.457 0.939-1.042 0.914-1.022 1.756-3.318
0.174 0.092 0.676 0.234 < 0.001
Variables with P < 0.05 in Table 2 were adjusted with the R2CHADS2 score in the multivariate Cox regression analysis. AF, atrial fibrillation; CI, confidence interval; LVEF, left ventricular ejection fraction; R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
R2CHADS2, CHA2DS2-VASc scores and adverse events in patients with AF How to identify patients with AF at risk of TE events who should receive long-term OAT is an important issue. The CHA2DS2-VASc score, which extends the CHADS2 scheme by considering additional stroke risk factors (vascular diseases and female sex), was recommended by the European Society of Cardiology (ESC) to guide antithrombotic therapy for patients with AF.16 The usefulness of the CHA2DS2VASc score in predicting AF-related TE events has been validated in several subsequent studies.17-19 The CHA2DS2VASc score is particularly useful and valuable in identifying “truly low-risk” patients.20 In a nationwide cohort study from Denmark, Olesen et al. demonstrated that for patients categorized as “low risk,” using a CHADS2 score ¼ 0, the CHA2DS2-VASc score significantly improved the predictive value of the CHADS2 score alone and a CHA2DS2-VASc score ¼ 0 could clearly identify truly low-risk patients.21 However, the best scoring scheme for the prediction of TE events for patients with AF is still an open issue and drawing much attention. Piccini et al. demonstrated that renal dysfunction was an important risk factor for stroke and systemic embolism in patients with AF enrolled 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) trial,8,22 and the R2CHADS2 scoring system was derived accordingly.8 In addition, the authors of the previous study showed that the R2CHADS2 score could improve the net reclassification index by 6.2% compared with the CHA2DS2-VASc score and by 8.2% compared with the CHADS2 score. In contrast, Roldán et al. investigated a similar issue in 978 patients with AF from an outpatient anticoagulation clinic and concluded that although renal dysfunction would confer a poor overall prognosis, adding it to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.23 The diverse results of these previous studies may be partly explained by the essential differences between the “trial cohorts” and “real world,” and may imply that whether renal dysfunction could improve the accuracy of current scoring systems in predicting clinical outcomes for patients with AF remained uncertain. It should also be emphasized that the R2CHADS2 score was derived from the ROCKET-AF cohort,22 and therefore several limitations of such a derivation were present.24 First, ROCKET-AF was an anticoagulation trial, and to test the added value of a risk factor should ideally be made in a cohort not receiving anticoagulation. Second, the ROCKET-AF trial excluded patients with severe renal dysfunction. To test the value of adding renal impairment to the CHADS2 score, we should see the broad range of renal function in the study population. Third, the ROCKET-AF trial focused only on high-risk patients with a CHADS2 score 2. To test the improvement of adding a risk factor to the present scoring systems, we need to test in a broad range of patients with AF. Based on the limitations mentioned, the anticoagulated ROCKET AF cohort may not be representative of the general AF population in clinical practice.
Chao et al. R2CHADS2 Score and Thromboembolic Events
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Figure 1. R2CHADS2 score and event rates. The thromboembolic event rate continuously increased when the scores became higher. R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
Validation of the R2CHADS2 score in patients with AF receiving catheter ablation In the present study, we validated the usefulness of the R2CHADS2 score for risk stratification in patients with AF receiving catheter ablation and compared its accuracy with the CHA2DS2-VASc score. Several previous studies have
demonstrated that patients who received catheter ablation had a better prognosis than those who did not undergo ablation procedures.3-5,25 Bunch et al. compared the long-term risk of death, dementia, and stroke in patients with AF treated with catheter ablation and patients with AF who did not receive ablation and non-AF patients.25 They found that patients with AF receiving ablation had a significantly lower risk of
Figure 2. Event-free survival curve for patients with different R2CHADS2 scores. A Kaplan-Meier survival analysis showed that an R2CHADS2 score of > 2 was associated with a higher event rate than a score of 0 or 1 (0.5% vs 7.7%, P < 0.001). R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
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schemes.26 Nevertheless, the CHA2DS2-VASc score can differentiate TE risk in the low-risk strata based on the R2CHADS2 score and may be superior in the subgroup with AF recurrence.26 Unlike this previous study, we included only patients not receiving OAT. Because the goals for developing scoring systems was to guide the use of oral anticoagulants, it may be better to validate the usefulness of these schemes in a cohort not receiving anticoagulation. However, the sample size of our study was smaller than that of the Leipzig Heart Center AF Ablation Registry, and therefore we were not able to perform further analysis for patients with a low R2CHADS2 score or specifically for those with AF recurrence. Clinical implications
Figure 3. Receiver operating characteristic (ROC) curves for the CHA2DS2-VASc and R2CHADS2 scores for predicting events. The areas under the ROC curves did not differ significantly between the CHA2DS2-VASc and R2CHADS2 scores for predicting thromboembolic events (difference between areas ¼ 0.04; P ¼ 0.338). CHA2DS2VASc, Congestive Heart Failure, Hypertension, Age ( 75 y), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 y), Sex (Female); R2CHADS2, Renal Dysfunction, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack.
adverse events in comparison with patients with AF not receiving ablation, despite the fact that 35.6% of patients with AF receiving ablation experienced AF recurrence. In a more recent study, the same group further showed that the stroke risk reduction conferred by catheter ablation was consistent across all CHADS2 profiles and ages.5 Similarly, we also demonstrated that there was a potential increased survival rate in patients with AF with rhythm control achieved by an ablation strategy, irrespective of the state of recurrence.4 The results of these observational studies may suggest that catheter ablation can modify the risk of adverse events presented by AF and may therefore change its natural course. Therefore, the scoring system in predicting adverse events that was derived from patients with AF who did not undergo ablation should be further validated to confirm its usefulness in those who received catheter ablation. The results of the present study suggested that the R2CHADS2 score could be used to predict TE events after AF ablation. Compared with the CHA2DS2-VASc score, which has already been validated in patients undergoing AF ablation,6 the area under the ROC curve was not statistically different between the R2CHADS2 and CHA2DS2-VASc scores. In addition, these 2 scoring systems did not differ from each other regarding the predictive accuracy assessed by the net reclassification index. In a recent study that analyzed the accuracy of the R2CHADS2 and CHA2DS2-VASc scores in predicting TE events using the Leipzig Heart Center AF Ablation Registry, Kornej et al. also found that the area under the ROC curve was similar between these 2 scoring
Similar to the CHA2DS2-VASc score, the R2CHADS2 score could predict the occurrence of TE events among patients with AF receiving catheter ablation. However, renal impairment is an important factor associated with the occurrence of bleeding events,27 even for those with mild kidney disease.28 In the study performed by Manzano-Fernández et al., patients with AF with mild renal dysfunction (eGFR ¼ 60-89 mL/min/1.73m2) receiving antithrombotic treatment had a more than 2-fold higher risk of major bleeding compared with patients with normal renal function.28 Therefore, adding renal dysfunction, a significant risk factor for bleeding, to a scoring scheme that aims to estimate the risk of TE events and guide antithrombotic therapy may be inappropriate. Because the results of the present study did not show significant differences between the R2CHADS2 and the CHA2DS2-VASc scores regarding their accuracy in predicting TE events after AF ablation, the CHA2DS2-VASc score is a preferred scoring system for risk stratification because it has been validated in a broad range of patients with AF. Study limitations There were several limitations of the present study. First, there were only 14 patients with TE events during the followup period. Therefore, there may be concern about the overfitness of the multivariate Cox regression model used to evaluate the usefulness of the R2CHADS2 score in predicting TE events. However, the problem of a small number of events in the regression model should be a type 2 error,29 which is not the case in this study. Second, although the diagnoses of 9 patients with ischemic strokes and 4 patients with TIAs were all confirmed by neurologists and imaging studies of the brain, it was still possible that these ischemic events were caused by thrombosis of the cerebral artery rather than AF-related thromboembolism. In addition, the telephone interviews may have missed some stroke events. Third, although the predictive accuracy of the R2CHADS2 and CHA2DS2-VASc scores was similar when assessed by ROC curves and the net reclassification index, we cannot exclude the possibility that the number of events was too small to demonstrate statistically significant differences. Finally, R2CHADS2 and CHA2DS2VASc scores may change over time, and thus the baseline values may not be appropriately representative of the risk of TE events during the follow-up period. However, it is a common limitation that was frequently present in previous studies. The relationship between the “dynamic” changes of
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risk scores and TE events has not been well investigated before, and it is an important issue that deserves more investigation. Based on the limitations mentioned, the results of the present study with its small sample size should be interpreted carefully. A further large-scale prospective trial is necessary to confirm the findings presented here.
10. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70.
Conclusions In summary, the R2CHADS2 and CHA2DS2-VASc scores could be used to predict TE events for patients with AF receiving catheter ablation. The predictive accuracy of both scores was similar in this relatively small cohort undergoing ablation.
12. Chao TF, Tsao HM, Lin YJ, et al. Clinical outcome of catheter ablation in patients with nonparoxysmal atrial fibrillation: results of 3-year followup. Circ Arrhythm Electrophysiol 2012;5:514-20.
Funding Sources This work was supported in part by grants from the National Science Council (NSC98-2410-H-010-003-MY2), and Taipei Veterans General Hospital (V99C1-140, V99A-153, V100D-002-3, and V101D-001-2). Disclosures The authors have no conflicts of interest to disclose. References 1. Potpara TS, Lip GY. Lone atrial fibrillation: what is known and what is to come. Int J Clin Pract 2011;65:446-57.
11. Chao TF, Ambrose K, Tsao HM, et al. Relationship between the CHADS(2) score and risk of very late recurrences after catheter ablation of paroxysmal atrial fibrillation. Heart Rhythm 2012;9:1185-91.
13. Chang SL, Tai CT, Lin YJ, et al. The efficacy of inducibility and circumferential ablation with pulmonary vein isolation in patients with paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2007;18: 607-11. 14. Lin YJ, Tai CT, Kao T, et al. Consistency of complex fractionated atrial electrograms during atrial fibrillation. Heart Rhythm 2008;5:406-12. 15. Lin YJ, Tai CT, Chang SL, et al. Efficacy of additional ablation of complex fractionated atrial electrograms for catheter ablation of nonparoxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2009;20: 607-15. 16. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31: 2369-429. 17. 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.
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8. Piccini JP, Stevens SR, Chang Y, et al. 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;127:224-32.
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26. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of TE events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013;6: 868-74.
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