- Email: [email protected]
Anticoagulation, CHA2DS2VASc Score, and Thromboembolic Risk of Cardioversion of Acute Atrial Fibrillation (from the FinCV Study)
Anticoagulation, CHA2DS2VASc Score, and Thromboembolic Risk of Cardioversion of Acute Atrial Fibrillation (from the FinCV Study) Toni Grönberg, BMa, Juha E.K. Hartikainen, MD, PhDb, Ilpo Nuotio, MD, PhDc, Fausto Biancari, MD, PhDd, Antti Ylitalo, MD, PhDe,f, and K.E. Juhani Airaksinen, MD, PhDe,* The efficacy of the anticoagulation in preventing thromboembolic complications (TEC) and the usefulness of the CHA2DS2VASc score for assessing stroke risk during cardioversion of acute atrial fibrillation (AF) are unclear. Thus, our objectives were to assess the ability of the CHA2DS2VASc score to predict TEC and to evaluate the efficacy of anticoagulation in the prevention of TEC in Finnish CardioVersion (FinCV) study. The FinCV is a retrospective, multicenter study of 3,143 patients, who underwent 7,660 cardioversions for acute AF. The value of the CHA2DS2VASc score in predicting TEC was analyzed separately in cardioversions performed without and with anticoagulation. A total of 40 definite TEC (0.6%) occurred after 7,237 successful cardioversions and 1 stroke (0.2%) after 423 unsuccessful procedures. In 5,362 cardioversions performed without anticoagulation, the risk of definite TEC increased significantly from 0.4% in patients with a CHA2DS2VASc score of 0 to 1 to 2.3% in those with score of ‡5 (p <0.001 for trend). The C-statistic of the CHA2DS2VASc score was 0.72 (0.61 to 0.83) in predicting definite TEC in non-anticoagulated patients with first cardioversion. The incidence of definite TEC was significantly lower in 2,298 cardioversions performed during anticoagulation (0.1% vs 0.7%, p [ 0.001), and the preventive effect of anticoagulation was significant in patients with a score of ‡2 (0.2% vs 1.1%, p [ 0.001). In conclusion, CHA2DS2VASc score is a strong predictor of TEC in cardioversion of acute AF performed without anticoagulation. Importantly, periprocedural anticoagulation reduced the risk of TEC by 82%. The overall risk of these complications was low after failed cardioversion. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;-:-e-) The CHA2DS2VASc score is the risk stratification scheme in everyday clinical practice to assess the need of anticoagulation in patients with atrial fibrillation (AF),1 but its value in predicting adverse events in patients who underwent cardioversion of acute AF has not been assessed. Anticoagulation therapy is recommended for patients with acute (duration 48 hours) AF and high risk for stroke with no specific CHA2DS2VASc score limits,2,3 but there is limited research data on the efficacy of anticoagulation in this acute setting. Our previous analysis of the Finnish CardioVersion (FinCV) study confirmed the high risk of stroke when cardioversion was performed without adequate periprocedural anticoagulation in patients with conventional a University of Turku, Turku, Finland; bHeart Center, Kuopio University Hospital, Kuopio, Finland; cDivision of Medicine, Department of Acute Internal Medicine, Turku University Hospital, Turku, Finland; dDepartment of Surgery, Oulu University Hospital, Oulu, Finland; eHeart Center, University of Turku and Turku University Hospital, Turku; and fSatakunta Central Hospital, Pori, Finland. Manuscript received November 23, 2015; revised manuscript received and accepted January 19, 2016. This study was funded by The Finnish Foundation for Cardiovascular Research, Helsinki, Finland, and Clinical Research Fund (EVO) of Turku University Hospital, Turku, Finland. See page 4 for disclosure information. *Corresponding author: Tel: (þ358) 2 3131005; fax: (þ358) 2 3138651. E-mail address: juhani.airaksinen@tyks.fi (K.E.J. Airaksinen).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.01.024
stroke risk factors.4 In the present analysis, we sought to determine whether the CHA2DS2VASc score is useful to predict the risk of thromboembolic complications (TEC) after cardioversion of acute AF and whether anticoagulation prevents TEC in high- and low-risk patients. Third, we evaluated whether the CHA2DS2VASc score predicts failure of cardioversion, early recurrence of AF, and bradyarrhythmic complications. Methods The FinCV study (ClinicalTrials.gov identifier: NCT01380574) is a multicenter retrospective study including patients who underwent cardioversion for acute AF. The study is a part of wider protocol in progress to assess acute cardiac procedures in Western Finland.5e7 Study protocol was approved by the Ethics Committees of the Hospital District of Southwest Finland and the National Institutes for Health and Welfare. Patients with a diagnosis of AF at 2 university hospitals from 2003 to 2010 and at 1 central hospital in 2010 were identified from institutional discharge registers by the International Classification of Diseases, Tenth Revision, code I48.0. The emergency clinic admission records were reviewed to include all patients with acute AF who underwent cardioversion within 48 hours from symptom onset during the study period. All patient records were reviewed with a standardized data collection protocol, and only patients >18 years and living in the www.ajconline.org
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Table 1 Baseline characteristics of 7660 cardioversions according to the CHA2DS2VASc score CHA2DS2VASc score
Characteristic
Age (years) Women Heart failure Hypertension Diabetes mellitus Vascular disease Previous thromboembolism Implanted pacemaker First episode of atrial fibrillation Electrical cardioversion Duration of symptoms < 12 hours Ventricular rate of atrial fibrillation (bmp) Anticoagulation therapy Beta-blockers Class I antiarrhythmic drugs Class III antiarrhythmic drugs
P value
0-1 (n¼3362)
2 (n¼1610)
3-4 (n¼1997)
5-9 (n ¼ 691)
54.3 10.3 416 (12.4%) 33 (1.0%) 762 (22.7%) 24 (0.7%) 250 (7.4%) 0 102 (3.0%) 794 (23.6%) 2997 (89.1%) 1520 (45.2%) 108.5 26.9 590 (17.5%) 2293 (68.2%) 885 (26.3%) 130 (3.9%)
63.4 10.8 690 (42.9%) 54 (3.4%) 913 (56.7%) 124 (7.7%) 468 (29.1%) 36 (2.2%) 101 (6.3%) 315 (19.6%) 1445 (89.8%) 785 (48.8%) 109.6 25.1 516 (32.0%) 1327 (82.4%) 372 (23.1%) 73 (4.5%)
70.0 8.5 1174 (58.8%) 179 (9.0%) 1438 (72.0%) 361 (18.1%) 974 (48.8%) 241 (12.1%) 105 (5.3%) 445 (22.3%) 1826 (91.4%) 904 (45.3%) 111.1 33.4 852 (42.7%) 1688 (84.5%) 343 (17.2%) 77 (3.9%)
74.8 6.7 518 (75.0%) 137 (19.8%) 610 (88.3%) 233 (33.7%) 523 (75.7%) 419 (60.6%) 83 (12.0%) 141 (20.4%) 638 (92.3%) 334 (48.3%) 114.5 24.4 340 (49.2%) 601 (87.0%) 89 (12.9%) 45 (6.5%)
< < < < < < < <
< < < <
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.01 0.01 0.06 0.001 0.001 0.001 0.001 0.01
Values are mean SD or n (%).
hospital catchment area were included to ensure adequate follow-up data of 30 days after the cardioversion.4 The study hospitals are the only referral hospital responsible for acute care of patients with cardiac and stroke events in their catchment areas. Cardioversions were performed according to contemporary guidelines as previously described.8 Electrical cardioversions (90%) were performed under general anesthesia, and majority of pharmacologic cardioversions were performed using flecainide. In anticoagulated patients, cardioversions were performed during long-term warfarin treatment (98%) or under cover of heparins. We identified 3,143 patients who underwent 7,660 cardioversions for acute AF. Cardioversions were divided into 4 groups according to the CHA2DS2VASc score of the patients: score 1, 2, 3 to 4, and 5. The risk of TEC in patients with and without anticoagulation was compared in these 4 groups. The independent predictors of TEC were sought, and the value of CHA2DS2VASc score and the CHADS2 score in predicting TEC was evaluated. Finally, we evaluated whether CHA2DS2VASc score predicts failure of cardioversion, recurrence of AF after successful cardioversion, and bradyarrhythmic complications. The primary end point of the study was TEC, which was defined as stroke or systemic embolism confirmed by imaging (magnetic resonance imaging or computerized tomography), surgery, or autopsy. Transient ischemic attack (TIA) was classified as probable TEC.4 Secondary end points were unsuccessful cardioversion, early recurrence of AF episode after successful cardioversion, and bradyarrhythmic complications after cardioversion. Cardioversion was defined as successful if sinus rhythm was obtained and patient was discharged in sinus rhythm. Early recurrence was assessed from patient records during the 30-day follow-up period. Bradyarrhythmia was defined as heart rate <40 beats/min and/or asystole >5 seconds immediately after the cardioversion.8 Continuous variables are presented as means and SD or medians and interquartile range as appropriate and analyzed with the Student’s t test, Mann-Whitney U test, and
Kruskal-Wallis test. Categorical variables are expressed as absolute numbers and percentages and analyzed with the chi-square test, Fisher’s exact test, and Cochran-Armitage test for trend. Multivariable logistic regression analysis with repeated measure option with covariates chosen according to our earlier reports was used in the evaluation of primary and secondary end points.4,8e10 Because the same patient could have repeated cardioversions during study period, only the first cardioversion of a patient was included in the receiver-operating characteristic (ROC) area under the curve analyses of CHA2DS2VASc and CHADS2 scores. The method of DeLong was used to calculate the difference between these area under the curves of ROC curves.11 A 2sided p value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows 22.0 software (IBM Corp., Armonk, NY) and SAS software, version 9.3 (SAS Institute Inc., Cary, NC). Results At the time of cardioversion, the mean age of patients was 62.2 12.3 years, 2,798 (36.5%) were women, and the median CHA2DS2VASc score was 2 (interquartile range 1 to 3). The baseline characteristics of patients according to their CHA2DS2VASc scores are presented in Table 1. The overall success rate of cardioversions was 94.5% (7,237 of 7,660), and 5,362 (70.0%) cardioversions were performed without anticoagulation. A total of 41 (0.5%) definite TEC occurred within 30 days after the cardioversion with a median delay of 2 days (range 1 to 27 days). Forty (0.6%) definite TEC occurred after 7,237 successful procedures, and patients were on anticoagulation therapy only during 2 of these cardioversions. The INR values of patients on oral anticoagulation ranged from 2.9 to 3.5 at the time of cardioversion and the thromboembolic event occurred at 2 and 23 days after cardioversion. A total of 423 cardioversions (5.5%) failed and 1 patient (0.2%) treated with
Arrhythmias and Conduction/CHA2DS2VASc Score and Cardioversion of AF
Figure 1. The incidence of definite thromboembolic complications after cardioversion of acute atrial fibrillation according to the CHA2DS2VASc score and use of anticoagulation. p Values calculated using CochranArmitage test for trend.
3
gender (OR 2.11; 95% CI 1.04 to 4.28, p ¼ 0.038) were independent predictors of definite TEC in cardioversions performed without anticoagulation. In addition to definite TEC, 6 TIA episodes (0.1%) occurred within 30 days after cardioversion, 5 after successful cardioversion and 4 in patients without anticoagulation. The median CHA2DS2VASc score was 2.5 in patients without anticoagulation. Two patients with anticoagulation had CHA2DS2VASc scores of 4 and 5. The failure rate of cardioversion, the rate of early recurrence of AF after successful cardioversion, and incidence of bradyarrhythmic complications increased with higher CHA2DS2VASc scores (Figure 2). The CHA2DS2VASc score was an independent predictor of unsuccessful cardioversion (OR 1.09; 95% CI 1.03 to 1.16, p ¼ 0.006), recurrence of AF after successful cardioversion (OR 1.17; 95% CI 1.12 to 1.22, p <0.001), and bradyarrhythmic complications (OR 1.44; 95% CI 1.27 to 1.62, p <0.001). Discussion
Figure 2. The incidence of secondary end points according to the CHA2DS2VASC score. Secondary end points of the study were unsuccessful cardioversion, early recurrence of atrial fibrillation episode after successful cardioversion, and bradyarrhythmic complications after cardioversion. p values calculated using the Cochran-Armitage test for trend.
periprocedural heparin had a stroke 2 days after failed cardioversion. This patient underwent spontaneous conversion to sinus rhythm before the stroke. The incidence of definite TEC after cardioversion was significantly lower in the anticoagulated patients (0.1% [3 of 2,298] vs 0.7% [38 of 5,362], p ¼ 0.001). There was a significant increase in the incidence of definite TEC with higher CHA2DS2VASc scores in cardioversions performed without anticoagulation (p <0.001 for trend; Figure 1). In patients with a CHA2DS2VASc score of 2, the rate of definite TEC was significantly lower after cardioversion performed with anticoagulation (0.2% [3 of 1,708] vs 1.1% [28 of 2,590], p ¼ 0.001), but the benefit of anticoagulation did not reach statistical significance in patients with a CHA2DS2VASc score of 0 to 1 (0.0% [0 of 590] vs 0.4% [10 of 2,772], p ¼ 0.23). In nonanticoagulated patients with the first cardioversion during the study period, the C-statistics were 0.72 (95% confidence interval [CI] 0.61 to 0.83, p <0.001) for CHA2DS2VASc score and 0.66 (95% CI 0.55 to 0.78, p ¼ 0.006) for CHADS2 score in predicting definite TEC, and CHA2DS2VASc score was a better (p ¼ 0.003) predictor of the risk of definite TEC than CHADS2 score. Multivariable analysis showed that age (per year) (odds ratio [OR] 1.05; 95% CI 1.02 to 1.09, p <0.001), duration of AF episode >12 hours (OR 3.89; 95% CI 1.76 to 8.60, p ¼ 0.001), heart failure (OR 3.37; 95% CI 1.39 to 8.19, p ¼ 0.007), diabetes mellitus (OR 2.66; 95% CI 1.25 to 5.69, p ¼ 0.012), and female
The main finding of our study was that the CHA2DS2VASc score was a significant predictor of TEC in cardioversion of acute AF performed without anticoagulation. More importantly, adequate periprocedural anticoagulation reduced the risk of TEC by 82%. In addition, the overall risk of these complications was low after failed cardioversion. In our study, the CHA2DS2VASc score was a significant predictor of embolic complications and the increase of thromboembolic risk with increasing CHA2DS2VASc score was as steep as in predicting the long-term risk. Moreover, the predictive value of the CHA2DS2VASc score was as good as in the original validation study of the CHA2DS2VASc score published in 2010 (C-statistics 0.72 [95% CI 0.61 to 0.83] vs 0.61 [95% CI 0.51 to 0.70]).12 Of the score components, age, heart failure, diabetes, and female gender were independent predictors of embolic events. One explanation might be that these risk factors reflect better the high embolic risk after cardioversion, whereas hypertension and vascular disease may reflect more atherothrombotic etiology of stroke. As expected, the CHA2DS2VASc score fared better than the CHADS2 score in predicting TEC. This difference was mostly driven by female gender.4 Historically, the risk of TEC has been reported to be w5% in non-anticoagulated patients after elective cardioversion.13,14 Using periprocedural anticoagulation therapy, the risk has decreased to 0.5% to 1.6% during the first 30 days after cardioversion.15e18 We observed that the risk of TEC was comparable (0.7%) in patients with acute AF who underwent cardioversion without periprocedural anticoagulation. In contrast, the mean monthly thromboembolic risk in AF is w0.3% depending on stroke risk factors, and vitamin K antagonists reduce this risk by w64%.19 Recently published large randomized multicenter studies confirm these findings showing that the thromboembolic risk during long-term anticoagulation has decreased to 0.1% to 0.2% per month.20e22 In the FinCV study, the risk of TEC was only 0.1% in the acute cardioversions performed during anticoagulation treatment compared with the risk of 0.5% to 1.6% after elective cardioversion during therapeutic anticoagulation.15e18 These findings support the view that
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unnecessary delays in cardioversions of rhythm control strategy may increase the risk of TEC in spite of therapeutic oral anticoagulation, whereas cardioversion in the acute phase of AF does not increase the risk of TEC in anticoagulated patients. The overall incidence of TEC was low after failed cardioversion, which suggests that it is the conversion to sinus rhythm that results in elevated risk of TEC. This is supported by the finding that spontaneous conversion to sinus rhythm after failed cardioversion resulted in 1 stroke and 1 TIA in our study. Spontaneous conversion to sinus rhythm23,24 is not uncommon after failed cardioversion, and these patients are at increased risk of stroke if adequate anticoagulation is not used.25 Current guidelines recommend intravenous heparin or lowemolecular weight heparin or administration of factor Xa or direct thrombin inhibitor before or immediately after cardioversion of acute AF in patients with high stroke risk. For low-risk patients, these treatment strategies may be considered.3 In our study, the cardioversion was not without risk in non-anticoagulated patients with a CHA2DS2VASc score of 1, although only patients with a higher CHA2DS2VASc score derived statistically significant benefit from anticoagulation therapy. Importantly, if the delay from the symptoms to cardioversion was >12 hours the risk for thromboembolism varied from 0.4% to 0.9% if no anticoagulation was used.9 Anticoagulation therapy exposes patients to bleedings, but the rate of major bleeding events has been reported to vary from only 0.2% to 0.3% per month during long-term treatment with warfarin or novel oral anticoagulants.20e22 Furthermore, it is clear that the risk of major bleedings is even lower in these low-risk patients.26 Consequently, short-term anticoagulation should be considered also for patients with a low CHA2DS2VASc score especially if the delay to cardioversion is >12 hours. It is not surprising that patients with the highest CHA2DS2VASc score were in the highest risk for other adverse events. Almost 1/3 of these patients had failed cardioversion, bradyarrhythmic complications, or an early recurrence of AF (Figure 2). Therefore, the high CHA2DS2VASc score challenges the rationality of rhythm control strategy in these patients. Although our study is the largest study focusing on cardioversion of acute AF, it is limited by its retrospective nature. We are also dependent on reported co-morbidities of patients, treatments, and outcomes by treating physicians. The study might underestimate the number of minor events, which were not deemed clinically significant. All these limitations must be weighed against that large retrospective study avoids selection bias and may, thus, reflect real life more accurately. Acknowledgment: The authors are grateful to study coordinator Tuija Vasankari, RN, for her input in data and study management. Acknowledgments of clinical investigators for the collection of the data by center: Turku University Hospital, Turku: I. Nuotio, T. Grönberg, A. Karmi; Satakunta Central Hospital, Pori: M. Ampio, K. Ruuhijärvi, A. Ylitalo; Kuopio University Hospital, Kuopio:
M. Nikkinen, P. Autere, E. Parikka, T. Rautiainen, S. Rissanen, M-L. Sutinen, and M. Tuhkalainen. Disclosures The authors have no conflicts of interest to disclose. 1. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice GuidelinesCPG; Document Reviewers. 2012 Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation—developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14:1385e1413. 2. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. 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;31:2369e2429. 3. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1ee76. 4. Airaksinen KE, Gronberg T, Nuotio I, Nikkinen M, Ylitalo A, Biancari F, Hartikainen JE. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013;62:1187e1192. 5. Korkeila P, Mustonen P, Koistinen J, Nyman K, Ylitalo A, Karjalainen P, Lund J, Airaksinen J. Clinical and laboratory risk factors of thrombotic complications after pacemaker implantation: a prospective study. Europace 2010;12:817e824. 6. Airaksinen KE, Biancari F, Karjalainen P, Mikkola R, Kuttila K, Porela P, Laitio T, Lip GY. Safety of coronary artery bypass surgery during therapeutic oral anticoagulation. Thromb Res 2011;128:435e439. 7. Airaksinen KE, Korkeila P, Lund J, Ylitalo A, Karjalainen P, Virtanen V, Raatikainen P, Koivisto UM, Koistinen J. Safety of pacemaker and implantable cardioverter-defibrillator implantation during uninterrupted warfarin treatment—the FinPAC study. Int J Cardiol 2013;168: 3679e3682. 8. Gronberg T, Nuotio I, Nikkinen M, Ylitalo A, Vasankari T, Hartikainen JE, Airaksinen KE. Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: the FinCV study. Europace 2013;15: 1432e1435. 9. Nuotio I, Hartikainen JE, Gronberg T, Biancari F, Airaksinen KE. Time to cardioversion for acute atrial fibrillation and thromboembolic complications. JAMA 2014;312:647e649. 10. Gronberg T, Hartikainen JE, Nuotio I, Biancari F, Vasankari T, Nikkinen M, Ylitalo A, Airaksinen KE. Can we predict the failure of electrical cardioversion of acute atrial fibrillation? The FinCV study. Pacing Clin Electrophysiol 2015;38:368e375. 11. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837e845. 12. 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;137:263e272. 13. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969;23:208e216. 14. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992;19: 851e855.
Arrhythmias and Conduction/CHA2DS2VASc Score and Cardioversion of AF 15. Apostolakis S, Haeusler KG, Oeff M, Treszl A, Andresen D, Borggrefe M, Lip GY, Meinertz T, Parade U, Samol A, Steinbeck G, Wegscheider K, Breithardt G, Kirchhof P. Low stroke risk after elective cardioversion of atrial fibrillation: an analysis of the Flec-SL trial. Int J Cardiol 2013;168:3977e3981. 16. Gallagher MM, Hennessy BJ, Edvardsson N, Hart CM, Shannon MS, Obel OA, Al-Saady NM, Camm AJ. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002;40:926e933. 17. Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH, Flaker G, Brugada J, Kamensky G, Parekh A, Reilly PA, Yusuf S, Connolly SJ. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011;123:131e136. 18. Stellbrink C, Nixdorff U, Hofmann T, Lehmacher W, Daniel WG, Hanrath P, Geller C, Mugge A, Sehnert W, Schmidt-Lucke C, SchmidtLucke JA; ACE (Anticoagulation in Cardioversion using Enoxaparin) Study Group. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004;109:997e1003. 19. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857e867. 20. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD,
21.
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23. 24. 25.
26.
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Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139e1151. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883e891. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981e992. Lindberg S, Hansen S, Nielsen T. Spontaneous conversion of first onset atrial fibrillation. Intern Med J 2012;42:1195e1199. Danias PG, Caulfield TA, Weigner MJ, Silverman DI, Manning WJ. Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm. J Am Coll Cardiol 1998;31:588e592. Weigner MJ, Caulfield TA, Danias PG, Silverman DI, Manning WJ. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med 1997;126:615e620. Marcucci M, Lip GY, Nieuwlaat R, Pisters R, Crijns HJ, Iorio A. Stroke and bleeding risk co-distribution in real-world patients with atrial fibrillation: the Euro Heart Survey. Am J Med 2014;127: 979e986.e2.
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.01.024
stroke risk factors.4 In the present analysis, we sought to determine whether the CHA2DS2VASc score is useful to predict the risk of thromboembolic complications (TEC) after cardioversion of acute AF and whether anticoagulation prevents TEC in high- and low-risk patients. Third, we evaluated whether the CHA2DS2VASc score predicts failure of cardioversion, early recurrence of AF, and bradyarrhythmic complications. Methods The FinCV study (ClinicalTrials.gov identifier: NCT01380574) is a multicenter retrospective study including patients who underwent cardioversion for acute AF. The study is a part of wider protocol in progress to assess acute cardiac procedures in Western Finland.5e7 Study protocol was approved by the Ethics Committees of the Hospital District of Southwest Finland and the National Institutes for Health and Welfare. Patients with a diagnosis of AF at 2 university hospitals from 2003 to 2010 and at 1 central hospital in 2010 were identified from institutional discharge registers by the International Classification of Diseases, Tenth Revision, code I48.0. The emergency clinic admission records were reviewed to include all patients with acute AF who underwent cardioversion within 48 hours from symptom onset during the study period. All patient records were reviewed with a standardized data collection protocol, and only patients >18 years and living in the www.ajconline.org
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The American Journal of Cardiology (www.ajconline.org)
Table 1 Baseline characteristics of 7660 cardioversions according to the CHA2DS2VASc score CHA2DS2VASc score
Characteristic
Age (years) Women Heart failure Hypertension Diabetes mellitus Vascular disease Previous thromboembolism Implanted pacemaker First episode of atrial fibrillation Electrical cardioversion Duration of symptoms < 12 hours Ventricular rate of atrial fibrillation (bmp) Anticoagulation therapy Beta-blockers Class I antiarrhythmic drugs Class III antiarrhythmic drugs
P value
0-1 (n¼3362)
2 (n¼1610)
3-4 (n¼1997)
5-9 (n ¼ 691)
54.3 10.3 416 (12.4%) 33 (1.0%) 762 (22.7%) 24 (0.7%) 250 (7.4%) 0 102 (3.0%) 794 (23.6%) 2997 (89.1%) 1520 (45.2%) 108.5 26.9 590 (17.5%) 2293 (68.2%) 885 (26.3%) 130 (3.9%)
63.4 10.8 690 (42.9%) 54 (3.4%) 913 (56.7%) 124 (7.7%) 468 (29.1%) 36 (2.2%) 101 (6.3%) 315 (19.6%) 1445 (89.8%) 785 (48.8%) 109.6 25.1 516 (32.0%) 1327 (82.4%) 372 (23.1%) 73 (4.5%)
70.0 8.5 1174 (58.8%) 179 (9.0%) 1438 (72.0%) 361 (18.1%) 974 (48.8%) 241 (12.1%) 105 (5.3%) 445 (22.3%) 1826 (91.4%) 904 (45.3%) 111.1 33.4 852 (42.7%) 1688 (84.5%) 343 (17.2%) 77 (3.9%)
74.8 6.7 518 (75.0%) 137 (19.8%) 610 (88.3%) 233 (33.7%) 523 (75.7%) 419 (60.6%) 83 (12.0%) 141 (20.4%) 638 (92.3%) 334 (48.3%) 114.5 24.4 340 (49.2%) 601 (87.0%) 89 (12.9%) 45 (6.5%)
< < < < < < < <
< < < <
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.01 0.01 0.06 0.001 0.001 0.001 0.001 0.01
Values are mean SD or n (%).
hospital catchment area were included to ensure adequate follow-up data of 30 days after the cardioversion.4 The study hospitals are the only referral hospital responsible for acute care of patients with cardiac and stroke events in their catchment areas. Cardioversions were performed according to contemporary guidelines as previously described.8 Electrical cardioversions (90%) were performed under general anesthesia, and majority of pharmacologic cardioversions were performed using flecainide. In anticoagulated patients, cardioversions were performed during long-term warfarin treatment (98%) or under cover of heparins. We identified 3,143 patients who underwent 7,660 cardioversions for acute AF. Cardioversions were divided into 4 groups according to the CHA2DS2VASc score of the patients: score 1, 2, 3 to 4, and 5. The risk of TEC in patients with and without anticoagulation was compared in these 4 groups. The independent predictors of TEC were sought, and the value of CHA2DS2VASc score and the CHADS2 score in predicting TEC was evaluated. Finally, we evaluated whether CHA2DS2VASc score predicts failure of cardioversion, recurrence of AF after successful cardioversion, and bradyarrhythmic complications. The primary end point of the study was TEC, which was defined as stroke or systemic embolism confirmed by imaging (magnetic resonance imaging or computerized tomography), surgery, or autopsy. Transient ischemic attack (TIA) was classified as probable TEC.4 Secondary end points were unsuccessful cardioversion, early recurrence of AF episode after successful cardioversion, and bradyarrhythmic complications after cardioversion. Cardioversion was defined as successful if sinus rhythm was obtained and patient was discharged in sinus rhythm. Early recurrence was assessed from patient records during the 30-day follow-up period. Bradyarrhythmia was defined as heart rate <40 beats/min and/or asystole >5 seconds immediately after the cardioversion.8 Continuous variables are presented as means and SD or medians and interquartile range as appropriate and analyzed with the Student’s t test, Mann-Whitney U test, and
Kruskal-Wallis test. Categorical variables are expressed as absolute numbers and percentages and analyzed with the chi-square test, Fisher’s exact test, and Cochran-Armitage test for trend. Multivariable logistic regression analysis with repeated measure option with covariates chosen according to our earlier reports was used in the evaluation of primary and secondary end points.4,8e10 Because the same patient could have repeated cardioversions during study period, only the first cardioversion of a patient was included in the receiver-operating characteristic (ROC) area under the curve analyses of CHA2DS2VASc and CHADS2 scores. The method of DeLong was used to calculate the difference between these area under the curves of ROC curves.11 A 2sided p value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows 22.0 software (IBM Corp., Armonk, NY) and SAS software, version 9.3 (SAS Institute Inc., Cary, NC). Results At the time of cardioversion, the mean age of patients was 62.2 12.3 years, 2,798 (36.5%) were women, and the median CHA2DS2VASc score was 2 (interquartile range 1 to 3). The baseline characteristics of patients according to their CHA2DS2VASc scores are presented in Table 1. The overall success rate of cardioversions was 94.5% (7,237 of 7,660), and 5,362 (70.0%) cardioversions were performed without anticoagulation. A total of 41 (0.5%) definite TEC occurred within 30 days after the cardioversion with a median delay of 2 days (range 1 to 27 days). Forty (0.6%) definite TEC occurred after 7,237 successful procedures, and patients were on anticoagulation therapy only during 2 of these cardioversions. The INR values of patients on oral anticoagulation ranged from 2.9 to 3.5 at the time of cardioversion and the thromboembolic event occurred at 2 and 23 days after cardioversion. A total of 423 cardioversions (5.5%) failed and 1 patient (0.2%) treated with
Arrhythmias and Conduction/CHA2DS2VASc Score and Cardioversion of AF
Figure 1. The incidence of definite thromboembolic complications after cardioversion of acute atrial fibrillation according to the CHA2DS2VASc score and use of anticoagulation. p Values calculated using CochranArmitage test for trend.
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gender (OR 2.11; 95% CI 1.04 to 4.28, p ¼ 0.038) were independent predictors of definite TEC in cardioversions performed without anticoagulation. In addition to definite TEC, 6 TIA episodes (0.1%) occurred within 30 days after cardioversion, 5 after successful cardioversion and 4 in patients without anticoagulation. The median CHA2DS2VASc score was 2.5 in patients without anticoagulation. Two patients with anticoagulation had CHA2DS2VASc scores of 4 and 5. The failure rate of cardioversion, the rate of early recurrence of AF after successful cardioversion, and incidence of bradyarrhythmic complications increased with higher CHA2DS2VASc scores (Figure 2). The CHA2DS2VASc score was an independent predictor of unsuccessful cardioversion (OR 1.09; 95% CI 1.03 to 1.16, p ¼ 0.006), recurrence of AF after successful cardioversion (OR 1.17; 95% CI 1.12 to 1.22, p <0.001), and bradyarrhythmic complications (OR 1.44; 95% CI 1.27 to 1.62, p <0.001). Discussion
Figure 2. The incidence of secondary end points according to the CHA2DS2VASC score. Secondary end points of the study were unsuccessful cardioversion, early recurrence of atrial fibrillation episode after successful cardioversion, and bradyarrhythmic complications after cardioversion. p values calculated using the Cochran-Armitage test for trend.
periprocedural heparin had a stroke 2 days after failed cardioversion. This patient underwent spontaneous conversion to sinus rhythm before the stroke. The incidence of definite TEC after cardioversion was significantly lower in the anticoagulated patients (0.1% [3 of 2,298] vs 0.7% [38 of 5,362], p ¼ 0.001). There was a significant increase in the incidence of definite TEC with higher CHA2DS2VASc scores in cardioversions performed without anticoagulation (p <0.001 for trend; Figure 1). In patients with a CHA2DS2VASc score of 2, the rate of definite TEC was significantly lower after cardioversion performed with anticoagulation (0.2% [3 of 1,708] vs 1.1% [28 of 2,590], p ¼ 0.001), but the benefit of anticoagulation did not reach statistical significance in patients with a CHA2DS2VASc score of 0 to 1 (0.0% [0 of 590] vs 0.4% [10 of 2,772], p ¼ 0.23). In nonanticoagulated patients with the first cardioversion during the study period, the C-statistics were 0.72 (95% confidence interval [CI] 0.61 to 0.83, p <0.001) for CHA2DS2VASc score and 0.66 (95% CI 0.55 to 0.78, p ¼ 0.006) for CHADS2 score in predicting definite TEC, and CHA2DS2VASc score was a better (p ¼ 0.003) predictor of the risk of definite TEC than CHADS2 score. Multivariable analysis showed that age (per year) (odds ratio [OR] 1.05; 95% CI 1.02 to 1.09, p <0.001), duration of AF episode >12 hours (OR 3.89; 95% CI 1.76 to 8.60, p ¼ 0.001), heart failure (OR 3.37; 95% CI 1.39 to 8.19, p ¼ 0.007), diabetes mellitus (OR 2.66; 95% CI 1.25 to 5.69, p ¼ 0.012), and female
The main finding of our study was that the CHA2DS2VASc score was a significant predictor of TEC in cardioversion of acute AF performed without anticoagulation. More importantly, adequate periprocedural anticoagulation reduced the risk of TEC by 82%. In addition, the overall risk of these complications was low after failed cardioversion. In our study, the CHA2DS2VASc score was a significant predictor of embolic complications and the increase of thromboembolic risk with increasing CHA2DS2VASc score was as steep as in predicting the long-term risk. Moreover, the predictive value of the CHA2DS2VASc score was as good as in the original validation study of the CHA2DS2VASc score published in 2010 (C-statistics 0.72 [95% CI 0.61 to 0.83] vs 0.61 [95% CI 0.51 to 0.70]).12 Of the score components, age, heart failure, diabetes, and female gender were independent predictors of embolic events. One explanation might be that these risk factors reflect better the high embolic risk after cardioversion, whereas hypertension and vascular disease may reflect more atherothrombotic etiology of stroke. As expected, the CHA2DS2VASc score fared better than the CHADS2 score in predicting TEC. This difference was mostly driven by female gender.4 Historically, the risk of TEC has been reported to be w5% in non-anticoagulated patients after elective cardioversion.13,14 Using periprocedural anticoagulation therapy, the risk has decreased to 0.5% to 1.6% during the first 30 days after cardioversion.15e18 We observed that the risk of TEC was comparable (0.7%) in patients with acute AF who underwent cardioversion without periprocedural anticoagulation. In contrast, the mean monthly thromboembolic risk in AF is w0.3% depending on stroke risk factors, and vitamin K antagonists reduce this risk by w64%.19 Recently published large randomized multicenter studies confirm these findings showing that the thromboembolic risk during long-term anticoagulation has decreased to 0.1% to 0.2% per month.20e22 In the FinCV study, the risk of TEC was only 0.1% in the acute cardioversions performed during anticoagulation treatment compared with the risk of 0.5% to 1.6% after elective cardioversion during therapeutic anticoagulation.15e18 These findings support the view that
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The American Journal of Cardiology (www.ajconline.org)
unnecessary delays in cardioversions of rhythm control strategy may increase the risk of TEC in spite of therapeutic oral anticoagulation, whereas cardioversion in the acute phase of AF does not increase the risk of TEC in anticoagulated patients. The overall incidence of TEC was low after failed cardioversion, which suggests that it is the conversion to sinus rhythm that results in elevated risk of TEC. This is supported by the finding that spontaneous conversion to sinus rhythm after failed cardioversion resulted in 1 stroke and 1 TIA in our study. Spontaneous conversion to sinus rhythm23,24 is not uncommon after failed cardioversion, and these patients are at increased risk of stroke if adequate anticoagulation is not used.25 Current guidelines recommend intravenous heparin or lowemolecular weight heparin or administration of factor Xa or direct thrombin inhibitor before or immediately after cardioversion of acute AF in patients with high stroke risk. For low-risk patients, these treatment strategies may be considered.3 In our study, the cardioversion was not without risk in non-anticoagulated patients with a CHA2DS2VASc score of 1, although only patients with a higher CHA2DS2VASc score derived statistically significant benefit from anticoagulation therapy. Importantly, if the delay from the symptoms to cardioversion was >12 hours the risk for thromboembolism varied from 0.4% to 0.9% if no anticoagulation was used.9 Anticoagulation therapy exposes patients to bleedings, but the rate of major bleeding events has been reported to vary from only 0.2% to 0.3% per month during long-term treatment with warfarin or novel oral anticoagulants.20e22 Furthermore, it is clear that the risk of major bleedings is even lower in these low-risk patients.26 Consequently, short-term anticoagulation should be considered also for patients with a low CHA2DS2VASc score especially if the delay to cardioversion is >12 hours. It is not surprising that patients with the highest CHA2DS2VASc score were in the highest risk for other adverse events. Almost 1/3 of these patients had failed cardioversion, bradyarrhythmic complications, or an early recurrence of AF (Figure 2). Therefore, the high CHA2DS2VASc score challenges the rationality of rhythm control strategy in these patients. Although our study is the largest study focusing on cardioversion of acute AF, it is limited by its retrospective nature. We are also dependent on reported co-morbidities of patients, treatments, and outcomes by treating physicians. The study might underestimate the number of minor events, which were not deemed clinically significant. All these limitations must be weighed against that large retrospective study avoids selection bias and may, thus, reflect real life more accurately. Acknowledgment: The authors are grateful to study coordinator Tuija Vasankari, RN, for her input in data and study management. Acknowledgments of clinical investigators for the collection of the data by center: Turku University Hospital, Turku: I. Nuotio, T. Grönberg, A. Karmi; Satakunta Central Hospital, Pori: M. Ampio, K. Ruuhijärvi, A. Ylitalo; Kuopio University Hospital, Kuopio:
M. Nikkinen, P. Autere, E. Parikka, T. Rautiainen, S. Rissanen, M-L. Sutinen, and M. Tuhkalainen. Disclosures The authors have no conflicts of interest to disclose. 1. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice GuidelinesCPG; Document Reviewers. 2012 Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation—developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14:1385e1413. 2. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. 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;31:2369e2429. 3. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1ee76. 4. Airaksinen KE, Gronberg T, Nuotio I, Nikkinen M, Ylitalo A, Biancari F, Hartikainen JE. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013;62:1187e1192. 5. Korkeila P, Mustonen P, Koistinen J, Nyman K, Ylitalo A, Karjalainen P, Lund J, Airaksinen J. Clinical and laboratory risk factors of thrombotic complications after pacemaker implantation: a prospective study. Europace 2010;12:817e824. 6. Airaksinen KE, Biancari F, Karjalainen P, Mikkola R, Kuttila K, Porela P, Laitio T, Lip GY. Safety of coronary artery bypass surgery during therapeutic oral anticoagulation. Thromb Res 2011;128:435e439. 7. Airaksinen KE, Korkeila P, Lund J, Ylitalo A, Karjalainen P, Virtanen V, Raatikainen P, Koivisto UM, Koistinen J. Safety of pacemaker and implantable cardioverter-defibrillator implantation during uninterrupted warfarin treatment—the FinPAC study. Int J Cardiol 2013;168: 3679e3682. 8. Gronberg T, Nuotio I, Nikkinen M, Ylitalo A, Vasankari T, Hartikainen JE, Airaksinen KE. Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: the FinCV study. Europace 2013;15: 1432e1435. 9. Nuotio I, Hartikainen JE, Gronberg T, Biancari F, Airaksinen KE. Time to cardioversion for acute atrial fibrillation and thromboembolic complications. JAMA 2014;312:647e649. 10. Gronberg T, Hartikainen JE, Nuotio I, Biancari F, Vasankari T, Nikkinen M, Ylitalo A, Airaksinen KE. Can we predict the failure of electrical cardioversion of acute atrial fibrillation? The FinCV study. Pacing Clin Electrophysiol 2015;38:368e375. 11. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837e845. 12. 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;137:263e272. 13. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969;23:208e216. 14. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992;19: 851e855.
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