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Effect of Early Direct Current Cardioversion on the Recurrence of Atrial Fibrillation in Patients With Persistent Atrial Fibrillation
Effect of Early Direct Current Cardioversion on the Recurrence of Atrial Fibrillation in Patients With Persistent Atrial Fibrillation Armin Osmanagic, MDa,*, Sören Möller, MSc, Phdb, Azra Osmanagic, MDc, Hussam M. Sheta, MDa, Kristina H. Vinther, MDa, and Kenneth Egstrup, MD, DMSca In patients with persistent atrial fibrillation (AF), the sinus rhythm (SR) can be restored by direct current cardioversion (DCC), although the recurrence of AF after successful DCC is common. We examined whether transesophageal echocardiography (TEE)eguided early DCC, compared with the conventional approach of DCC after 3 weeks of anticoagulation with dabigatran-etexilat, reduces the recurrence of AF. A total of 126 consecutive patients with persistent AF were randomly assigned to a TEE followed by early DCC (n [ 65) or to a conventional treatment with dabigatran-etexilat for 3 weeks followed by DCC (n [ 61). None of the patients received any antiarrhythmic treatment other than b blockers, and all the DCCs were successful. Forty-eightehour Holter monitoring was performed at 28 days and at 3, 6, and 12 months after the DCC. The primary outcome was AF recurrence lasting ‡30 seconds. The analysis was stratified by AF duration <60 (n [ 62) or >60 days (n [ 64) before DCC. We observed a significant reduction in the AF recurrence risk (p [ 0.003) in patients with persistent AF <60 days who received early DCC, but there was no significant benefit of early DCC (p [ 0.456) in patients with persistent AF lasting >60 days. The recurrence-free survival probability at 28 days in patients with persistent AF <60 days was 0.27 (95% confidence interval 0.14 to 0.51) in the conventional treatment group compared with 0.69 (95% confidence interval 0.54 to 0.87; p [ 0.006) in the early DCC group. A benefit of early DCC persisted throughout 12 months of follow-up. In conclusion, TEE-guided early DCC in patients with persistent AF <60 days results in a significant reduction of AF recurrence. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-) Atrial fibrillation (AF)1 affects 1% to 2% of the population, with its prevalence increasing with age to 17% in those aged 80 years.2 The disorder is associated with a nearly twofold mortality risk3 and a fivefold to sevenfold ischemic stroke risk4 compared with the background population. In patients with an AF duration of <7 days, rhythm control treatment is common practice. Permanent patients with AF, however, have little, if any, chance of achieving a sinus rhythm (SR) because of irreversible remodeling and left atrium (LA) dilation, meaning that rate control and symptom relief is often the best strategy.5 The most appropriate treatment approach for patients with persistent AF,1 which is accountable for 25% to 30% of cases, is more complicated.5 We, therefore, set out to examine the benefits of the transesophageal echocardiography (TEE)eguided early direct current cardioversion (DCC) on AF recurrence in patients with the condition 4 months, dividing them into 2 subgroups of persistent AF lasting for <60 or >60 days. We hypothesized that the early DCC restoration of an SR in a Department of Medical Research, OUH Svendborg Hospital, Svendborg, Denmark; bEpidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark; and cDepartment of Geriatric Medicine, Odense University Hospital OUH, Odense, Denmark. Manuscript received February 24, 2015; revised manuscript received and accepted April 9, 2015. See page 4 for disclosure information. *Corresponding author: Tel: 28573184; fax: þ45 63202407. E-mail address: [email protected] (A. Osmanagic).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.04.013
patients with persistent AF for <4 months would significantly reduce AF recurrence rates compared with treatment with dabigatran-etexilat for 3 weeks followed by DCC (conventional treatment). We also hypothesized that the benefits of early SR restoration would be more pronounced in patients with persistent AF for <60 days than in those with the condition for >60 days. Methods We conducted a randomized controlled study, enrolling 141 consecutive patients with persistent AF for a 2-year period (2011 to 2013). These patients were either admitted to the Department of Cardiology of Odense University Svendborg Hospital or referred to the outpatient clinic with a symptomatic (European Heart Rhythm Association score II to III)6 persistent AF duration of <120 days and an indication for DCC. Both groups were given dabigatran-etexilat (150 mg twice daily) immediately after randomization. In the early DCC group, TEE using a 3.5 MHz Vingmed System probe (GE Healthcare, Norway) was performed within 48 hours after randomization, and DCC was attempted after left atrial appendage thrombus exclusion. The conventional group received dabigatran-etexilat for 3 weeks before the DCC attempt. Both treatment groups continued with dabigatran-etexilat (150 mg twice daily) for a minimum of 4 weeks after DCC according to international guidelines.7 All patients also received 50 to 100 mg of metoprolol at the time of randomization as a rate control and for symptom relief. No www.ajconline.org
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Table 1 Clinical baseline characteristics of the randomized treatment groups Variable
Conventional N ¼ 61
TEE N ¼ 65
P-value
Sex ( Female) Age (Years) AF time (Days) Diabetes Hypertension Dyslipidemia Body mass index EHRA score (I/II/III/IV) CHA2DS2-VASc total HAS-BLED total Angiotensin receptor inhibitor Angiotensin II receptor blocker Statins Dabigatran etexilat Beta blocker Calcium channel blockers Digitalis
13 (21%) 69.1 8.48 63.4 28.7 7 (12%) 31 (52%) 16 (27%) 29.2 4.60 1/44/16/0 1.97 1.38 1.21 0.78 8 (13%) 13 (21%) 17 (28%) 61 (100%) 58 (95%) 13 (21%) 7 (11%)
7 (11%) 66.3 8.54 63.0 36.6 7 (11%) 30 (46%) 16 (25%) 29.4 4.67 0/22/43/0 1,41 1.00 1.02 0.75 7 (11%) 4 (6%) 12 (18%) 65 (100%) 60 (93%) 8 (12%) 9 (14%)
0.17 0.043 0.71 1 0.66 0.95 0.94 3.39*10-5 0.25 0.12 0.87 0.026 0.30 0.72 0.20 0.26 0.90
Left atrial volume (ml) Left ventricular ejection fraction (%) Left ventricular volume (ml) E/a (post DC) E/E’ Left ventricular septum (cm)
72.7 10.5 54.2 7.90
Baseline Echocardiography : 71.8 8.86 49.3 8.03
103.7 15.4 106.2 14.9 1.11 0.427 1.12 0.463 8.00 2.29 7.94 2.40 1.06 0.116 1.09 0.137
0.83 0.0041 0.28 0.66 0.87 0.45
other antiarrhythmic drug was used. After successful DCC, a maintenance dose of metoprolol was continued in both treatment groups. The DCCs were performed using a R Series ALS defibrillator (Zoll, Pittsburg, PA) and in accordance with the current guidelines.7 Before the DCC, a standard transthoracic echocardiography was performed. During the follow-up period of 12 months, all the patients had an electrocardiogram (ECG) and additional 48-hour Holter monitoring using a Modular Digital Holter recorder (Spacelabs Healthcare, Snoqualmie, WA) at 4 weeks and then after 3, 6, and 12 months after DCC. Analysis of the Holter recordings was conducted by trained and experienced technicians using the Sentinel software (Spacelabs Healthcare). The primary outcome was ECG/Holter-documented AF recurrence lasting for 30 seconds. The study was approved by the local ethics committee and was carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from the patients before their inclusion in the study, which is registered at ClinicalTrials.gov with the study ID number S-20110075. The statistical methods used are as follows: the continuous variables are expressed as a mean SD, whereas the categorical variables are presented as counts and percentages of the 2 treatment groups. The categorical baseline values were compared with the chi-square test, whereas the continuous values were analyzed using the Wilcoxon rank-sum test. We also calculated nonparametric Kaplan-Meier survival plots and used these to predict the recurrence risk, using a cutoff of an AF duration of 60 days. We compared the recurrence-free survival at 28 days and at 3, 6, and 12 months, stratified by AF duration using the chi-square test.8,9
Results We screened 199 patients and excluded those with an AF duration of >120 days (n ¼ 24) and those with reversible causes of the condition (thyrotoxicosis, n ¼ 4; infection, n ¼ 14; acute coronary syndrome, n ¼ 3; and valvular AF,1 n ¼ 13). Of 141 suitable patients, we excluded a further 11 because of spontaneous conversion and 4 because of the presence of thrombi in the left atrial appendage. This left 126 patients who were suitable for DCC. These 126 participants with persistent AF underwent a successful DCC either early (n ¼ 65) or after conventional treatment with dabigatran-etexilat for 3 weeks (n ¼ 61). The baseline characteristics in the 2 treatment groups were very similar. However, although the patients were randomly assigned to the conventional or early DCC groups, the mean ages did differ significantly Table 1. We observed a significant reduction in AF recurrence at 28 days and at 3, 6, and 12 months, in patients with AF persisting for <60 days who received early DCC. The recurrence-free survival probability follow-up at 28 days in the patients with AF for <60 days was 0.27 (95% confidence interval 0.14 to 0.51) in the conventional group versus 0.69 (95% confidence interval 0.54 to 0.87; p ¼ 0.006) in the early DCC group. The statistically significant benefit of early DCC persisted throughout the follow-up period and was still present at 12 months after cardioversion (Table 2). The impact of early DCC is also visualized in the KaplanMeier plot (Figure 1), which shows no significant effect on recurrence-free survival if AF duration before DCC is disregarded. However, if stratified by AF duration >60 or <60 days before DCC, the Kaplan-Meier plot clearly illustrates the benefit of early DCC on recurrence-free survival in those with AF for <60 days (Figure 2). During the follow-up, 94 (96.9%) of the recurrences were typepersistent AF, and only 3 (3.1%) were episodes of paroxysmal AF lasting for >30 seconds. The mean number of AF-related hospitalization days, during a 12 month follow-up period, was significantly lower in the early DCC group at 1.13 versus 3.03 days (p ¼ 0.0004) for the conventional treatment group. During the same period, the mean number of AF-related outpatient visits also differed significantly being 2.88 in the early DCC group versus 4.47 visits (p ¼ 0.0001) in the conventional treatment group. Discussion The purpose of our study was to assess the potential benefits of early DCC on the recurrence of AF in patients with persistent AF. We observed a significant reduction in the AF recurrence rate in the patients who had experienced persistent AF for <60 days who underwent early DCC compared with those assigned to the group who underwent conventional treatment with dabigatran-etexilat for 3 weeks followed by DCC. Although several studies have questioned the benefit of early DCC, some have produced results similar to ours, although the populations used in previous studies consisted of patients with persistent AF of a shorter duration than was the case for those in our study10,11 resulting in AF recurrence rates of around 50% to 60%. This level of recurrence is considerably
Arrhythmias and Conduction Disturbances/Effect of Early DCC on the Recurrence of AF in Patients With Persistent AF
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Table 2 Recurrence free survival probability over time in the treatment groups (TEE & conventional) stratified by persistent AF lasting for more or less than 60 days Variable
28 days
3 months
6 months
12 months
Recurrence free survival probability
CI (95%)
Recurrence free survival probability
CI (95%)
Recurrence free survival probability
CI (95%)
Recurrence free survival probability
CI (95%)
Conventional AF < 60 days Early DCC AF < 60 days P-value for difference
0.27 0.69
0.14-0.51 0.54-0.87
0.23 0.56
0.11-0.47 0.41-0.76
0.19 0.47
0.09-0.89 0.32-0.68
0.08 0.38
0.02-0.29 0.24-0.59
Conventional AF > 60 days Early DCC AF > 60 days P-value for difference
0.40 0.30
0.0017
0.0059 0.27-0.60 0.18-0.50
0.37 0.30
0.41
0.010 0.24-0.57 0.18-0.50
0.55
0.34 0.27
0.0027 0.22-0.54 0.16-0.48
0.53
0.25 0.18
0.15-0.45 0.08-0.38 0.46
Figure 1. Kaplan-Meier recurrence-free survival in the 2 treatment groups during the 12-month follow-up, regardless of persistent AF duration before DCC.
Figure 2. Kaplan-Meier recurrence-free survival in the 2 treatment groups during the 12-month follow-up, stratified by persistent AF lasting for <60 or >60 days before DCC.
less than in our study, where the disorder recurred in 77% of patients during the 12-month follow-up period. A possible explanation for this difference is that the more persistent AF among the patients in our study may have resulted in greater structural LA remodeling, which may be a substrate for the recurrence of AF, a theory that is consistent with the findings in earlier studies.12,13 Smaller studies that included patients with a persistent AF duration of up to 12 months have also demonstrated that a shorter length of persistent AF before DCC results in a reduction in the rate of AF recurrence, although these studies were not randomized trials.14e16 In theory, if rhythm control is chosen as a treatment, it should be performed as soon as possible. However, the time window in which the benefit of early DCC persists is less well understood, although it is clinically very relevant. With this in mind, we set out to examine whether persistent AF (<120 days) would eliminate the benefit of early DCC demonstrated in previous studies. Furthermore, we stratified the patients by a persistent AF duration of <60 or >60 days before DCC. The 60-day division was chosen
because it represents half of the maximum allowed persistent AF duration. It is also very close to the mean AF duration observed before outpatient clinic consultation. Our findings suggest that the beneficial effect of early DCC persists in patients with persistent AF up to 60 days before the treatment. However, in those with persistent AF for >60 days, there is no longer any benefit of early DCC and the usual care strategy should, therefore, be applied. The importance of early DCC is amplified by a 30-day delay in administering the treatment in our population that resulted in an approximate doubling of the AF recurrence risk. Unlike earlier studies, we did not use antiarrhythmic drugs other than b blockers, which are known for their very modest antiarrhythmic impact. This allowed us to study the consequence of early DCC without the potential confounding effects of these drugs. However, the absence of such medications in our study may account for the higher AF recurrence rates compared with earlier research. With our observations in mind, further randomized studies in a population similar to ours, but using more potent
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antiarrhythmic drugs, could contribute to our understanding of the full potential of early DCC when combined with these medications. The conventional approach with dabigatranetexilat for 3 weeks before DCC is in accordance with current guidelines.1 However, it is unknown whether an earlier DCC could be performed because of the rapid onset of the anticoagulation action of dabigatran-etexilat. In our study, the baseline characteristics of the patients in the 2 groups are very similar (Table 1). However, despite the randomization, the ages differed significantly at 69.1 versus 66.3 years (p ¼ 0.03), with the patients receiving the conventional treatment being the older subjects. We, therefore, looked at age, which was not normally distributed, as a possible explanation for our findings, but the logistic regression model showed no predictive value of this factor on AF recurrence. This lack of a significant interaction between age and AF is consistent with observations in earlier large-scale studies, which demonstrated that the significance of age in patients with a dilated LA is much less pronounced than in those with an LA of a normal size.17 Because of the higher mean age in the conventional group in our study, these patients had slightly higher HAS-BLED and CHA2DS2-VASc scores, although we observed no major hemorrhage complications and only 1 thromboembolic episode in a mesenteric artery. The thromboembolic episode was observed in 1 (0.8%) of 126 DCCs, which is consistent with the findings in previous studies.18 Earlier studies have demonstrated the safety of TEE-guided DCC, with procedural complication rates in the region of 0.5%.19 Meanwhile, the thromboembolic rates for both the conventional and the TEE-guided DCC are <0.9%.20 The economic aspects of both treatments have also been studied and do not differ significantly for the 2 treatment groups.21 However, we observed that the early DCC approach led to a significant reduction of both AF-related hospitalizations and the number of outpatient visits compared with the conventional treatment. Most of our study population consisted of male patients, which is not completely representative of the background population. However, there is no obvious explanation for this anomaly. The study has several limitations. The duration of persistent AF before inclusion was determined by structured interviews involving a set of predetermined standardized questions in an attempt to achieve results that were as reproducible as possible. However, even under ideal circumstances, self-reported data are always subject to some uncertainty. The randomization of patients should, however, ensure that those with different persistent AF durations are evenly distributed between the 2 treatment groups, reducing the importance of the precise duration of the persistent AF. The recurrence of AF was documented by 48-hour Holter monitoring or an ECG, which was performed at each visit. Furthermore, patients with symptoms consistent with AF recurrence were immediately taken in for an extra ECG. The method of monitoring leaves room for episodes of silent AF that could pass undetected, although in daily clinical practice it is impossible to continuously monitor all patients with persistent AF treated with DCC. Undetected and asymptomatic short paroxysmal AF has no clinical relevance as all patients already receive relevant treatment. Furthermore, the size of the study population, with only 61 and 65 patients in the 2 treatment groups, resulted in
relatively low power for the logistic regression, which could explain the only slightly significant results when disregarding AF duration before DCC. Disclosures None of the authors have any disclosures to make or any potential conflicts of interest. This article is not under consideration elsewhere, and none of its contents have been published previously. 1. 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. 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. 2. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6: 213e220. 3. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946e952. 4. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith SC Jr, Priori SG, Estes NA III, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;123:e269ee367. 5. 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). Europace 2010;12: 1360e1420. 6. Wynn GJ, Todd DM, Webber M, Bonnett L, McShane J, Kirchhof P, Gupta D. The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification. Europace 2014;16:965e972. 7. Kirchhof P, Ammentorp B, Darius H, De Caterina R, Le Heuzey JY, Schilling RJ, Schmitt J, Zamorano JL. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events—European Registry in Atrial Fibrillation (PREFER in AF). Europace 2014;16:6e14. 8. Therneau TM. A package for survival analysis in S 2014. 9. Team RC. A language and environment for statistical computing 2014. 10. Klein AL, Grimm RA, Jasper SE, Murray RD, Apperson-Hansen C, Lieber EA, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF. Efficacy of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation at 6 months: a randomized controlled trial. Am Heart J 2006;151: 380e389. 11. Weigner MJ, Thomas LR, Patel U, Schwartz JG, Burger AJ, Douglas PS, Silverman DI, Manning WJ. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2001;110:694e702. 12. Lu Z, Scherlag BJ, Lin J, Niu G, Fung KM, Zhao L, Ghias M, Jackman WM, Lazzara R, Jiang H, Po SS. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 2008;1:184e192.
Arrhythmias and Conduction Disturbances/Effect of Early DCC on the Recurrence of AF in Patients With Persistent AF 13. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954e1968. 14. Fornengo C, Antolini M, Frea S, Gallo C, Grosso Marra W, Morello M, Gaita F. Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation. Eur Heart J Cardiovasc Imaging 2015;16:335e341. 15. Verhorst PM, Kamp O, Welling RC, Van Eenige MJ, Visser CA. Transesophageal echocardiographic predictors for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. Am J Cardiol 1997;79:1355e1359. 16. Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989;63: 193e197. 17. Qureshi W, Soliman EZ, Solomon SD, Alonso A, Arking DE, Shah A, Gupta DK, Wagenknecht LE, Herrington D. Risk factors for atrial fibrillation in patients with normal versus dilated left atrium (from the Atherosclerosis Risk in Communities Study). Am J Cardiol 2014;114: 1368e1372.
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18. Seidl K, Rameken M, Drogemuller A, Vater M, Brandt A, Schwacke H, Bergmeier C, Zahn R, Senges J. Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion. Final results of the Ludwigshafen Observational Cardioversion Study. J Am Coll Cardiol 2002;39:1436e1442. 19. Khandheria BK, Seward JB, Tajik AJ. Biplane transesophageal echocardiography: technique, anatomic orientation, complications, and future directions. J Invasive Cardiol 1992;4:413e424. 20. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344: 1411e1420. 21. Klein AL, Murray RD, Becker ER, Culler SD, Weintraub WS, Jasper SE, Lieber EA, Apperson-Hansen C, Heerey AM, Grimm RA. Economic analysis of a transesophageal echocardiography-guided approach to cardioversion of patients with atrial fibrillation: the ACUTE economic data at eight weeks. J Am Coll Cardiol 2004;43: 1217e1224.
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.04.013
patients with persistent AF for <4 months would significantly reduce AF recurrence rates compared with treatment with dabigatran-etexilat for 3 weeks followed by DCC (conventional treatment). We also hypothesized that the benefits of early SR restoration would be more pronounced in patients with persistent AF for <60 days than in those with the condition for >60 days. Methods We conducted a randomized controlled study, enrolling 141 consecutive patients with persistent AF for a 2-year period (2011 to 2013). These patients were either admitted to the Department of Cardiology of Odense University Svendborg Hospital or referred to the outpatient clinic with a symptomatic (European Heart Rhythm Association score II to III)6 persistent AF duration of <120 days and an indication for DCC. Both groups were given dabigatran-etexilat (150 mg twice daily) immediately after randomization. In the early DCC group, TEE using a 3.5 MHz Vingmed System probe (GE Healthcare, Norway) was performed within 48 hours after randomization, and DCC was attempted after left atrial appendage thrombus exclusion. The conventional group received dabigatran-etexilat for 3 weeks before the DCC attempt. Both treatment groups continued with dabigatran-etexilat (150 mg twice daily) for a minimum of 4 weeks after DCC according to international guidelines.7 All patients also received 50 to 100 mg of metoprolol at the time of randomization as a rate control and for symptom relief. No www.ajconline.org
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The American Journal of Cardiology (www.ajconline.org)
Table 1 Clinical baseline characteristics of the randomized treatment groups Variable
Conventional N ¼ 61
TEE N ¼ 65
P-value
Sex ( Female) Age (Years) AF time (Days) Diabetes Hypertension Dyslipidemia Body mass index EHRA score (I/II/III/IV) CHA2DS2-VASc total HAS-BLED total Angiotensin receptor inhibitor Angiotensin II receptor blocker Statins Dabigatran etexilat Beta blocker Calcium channel blockers Digitalis
13 (21%) 69.1 8.48 63.4 28.7 7 (12%) 31 (52%) 16 (27%) 29.2 4.60 1/44/16/0 1.97 1.38 1.21 0.78 8 (13%) 13 (21%) 17 (28%) 61 (100%) 58 (95%) 13 (21%) 7 (11%)
7 (11%) 66.3 8.54 63.0 36.6 7 (11%) 30 (46%) 16 (25%) 29.4 4.67 0/22/43/0 1,41 1.00 1.02 0.75 7 (11%) 4 (6%) 12 (18%) 65 (100%) 60 (93%) 8 (12%) 9 (14%)
0.17 0.043 0.71 1 0.66 0.95 0.94 3.39*10-5 0.25 0.12 0.87 0.026 0.30 0.72 0.20 0.26 0.90
Left atrial volume (ml) Left ventricular ejection fraction (%) Left ventricular volume (ml) E/a (post DC) E/E’ Left ventricular septum (cm)
72.7 10.5 54.2 7.90
Baseline Echocardiography : 71.8 8.86 49.3 8.03
103.7 15.4 106.2 14.9 1.11 0.427 1.12 0.463 8.00 2.29 7.94 2.40 1.06 0.116 1.09 0.137
0.83 0.0041 0.28 0.66 0.87 0.45
other antiarrhythmic drug was used. After successful DCC, a maintenance dose of metoprolol was continued in both treatment groups. The DCCs were performed using a R Series ALS defibrillator (Zoll, Pittsburg, PA) and in accordance with the current guidelines.7 Before the DCC, a standard transthoracic echocardiography was performed. During the follow-up period of 12 months, all the patients had an electrocardiogram (ECG) and additional 48-hour Holter monitoring using a Modular Digital Holter recorder (Spacelabs Healthcare, Snoqualmie, WA) at 4 weeks and then after 3, 6, and 12 months after DCC. Analysis of the Holter recordings was conducted by trained and experienced technicians using the Sentinel software (Spacelabs Healthcare). The primary outcome was ECG/Holter-documented AF recurrence lasting for 30 seconds. The study was approved by the local ethics committee and was carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from the patients before their inclusion in the study, which is registered at ClinicalTrials.gov with the study ID number S-20110075. The statistical methods used are as follows: the continuous variables are expressed as a mean SD, whereas the categorical variables are presented as counts and percentages of the 2 treatment groups. The categorical baseline values were compared with the chi-square test, whereas the continuous values were analyzed using the Wilcoxon rank-sum test. We also calculated nonparametric Kaplan-Meier survival plots and used these to predict the recurrence risk, using a cutoff of an AF duration of 60 days. We compared the recurrence-free survival at 28 days and at 3, 6, and 12 months, stratified by AF duration using the chi-square test.8,9
Results We screened 199 patients and excluded those with an AF duration of >120 days (n ¼ 24) and those with reversible causes of the condition (thyrotoxicosis, n ¼ 4; infection, n ¼ 14; acute coronary syndrome, n ¼ 3; and valvular AF,1 n ¼ 13). Of 141 suitable patients, we excluded a further 11 because of spontaneous conversion and 4 because of the presence of thrombi in the left atrial appendage. This left 126 patients who were suitable for DCC. These 126 participants with persistent AF underwent a successful DCC either early (n ¼ 65) or after conventional treatment with dabigatran-etexilat for 3 weeks (n ¼ 61). The baseline characteristics in the 2 treatment groups were very similar. However, although the patients were randomly assigned to the conventional or early DCC groups, the mean ages did differ significantly Table 1. We observed a significant reduction in AF recurrence at 28 days and at 3, 6, and 12 months, in patients with AF persisting for <60 days who received early DCC. The recurrence-free survival probability follow-up at 28 days in the patients with AF for <60 days was 0.27 (95% confidence interval 0.14 to 0.51) in the conventional group versus 0.69 (95% confidence interval 0.54 to 0.87; p ¼ 0.006) in the early DCC group. The statistically significant benefit of early DCC persisted throughout the follow-up period and was still present at 12 months after cardioversion (Table 2). The impact of early DCC is also visualized in the KaplanMeier plot (Figure 1), which shows no significant effect on recurrence-free survival if AF duration before DCC is disregarded. However, if stratified by AF duration >60 or <60 days before DCC, the Kaplan-Meier plot clearly illustrates the benefit of early DCC on recurrence-free survival in those with AF for <60 days (Figure 2). During the follow-up, 94 (96.9%) of the recurrences were typepersistent AF, and only 3 (3.1%) were episodes of paroxysmal AF lasting for >30 seconds. The mean number of AF-related hospitalization days, during a 12 month follow-up period, was significantly lower in the early DCC group at 1.13 versus 3.03 days (p ¼ 0.0004) for the conventional treatment group. During the same period, the mean number of AF-related outpatient visits also differed significantly being 2.88 in the early DCC group versus 4.47 visits (p ¼ 0.0001) in the conventional treatment group. Discussion The purpose of our study was to assess the potential benefits of early DCC on the recurrence of AF in patients with persistent AF. We observed a significant reduction in the AF recurrence rate in the patients who had experienced persistent AF for <60 days who underwent early DCC compared with those assigned to the group who underwent conventional treatment with dabigatran-etexilat for 3 weeks followed by DCC. Although several studies have questioned the benefit of early DCC, some have produced results similar to ours, although the populations used in previous studies consisted of patients with persistent AF of a shorter duration than was the case for those in our study10,11 resulting in AF recurrence rates of around 50% to 60%. This level of recurrence is considerably
Arrhythmias and Conduction Disturbances/Effect of Early DCC on the Recurrence of AF in Patients With Persistent AF
3
Table 2 Recurrence free survival probability over time in the treatment groups (TEE & conventional) stratified by persistent AF lasting for more or less than 60 days Variable
28 days
3 months
6 months
12 months
Recurrence free survival probability
CI (95%)
Recurrence free survival probability
CI (95%)
Recurrence free survival probability
CI (95%)
Recurrence free survival probability
CI (95%)
Conventional AF < 60 days Early DCC AF < 60 days P-value for difference
0.27 0.69
0.14-0.51 0.54-0.87
0.23 0.56
0.11-0.47 0.41-0.76
0.19 0.47
0.09-0.89 0.32-0.68
0.08 0.38
0.02-0.29 0.24-0.59
Conventional AF > 60 days Early DCC AF > 60 days P-value for difference
0.40 0.30
0.0017
0.0059 0.27-0.60 0.18-0.50
0.37 0.30
0.41
0.010 0.24-0.57 0.18-0.50
0.55
0.34 0.27
0.0027 0.22-0.54 0.16-0.48
0.53
0.25 0.18
0.15-0.45 0.08-0.38 0.46
Figure 1. Kaplan-Meier recurrence-free survival in the 2 treatment groups during the 12-month follow-up, regardless of persistent AF duration before DCC.
Figure 2. Kaplan-Meier recurrence-free survival in the 2 treatment groups during the 12-month follow-up, stratified by persistent AF lasting for <60 or >60 days before DCC.
less than in our study, where the disorder recurred in 77% of patients during the 12-month follow-up period. A possible explanation for this difference is that the more persistent AF among the patients in our study may have resulted in greater structural LA remodeling, which may be a substrate for the recurrence of AF, a theory that is consistent with the findings in earlier studies.12,13 Smaller studies that included patients with a persistent AF duration of up to 12 months have also demonstrated that a shorter length of persistent AF before DCC results in a reduction in the rate of AF recurrence, although these studies were not randomized trials.14e16 In theory, if rhythm control is chosen as a treatment, it should be performed as soon as possible. However, the time window in which the benefit of early DCC persists is less well understood, although it is clinically very relevant. With this in mind, we set out to examine whether persistent AF (<120 days) would eliminate the benefit of early DCC demonstrated in previous studies. Furthermore, we stratified the patients by a persistent AF duration of <60 or >60 days before DCC. The 60-day division was chosen
because it represents half of the maximum allowed persistent AF duration. It is also very close to the mean AF duration observed before outpatient clinic consultation. Our findings suggest that the beneficial effect of early DCC persists in patients with persistent AF up to 60 days before the treatment. However, in those with persistent AF for >60 days, there is no longer any benefit of early DCC and the usual care strategy should, therefore, be applied. The importance of early DCC is amplified by a 30-day delay in administering the treatment in our population that resulted in an approximate doubling of the AF recurrence risk. Unlike earlier studies, we did not use antiarrhythmic drugs other than b blockers, which are known for their very modest antiarrhythmic impact. This allowed us to study the consequence of early DCC without the potential confounding effects of these drugs. However, the absence of such medications in our study may account for the higher AF recurrence rates compared with earlier research. With our observations in mind, further randomized studies in a population similar to ours, but using more potent
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The American Journal of Cardiology (www.ajconline.org)
antiarrhythmic drugs, could contribute to our understanding of the full potential of early DCC when combined with these medications. The conventional approach with dabigatranetexilat for 3 weeks before DCC is in accordance with current guidelines.1 However, it is unknown whether an earlier DCC could be performed because of the rapid onset of the anticoagulation action of dabigatran-etexilat. In our study, the baseline characteristics of the patients in the 2 groups are very similar (Table 1). However, despite the randomization, the ages differed significantly at 69.1 versus 66.3 years (p ¼ 0.03), with the patients receiving the conventional treatment being the older subjects. We, therefore, looked at age, which was not normally distributed, as a possible explanation for our findings, but the logistic regression model showed no predictive value of this factor on AF recurrence. This lack of a significant interaction between age and AF is consistent with observations in earlier large-scale studies, which demonstrated that the significance of age in patients with a dilated LA is much less pronounced than in those with an LA of a normal size.17 Because of the higher mean age in the conventional group in our study, these patients had slightly higher HAS-BLED and CHA2DS2-VASc scores, although we observed no major hemorrhage complications and only 1 thromboembolic episode in a mesenteric artery. The thromboembolic episode was observed in 1 (0.8%) of 126 DCCs, which is consistent with the findings in previous studies.18 Earlier studies have demonstrated the safety of TEE-guided DCC, with procedural complication rates in the region of 0.5%.19 Meanwhile, the thromboembolic rates for both the conventional and the TEE-guided DCC are <0.9%.20 The economic aspects of both treatments have also been studied and do not differ significantly for the 2 treatment groups.21 However, we observed that the early DCC approach led to a significant reduction of both AF-related hospitalizations and the number of outpatient visits compared with the conventional treatment. Most of our study population consisted of male patients, which is not completely representative of the background population. However, there is no obvious explanation for this anomaly. The study has several limitations. The duration of persistent AF before inclusion was determined by structured interviews involving a set of predetermined standardized questions in an attempt to achieve results that were as reproducible as possible. However, even under ideal circumstances, self-reported data are always subject to some uncertainty. The randomization of patients should, however, ensure that those with different persistent AF durations are evenly distributed between the 2 treatment groups, reducing the importance of the precise duration of the persistent AF. The recurrence of AF was documented by 48-hour Holter monitoring or an ECG, which was performed at each visit. Furthermore, patients with symptoms consistent with AF recurrence were immediately taken in for an extra ECG. The method of monitoring leaves room for episodes of silent AF that could pass undetected, although in daily clinical practice it is impossible to continuously monitor all patients with persistent AF treated with DCC. Undetected and asymptomatic short paroxysmal AF has no clinical relevance as all patients already receive relevant treatment. Furthermore, the size of the study population, with only 61 and 65 patients in the 2 treatment groups, resulted in
relatively low power for the logistic regression, which could explain the only slightly significant results when disregarding AF duration before DCC. Disclosures None of the authors have any disclosures to make or any potential conflicts of interest. This article is not under consideration elsewhere, and none of its contents have been published previously. 1. 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. 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. 2. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6: 213e220. 3. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946e952. 4. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith SC Jr, Priori SG, Estes NA III, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;123:e269ee367. 5. 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). Europace 2010;12: 1360e1420. 6. Wynn GJ, Todd DM, Webber M, Bonnett L, McShane J, Kirchhof P, Gupta D. The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification. Europace 2014;16:965e972. 7. Kirchhof P, Ammentorp B, Darius H, De Caterina R, Le Heuzey JY, Schilling RJ, Schmitt J, Zamorano JL. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention oF thromboemolic events—European Registry in Atrial Fibrillation (PREFER in AF). Europace 2014;16:6e14. 8. Therneau TM. A package for survival analysis in S 2014. 9. Team RC. A language and environment for statistical computing 2014. 10. Klein AL, Grimm RA, Jasper SE, Murray RD, Apperson-Hansen C, Lieber EA, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF. Efficacy of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation at 6 months: a randomized controlled trial. Am Heart J 2006;151: 380e389. 11. Weigner MJ, Thomas LR, Patel U, Schwartz JG, Burger AJ, Douglas PS, Silverman DI, Manning WJ. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2001;110:694e702. 12. Lu Z, Scherlag BJ, Lin J, Niu G, Fung KM, Zhao L, Ghias M, Jackman WM, Lazzara R, Jiang H, Po SS. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 2008;1:184e192.
Arrhythmias and Conduction Disturbances/Effect of Early DCC on the Recurrence of AF in Patients With Persistent AF 13. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954e1968. 14. Fornengo C, Antolini M, Frea S, Gallo C, Grosso Marra W, Morello M, Gaita F. Prediction of atrial fibrillation recurrence after cardioversion in patients with left-atrial dilation. Eur Heart J Cardiovasc Imaging 2015;16:335e341. 15. Verhorst PM, Kamp O, Welling RC, Van Eenige MJ, Visser CA. Transesophageal echocardiographic predictors for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. Am J Cardiol 1997;79:1355e1359. 16. Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989;63: 193e197. 17. Qureshi W, Soliman EZ, Solomon SD, Alonso A, Arking DE, Shah A, Gupta DK, Wagenknecht LE, Herrington D. Risk factors for atrial fibrillation in patients with normal versus dilated left atrium (from the Atherosclerosis Risk in Communities Study). Am J Cardiol 2014;114: 1368e1372.
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18. Seidl K, Rameken M, Drogemuller A, Vater M, Brandt A, Schwacke H, Bergmeier C, Zahn R, Senges J. Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion. Final results of the Ludwigshafen Observational Cardioversion Study. J Am Coll Cardiol 2002;39:1436e1442. 19. Khandheria BK, Seward JB, Tajik AJ. Biplane transesophageal echocardiography: technique, anatomic orientation, complications, and future directions. J Invasive Cardiol 1992;4:413e424. 20. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344: 1411e1420. 21. Klein AL, Murray RD, Becker ER, Culler SD, Weintraub WS, Jasper SE, Lieber EA, Apperson-Hansen C, Heerey AM, Grimm RA. Economic analysis of a transesophageal echocardiography-guided approach to cardioversion of patients with atrial fibrillation: the ACUTE economic data at eight weeks. J Am Coll Cardiol 2004;43: 1217e1224.