Long-term Outcomes of Stand-Alone Maze IV for Persistent or Long-standing Persistent Atrial Fibrillation

Accepted Manuscript Long-term outcomes of stand-alone Maze IV for persistent/long-standing persistent atrial fibrillation Elisabetta Lapenna, Michele De Bonis, Ilaria Giambuzzi, Benedetto Del Forno, Stefania Ruggeri, Manuela Cireddu, Simone Gulletta, Alessandro Castiglioni, Ottavio Alfieri, Paolo Della Bella, Stefano Benussi PII:

S0003-4975(19)31021-5

DOI:

https://doi.org/10.1016/j.athoracsur.2019.05.061

Reference:

ATS 32803

To appear in:

The Annals of Thoracic Surgery

Received Date: 23 November 2018 Revised Date:

1 April 2019

Accepted Date: 20 May 2019

Please cite this article as: Lapenna E, De Bonis M, Giambuzzi I, Del Forno B, Ruggeri S, Cireddu M, Gulletta S, Castiglioni A, Alfieri O, Della Bella P, Benussi S, Long-term outcomes of stand-alone Maze IV for persistent/long-standing persistent atrial fibrillation, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.05.061. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Long-term outcomes of stand-alone Maze IV for persistent/long-standing persistent atrial fibrillation Running Head: Long-term outcome of stand-alone Maze IV

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Elisabetta Lapenna1*, Michele De Bonis1*, Ilaria Giambuzzi1, Benedetto Del Forno1, Stefania Ruggeri1, Manuela Cireddu2, Simone Gulletta2, Alessandro Castiglioni1, Ottavio Alfieri1, Paolo Della Bella2, Stefano Benussi3

Department of Cardiac Surgery, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University,

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1

Milan, Italy

Department of Cardiac Electrophysiology and Arrhythmia, IRCCS San Raffaele Hospital, Vita-

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Salute San Raffaele University, Milan, Italy

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Department of Cardiac Surgery, Spedali Civili di Brescia, University Hospital, Brescia, Italy

Drs Lapenna and De Bonis contributed equally to this work and are co-first authors.

Correspondence to:

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Elisabetta Lapenna, MD

Department of Cardiac Surgery IRCCS San Raffaele Hospital “Vita-Salute” San Raffaele University Via Olgettina 60 20132 Milano, Italy E-mail: [email protected]

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ACCEPTED MANUSCRIPT ABSTRACT BACKGROUND: To assess the long-term outcomes of the stand-alone Cox-Maze IV procedure in symptomatic patients with refractory, persistent or long-standing persistent atrial fibrillation (AF). METHODS: Fifty-nine consecutive patients (mean age 52±10.5, previous catheter ablation 80%,

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LVEF 55±3.4%, median LA volume index 41[34;47]ml/m2) with symptomatic, refractory, persistent (56%) or longstanding persistent (44%) AF, underwent stand-alone Cox-Maze IV procedure. Biatrial ablations were performed with bipolar radiofrequency and cryoenergy. Left atrial appendage was

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excluded in 56/59 (95%) pts.

RESULTS: No hospital deaths occurred and one patient (1.7%) required postoperative pacemaker

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implantation. Follow-up was 97% complete (median 5.8 years, IQR3.92;7.11). The overall survival at 7-years was 97±2.3%. The 7-years Cumulative incidence function of AF recurrence and of AF recurrence off class I/III AADs, with death as competing risk, was 14.2±5.6% (95%CI 5.5;26.8) and 26.5±6.9% (95%CI 14.2;40.4), respectively. Multivariate analysis identified the duration of AF as the

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only predictor of AF recurrence (HR=1.01, 95%CI 1.01;1.02, p<0.001). At 7 years the proportion of pts in sinus rhythm was 84%, of whom 74% off class I/III AADs. At the last follow-up, 75% of pts were in class EHRA I, no stroke and thromboembolic events were documented and 70% of pts were

(p=0.003).

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off anticoagulation therapy. LVEF improved from 53±3.4 at baseline, to 59±3.4 at follow-up

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CONCLUSIONS: This study confirmed the safety and efficacy at long-term (7 years) of the standalone Maze IV surgical procedure for persistent/long-standing persistent AF. Indeed, more than 70% of the pts were in SR off class I/III AADs and off oral anticoagulation.

Abstract word count: 249

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ACCEPTED MANUSCRIPT In patients with persistent or long-standing persistent AF the late arrhythmia control remains challenging [1,2]. Catheter-based percutaneous ablation is associated with suboptimal results [3,4], justifying the growing interest for stand-alone AF surgery. The Cox-Maze IV operation, using bipolar radiofrequency (RF) energy and/or cryoablation, to replicate most of the incisions of the original cut-

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and-sew method, is widely considered the gold standard for surgical treatment of non-paroxysmal AF [5].

However, few studies [6-11] have assessed the results of the stand-alone Cox-Maze IV procedure in symptomatic patients with refractory, persistent or long-standing persistent AF. In particular, although

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a relatively high rate of sinus rhythm (SR) restoration has been reported with this operation, long-term outcome data are still scarce.

procedure in this subset of patients.

Patients and Methods

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Study population

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The aim of this study was to assess the long-term outcomes of the stand-alone Cox-Maze IV

The study population includes the first 59 consecutive patients with symptomatic, refractory, persistent or long-standing persistent AF, who underwent stand-alone Cox-Maze IV procedure

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between 2007 and 2014. Atrial fibrillation was defined as persistent or long-standing persistent based on the Heart Rhythm Society (HRS) guidelines [12].

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All patients underwent preoperative transthoracic (TTE) followed by transesophageal Doppler echocardiography (TEE) to exclude left atrial (LA) thrombi and concomitant structural heart disease. Measurement of LA diameter and volume was performed in all patients. For the purpose of this study, the preoperative, intraoperative, postoperative and follow-up data were prospectively entered into a dedicated database and retrospectively reviewed. The Institutional Ethic Committee approved this study and waived individual consent for this retrospective analysis.

Follow-up All patients underwent ECG before discharge. Follow-up was performed longitudinally in our

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ACCEPTED MANUSCRIPT dedicated Institutional outpatient clinic at 3, 6, 12 months, and then yearly or on indication thereafter, with physical examination, 12-lead ECG, 24-hour Holter monitoring and echocardiography. The first 3 months after surgery were considered as “blanking period” and were “locked out” in the outcome analysis.

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Recurrence was defined, according to current guidelines [13], as any episode of AF/atrial tachyarrhythmia (ATA) lasting ≥30 seconds and detected by symptoms and/or ECG/Holter recording, after the blanking period. In patients with an implanted cardioverter (ICD) or pacemaker device or an implantable loop recorder (ILR), interrogation of the device was used to rule out recurrence.

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Primary endpoint was defined, according to HRS guidelines, as SR without use of class I/III

antiarrhythmic drugs (AADs) or electrical cardioversion (ECV), verified using ECG and 24-hour

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Holter at each time point [12,13]. Arrhythmia Control (maintenance of SR with or without AADs/ECV) was evaluated, as well. A catheter ablation at follow-up was considered as a permanent failure.

Follow-up was 97% complete with a median of 5.8 years [3.92;7.11]. Two patients were lost at

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follow-up. Among the patients who were available for follow-up at 5 and 7 years, only one patient had incomplete rhythm data, determined via ECG only. Therefore, continuous monitoring by means 24-h Holter monitoring or pacemaker/ICD/loop recorder interrogation was obtained in 97% of patients at 5

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Statistical Analysis

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years and 95% of patients at 7 years.

Statistical analyses were performed using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) for Windows (Microsoft Corp, Redmond, WA) and Stata software version 13. Continuous data were expressed as mean±SD or as median and interquartile range (IQR), as appropriate. The distribution of variables was evaluated using the Shapiro-Wilk test. The Mann–Whitney U test was employed for independent samples when continuous data were not normally distributed. Baseline and last follow-up measurements of continuous, normally distributed data, were compared using the paired t-test. Categorical data were reported as number and percentage. Comparisons of the categorical variables were performed using the chi-square test and Fisher’s exact test, as indicate. Pre- and post-surgery

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ACCEPTED MANUSCRIPT European Heart Rhythm Association (EHRA) functional class were compared using the chi-square test. Kaplan-Meier estimates were employed for analyzing long-term survival and presented as mean±standard error. Predictors associated with death were assessed in univariate Cox proportional

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hazard models. Cumulative Incidence Function (CIF) were computed for recurrence of AF with death as competing risk. For actuarial estimates, data are presented as failure probability ± standard error. Because AF is a state that patients can move in and out of, during the course of follow-up, the CIF analysis should be

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interpreted as depicting the time to the first recorded incidence of AF recurrence. Graphs of recurrence of AF were truncated at 7 years, in order to have a high number of patients at risk. Fine and Gray

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models were used in competing risk analysis for the assessment of predictors of AF recurrence. All covariates with p-value <0.1 at univariate analysis were kept into multivariate analysis. A p-value <0.05 was employed to define statistical significance.

To describe the time-course of AF, we performed a longitudinal analysis using generalized estimating

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equations (GEE) with random intercept for correlated data. The GEE method was applied because ordinary logistic regression may result biased for repeated measures data [14].

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Results Patient characteristics

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At baseline, the majority of patients were young male (91.5%) with persistent AF (33 pts, 56%) who had failed treatment with ≥1 class I/III AADs and/or multiple electrical cardioversion. Forty-seven patients (80%) had previously been submitted to at least one catheter ablation of AF and one patient had also a surgical epicardial ablation through bilateral thoracoscopy. By definition, no patients had concomitant significant valve disease. Three patients (5%) were affected by hypertrophic nonobstructive cardiomyopathy. Two patients had an ICD because of ventricular tachyarrhythmia. At hospital admission, 8 (13.5%) patients were in SR, while 51 (86.5%) patients were in AF. Four patients (6.7%) suffered a previous neurological event (transitory ischemic attack/stroke). Most of the patients (37 pts, 63%) were in EHRA class III or IV and 6 of them (10%) had been previously

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ACCEPTED MANUSCRIPT hospitalized due to heart failure. The median LA volume index was 41[34;47] ml/m2 and the LVEF was 53±3.4%. The preoperative clinical and echocardiographic characteristics of the patients are listed in Table 1.

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Procedural data Thirty-one patients (53%) were operated on through a right mini-thoracotomy approach. A

conventional median sternotomy with standard CPB was preferred in the remaining 29 (47%) patients due to initial experience (14 pts), presence of peripheral vascular disease (2 pts), history of previous

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right thoracoscopy (2 pts), left ventricular dysfunction (10 pts), situs viscerum inversus (1 pts).

Biatrial ablations were performed with bipolar RF clamp (Atricure, Inc. Cincinnati, OH, USA) and

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cryoenergy (linear nitrous oxide cryoprobe, Atricure, Inc), according to the Maze IV lesion set, as previously described [15]. Four to five repeated applications of bipolar RF clamp were performed for each lesion to provide transmurality. Endo-epicardial cryoenergy was applied on the mitral annulus in all pts. The intercaval line was omitted in 5 pts (8.4%) with early persistent AF and normal right atrial

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volume. Left atrial appendage was excluded in 56/59 patients (95%) using an epicardial exclusion system (Atriclip, Atricure) (7 pts), amputation (3 pts) or endocardial over-sewn in double layer (46 pts). At the end of surgery, a TEE demonstrated a well-excluded LA appendage in all patients.

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Median CPB time and cross-clamp time were 113[85;132] minutes and 80.5[59;94] minutes, respectively and were both longer with the minimally invasive approach (131.5[116.5;142.5] vs

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85.5[73;100] minutes, P<0.001 and 94[84.5;101] vs 58.5[48;75] minutes, respectively, P<0.001).

Clinical hospital outcomes

No hospital deaths occurred. Postoperative complications are reported in Table 2. In particular, one patient (1.7%) required permanent pacemaker implantation due to sinus node dysfunction. Patients with postoperative atrial tachyarrhytmias (14/59, 24%) were pharmacologically or electrically cardioverted as needed. Postoperative median length-of-stay was 6 [5-8] days. At hospital discharge all patients but two (97%) were in sinus rhythm: one patient was in AF and the other one in junctional rhythm. All patients were discharged on oral anticoagulation (warfarin) and 42% (25/59) of patients

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ACCEPTED MANUSCRIPT on AADs (15 pts on amiodarone, 6 on sotalol and 4 on flecainide).

Follow-up Clinical outcomes

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During follow-up, 3 patients died (5%) and the cause of death was cardiac related in all cases: congestive heart failure (1 pt, in waiting-list for heart transplantation) and sudden death (2 pts). The overall survival at 7 years was 97±2.3%.

No stoke, thromboembolism or major bleeding events were documented during the follow-up period.

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One patient (1.7%) was submitted to pacemaker implantation, 2 years after surgery, as primary

prevention, because of asymptomatic bradycardia while on AADs. One more patient received an

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ICD/CRT, one year after the Cox-Maze operation, due to severe left ventricular dysfunction, already present preoperatively. In one patient an ILR was implanted for intermittent recurrent AF. At the last follow-up, EHRA class I was documented in 75% of the patients (43/57) and NYHA class I-II in 86% (49/57).

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At the last echocardiography, LVEF improved from 53±3.4 at baseline, to 59±3.4 at follow-up (P= 0.003), LA volume decreased from 80±27.9 to 73±19.7 (P=0.003) and systolic pulmonary artery

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pressure (SPAP) was 26.4±6.4 mmHg, not significantly different compared to baseline, p=0.15.

Anticoagulation treatment

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All patients were discharged on warfarin. Oral anticoagulants (OAC) were usually stopped 6 months after surgery, based on the CHA2DS2VASC score and after documenting stable SR off AADs at 24-h ECG Holter and no left atrial stasis (smoke effect) at echocardiography. At last follow-up, OAC therapy was discontinued in 70% of patients (40/57). In particular, at 3, 5 and 7-year follow-up, the percentage of patients off OAC was 78% (39/50), 73% (27/37) and 74% (14/19), respectively. Unsurprisingly, patients in stable sinus rhythm off AADs, were significantly more likely to be off OAC therapy than those who were in AF, intermittent SR or SR on AADs (32/40, 80% vs 8/17, 47%; P=0.01). Among the 8 patients on OAC while in stable SR off AADs, 5 patients had a CHA2DS2VASC score ≥2, whereas the other 3 patients remained on anticoagulation due to

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ACCEPTED MANUSCRIPT cardiologist preference, without other clinical indication. At last follow-up, new oral anticoagulants were adopted in 65% of the anticoagulated patients (11/17).

Recurrence of AF/ATA

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Antiarrhythmic drugs were not systematically used for the blanking period (25/59 pts on AADs, 42%) and anyway discontinued after that in all patients but 3 (5%), due to AF recurrence.

The 7-years Cumulative incidence function (CIF) of AF recurrence and of AF recurrence off class I/III AADs, with death as competing risk, was 14.2±5.58% (95% CI 5.5;26.8) and 26.5±6.87% (95% CI

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14.2;40.4), respectively (Figure 1 and 2). The duration of AF was identified as the only predictor of

1.01; 1.02, p<0.001) (Table 3).

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AF recurrence with 1% greater odds for AF, with each month increase in duration (HR =1.01, 95%CI

The proportion of patients in SR at 1, 3, 5 and 7 years after surgery was 94%, 90%, 92% and 84%, respectively, and in stable SR off class I/III AADs was 85%, 78%, 73% and 74%, respectively (Figure 3). There were no statistically significant differences between SR at 7 years compared to 1 year

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(p=0.162) and between SR off class I/III AADs/ECV at 7 years compared to 1 year (p=0.260). The majority of patients (40/57, 70%) remained in stable SR off AADs throughout the follow-up. Among the remaining 17 patients with recurrence, 6 returned to stable SR using AADs, 5 had intermittent SR

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with AADs/ECV, 4 returned definitively to AF, one was never in SR during follow-up and one resumed SR after trans-catheter ablation. The recurrent arrhythmia was AF in all patients. Four

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patients (7%) underwent ECV for recurrent AF, and one patient (1.7%) was submitted to a successful single trans-catheter ablation one year after surgery (conduction gap between the roof line and the left PV encircling).

In particular, SR was maintained in 90% of patients (30/33) with preoperative persistent AF (81% off ADDs) and in 67% of patients (16/24) with long-standing persistent AF (52% off AADs) (P=0.04; P=0.02 off AADs). Compared with the persistent AF group, the long-standing persistent patients had larger left atria (LA volume index 51±20.8 vs 41±14.9 ml/m2, P=0.005). Figure 4 shows the trend of predicted prevalence of SR (red line) and SR off class I/III AADs (lightblue line).

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ACCEPTED MANUSCRIPT Comment The main finding of this study is that the stand-alone Cox-Maze IV procedure is associated with satisfactory long term results in patients with symptomatic refractory persistent/long-standing persistent AF. To the best of our knowledge this is the first study reporting results up to 7 years.

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The treatment of patients with persistent and long-standing persistent AF remains challenging [2]. Currently, the Cox Maze IV operation is the gold standard for surgical treatment of non-paroxysmal AF [1,5] and several studies have confirmed its efficacy. Most of these reports, however, are limited by short-term follow-up [9] or have investigated a mixed population (including paroxysmal AF) or

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mixed surgical approaches [8,10,11]. Furthermore, in many studies, standardized reporting methods, as required by the HRS consensus statement, have not been used [12,13]. Very few studies have

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assessed the results of the stand-alone Cox-Maze IV procedure at long-term [7,8]. Recently, Ad et al [7] presented a series of 133 patients with non-paroxysmal AF, operated on since 2005 for lone AF. They used a right anterolateral mini-thoracotomy and argon-based cryothermal energy. The results were promising with 73% of the patients in SR off-AADs and follow-up catheter ablation at 5 years.

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The patients also had improved quality of life and a remarkably low stroke rate (0.8%) despite the fact that 81% of them were eventually taken off anticoagulation. Schill et al. [8] demonstrated the safety and efficacy of the stand-alone Cox-Maze IV performed both

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through median sternotomy or right mini-thoracotomy. They used a combination of RF and cryoablation and documented that the omission of the LA roof line was associated with a significantly

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higher rate of atrial tachyarrhythmia recurrence. At 5-year follow-up, the percentage of patients in SR off AADs was 59% (24/41) in the median sternotomy group and 71% (10/14) in the mini-thoracotomy one (p=ns), excluding patients who did not receive complete LA box lesion. The results of our study are comparable to those findings. Similarly, we focused only on patients with persistent or long-standing persistent AF who underwent stand-alone Cox-Maze IV. These patients had undergone multiple trials of antiarrhythmic drugs and most of them had failed catheter ablation procedures. Since they have no other cardiac pathology, it is imperative that procedures performed in these patients are as safe and effective as possible. In our series we had no hospital mortality and no perioperative stroke. Most complications were transient but 1/59 (1.7%) of patients required

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ACCEPTED MANUSCRIPT pacemaker implantation. Arrhythmia control was achieved in 84% of cases at 7 years with 74% being in SR off AADs. These findings are similar and possibly better than those reported in the literature [7,8]. In addition, our study accounted for the competing risk of death, which otherwise could mask the true long-term recurrence rate of AF. The 7-years Cumulative incidence function of AF recurrence

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and of AF recurrence off class I/III AADs, with death as competing risk, was 14.2% and 26.5%, respectively. A longer history of AF was identified as an independent predictor of failure, as in other studies [10,11,17]. The results of our study further emphasize the importance of early referral for AF intervention to improve success.

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While this series did show that the efficacy of surgery was maintained at 7 years, it did not determine whether failures were due to our inability to properly complete the lesion set or because of the

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underlying mechanism of AF. Indeed, only one patient with AF recurrence underwent electrophysiological study at follow-up which demonstrated a conduction gap between the roof line and the left PV encircling. We preferred to use bipolar RF for most ablation lines and cryoablation only near the atrioventricular groove, since cryoablation alone requires significantly more time. On the

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other hand, cryoablation is ideal over annular tissue because it preserves the fibrous skeleton of the heart and does not compromise valve competence [18]. The present study represents also an important contribution to the literature reporting no

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thromboembolic events or stroke/TIA at follow-up, despite 70% of the patients being off anticoagulation therapy. At the last follow-up, only 20% of patients remained on anticoagulation while

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in stable sinus rhythm off AADs. The absence of embolic stroke can be related to the relatively high percentage of restoration of sinus rhythm over time, to the LA appendage closure verified by intraoperative TEE, and to a close clinical monitoring with repeated follow-ups performed by a multidisciplinary team. Although current guidelines are not specific on discontinuation of anticoagulation after surgical ablation of AF and successful left atrial appendage exclusion/amputation, Ad et al [19-20] have shown that oral anticoagulants can be stopped safely in the majority of patients in SR off AADs after a successful Cox maze procedure. Currently, we consider to discontinue anticoagulation at 6 months after surgery, once stable sinus rhythm off AADs has been confirmed (by repeated 24-hours ECG Holter) and echocardiography has documented no

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ACCEPTED MANUSCRIPT echogenic smoke in the LA, according to CHA2DS2VASC score and provided that there are no other indications for the anticoagulation therapy. Indeed, SR restoration does not mean atrial contraction recovery, particularly in patients with AF duration longer than 5 years [21].

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In conclusion, our long-term data expand the current knowledge in the field of surgical ablation of AF demonstrating that the stand-alone Cox-Maze IV procedure for persistent/long-standing persistent AF is associated with satisfactory results up to 7 years after surgery. The 97% completeness of our longterm follow-up performed in a dedicate AF center, the competing risk and the longitudinal analyses,

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further reinforce the reliability of these results providing reference values to which other more recently

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introduced surgical off-pump and hybrid options need to be compared.

Study limitations

Although data were obtained from a prospectively collected database, this was a retrospective, singlecentre study and therefore subject to all the limitations of every retrospective data analysis. The

burden was not evaluated.

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relatively small sample size available at 7 years represents another limitation. Moreover, the AF

The rhythm assessment used at our center, based on ECG and 24-h Holter monitoring (according to

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the HRS guidelines [13]), may not capture all events [22] leading to an overestimation of the success rate compared with the use of continuous monitoring devices such as the ILR. However, there is still

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debate on what is the best method to follow these patients, given the limitations of the ILR, themselves [22]. Finally, our results reflect the experience of a single AF-dedicated center with a high volume of surgical ablation procedures performed by experienced surgeons.

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ACCEPTED MANUSCRIPT References [1] Pinho-Gomes AC, Amorima MJ, Oliveira SM and Leite-Moreira AF. Surgical treatment of atrial fibrillation: an updated review. European Journal of Cardio-Thoracic Surgery 2014;46:167–178 [2] Burkhardt JD, Di Biase L, Natale A. Long-standing persistent atrial fibrillation: the metastatic

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cancer of electrophysiology. J Am Coll Cardiol 2012;60:1930–2. [3] Weerasooriya R, Khairy P, Litalien J, Macle L, Hocini M, Sacher F, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011;57:160–6. [4] Tilz RR, Rillig A, Thum AM, Arya A, Wohlmuth P, Metzner A, et al. Catheter ablation of long-

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standing persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol. 2012;60:1921–1929

Electrophysiol. 2007;20:65–71.

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[5] Ad N. The Cox-Maze procedure: history, results, and predictors for failure. J Interv Card

[6] Ruaengsri C, Schill MR, Khiabani AJ, Schuessler RB, Melby SJ, Damiano RJ Jr. The Cox-maze IV procedure in its second decade: still the gold standard? Eur J Cardiothorac Surg.

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2018;53(suppl1):i19-i25.

[7] Ad N, Holmes SD, Friehling T. Minimally Invasive Stand-Alone Cox Maze Procedure for Persistent and Long-Standing Persistent Atrial Fibrillation. Perioperative Safety and 5-Year

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Outcomes. Circ Arrhythm Electrophysiol 2017;10:e005352. [8] Schill MR, Sinn LA, Greenberg JW, Henn MC, Lancaster TS, Schuessler RB, et al. A Minimally

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Invasive Stand-alone Cox-Maze Procedure Is as Effective as Median Sternotomy Approach. Innovations 2017;12(3):186-191. [9] Weimar T, Schena S, Bailey MS, Maniar HS, Schuessler RB, Cox JL, et al. The cox-maze procedure for lone atrial fibrillation: a single-center experience over 2 decades. Circ Arrhythm Electrophysiol 2012;5(1):8-14 [10] Henn MC, Lancaster TS, Miller JR, Sinn LA, Schuessler RB, Moon MR, et al. Late outcomes after the Cox maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2015;150:1168-1178. [11] Ad N, Holmes SD, Stone LE, Pritchard G, Henry L. Rhythm course over 5 years following surgical ablation for atrial fibrillation. Eur J Cardiothorac Surg. 2015;47:52-8.

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ACCEPTED MANUSCRIPT [12] Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528-606.

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[13] Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Europace. 2018;1;20(1):e1-e160

[14] Scott L. Zeger, Kung-Yee Liang and Paul S. Albert. Models for Longitudinal Data: A

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Generalized Estimating Equation Approach. Biometrics 1988;44,(4):1049-1060.

[15] Pozzoli A, Taramasso M, Coppola G, Kamami M, La Canna G, Della Bella P, et al. Maze surgery

Cardiothorac Surg. 2014;46(5):871-6.

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normalizes left ventricular function in patients with persistent lone atrial fibrillation. Eur J

[16] Maesen B, Pison L, Vroomen M, Luermans JG, Vernooy K, Maessen JG et al. Three-year followup of hybrid ablation for atrial fibrillation. Eur J Cardiothorac Surg. 2018;53(suppl-1):i26-i32.

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[17] Gaynor SL, Schuessler RB, Bailey MS, Ishii Y, Boineau JP, Gleva MJ, et al. Surgical treatment of atrial fibrillation: predictors of late recurrence. J Thorac Cardiovasc Surg. 2005;129:104-11. [18] Melby SJ, Schuessler RB, Damiano RJ Jr. Ablation technology for the surgical treatment of atrial

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fibrillation. ASAIO J. 2013;59(5):461-8.

[19] Ad N, Henry L, Schlauch K, Holmes SD, Hunt S. The CHADS score role in managing

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anticoagulation after surgical ablation for atrial fibrilla- tion. Ann Thorac Surg. 2010;90:1257–1262. [20] Ad N, Henry L, Shuman DJ, Holmes SD. A more specific anticoagulation regimen is required for patients after the cox-maze procedure. Ann Thorac Surg. 2014;98:1331–1338. [21] Boyd AC, Schiller NB, Ross DL, Thomas L. Differential recovery of regional atrial contraction after restoration of sinus rhythm after intraoperative linear radiofrequency ablation for atrial fibrillation. Am J Cardiol 2009;103:528–34. [22] Damiano RJ Jr, Lawrance CP, Saint LL, Henn MC, Sinn LA, Kruse J, et al. Detection of Atrial Fibrillation After Surgical Ablation: Conventional Versus Continuous Monitoring. Ann Thorac Surg 2016;101(1):42-7.

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ACCEPTED MANUSCRIPT Table 1. Baseline data (59 patients) Age, y (mean±SD)

52±10.5

Male sex (n,%)

54 (91.5)

BMI, Kg/m2 (median; IQR)

27.7 [25.8;30.1]

33 (56)

Long-standing persistent AF, n (%)

26 (44)

AF history, months (median; IQR)

60 [36;120]

Previous catheter ablation (n,%)

47 (80) 1.8±1.35

Prior electrical cardioversion > 4 (n,%) Stroke/ TIA (n,%)

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Mean ablations

26 (44) 4 (7)

EHRA class (n,%) I – II

22 (37) 37 (63)

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III - IV CHA2DS2-VASc score (n,%)

51 (86)

0-1

9 (15)

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≥2

Oral anticoagulation (n,%)

39 (66)

LVEF, % (mean±SD)

53±3.4

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Persistent AF (n,%)

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Preoperative AF (n,%)

LVEDD, mm (mean±SD)

52.1±5.33

LVEDV, ml (mean ±SD)

105.0±24.8

SPAP, mmHg (median; IQR)

28.5 [25;32]

LA Volume, ml (median; IQR)

81 [70;96.5]

LA volume index, ml/m2 (median; IQR)

41[34;47]

LA volume index > 48 ml/m2 (n,%)

11(19)

LA volume index > 34 ml/m2 (n,%)

42(80)

14

ACCEPTED MANUSCRIPT LA diameter, mm (mean ±SD)

45.1±6.64

BMI: body mass index; AF: atrial fibrillation; TIA: transient ischemic attack; EHRA: European Heart Rhythm Association; LVEF: left ventricular ejection fraction; LVEED: left ventricular end diastolic diameter; LVEDV: left ventricular end diastolic volume; SPAP: systolic pulmonary artery pressure;

AC C

EP

TE D

M AN U

SC

RI PT

LA: left atrium

15

ACCEPTED MANUSCRIPT

0

Acute renal failure requiring CVVH (n,%)

0

Stroke (n,%)

0

AMI (n,%)

0 2 (3.3)

Red blood cell transfusions (n,%)

9 (15.2)

Pericardial effusion drainage (n,%)

1 (1.7)

Pneumothorax drainage (n,%)

2 (3.3)

Mediastinitis (n,%)

1 (1.7)

Pacemaker implantation (n,%)

1 (1.7)

M AN U

Re-exploration for bleeding (n,%)

SC

Intra-aortic balloon pump (n,%)

RI PT

Table 2. Postoperative complications (59 patients).

AC C

EP

TE D

CVVH=continuous veno-venous haemofiltration; AMI= acute myocardial infarction

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ACCEPTED MANUSCRIPT Table 3. Predictors of recurrence of AF (Fine and Gray model) Univariate

Multivariate

HR (95%CI)

P value

HR (95%CI)

Age

0.98 (0.93-1.04)

0.48

BMI

1.05 (0.89-1.25)

0.53

Duration of AF history

1.01 (1.00-1.01)

0.01

1.01 (1.00-1.02)

0.0001

L-S persistent AF

3.15 (1.13-8.80)

0.02

2.89 (0.60-13.96)

0.18

LVEF

1.02 (0.97-1.06)

0.45

SPAP

1.08 (1.02-1.15)

0.01

1.05 (0.97-1.14)

0.15

LA volume index

1.00 (0.98-1.03)

0.82

SC

M AN U

Minimally invasive approach 0.64 (0.23-1.82)

P value

RI PT

Preoperative variables

0.40

BMI: body mass index; AF: atrial fibrillation; L-S long standing; LVEF: left ventricular ejection

AC C

EP

TE D

fraction; SPAP: systolic pulmonary artery pressure; LA: left atrium

17

ACCEPTED MANUSCRIPT Figure legends Figure 1. CIF of recurrence of AF with death as competing risk. Figure 2. CIF of recurrence of AF off class I/III AADs, with death as competing risk. Figure 3. Percent of patients in SR and in SR off class I/III AADs/ECV.

RI PT

Figure 4. Trend of predicted prevalence of SR (red line) and SR off class I/III AADs (light-blue line). Symbols represent grouped raw data without regard to repeated measures to provide a crude

verification of longitudinal model fit: red triangles represent observed grouped data of SR and light-

AC C

EP

TE D

M AN U

SC

blue squares represent observed grouped data of SR off AADs.

18

ACCEPTED MANUSCRIPT Abbreviations and acronyms AADs: antiarrhythmic drugs AF: atrial fibrillation AMI: acute myocardial infarction

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ATA: atrial tachyarrhythmia BMI: body mass index CIF: Cumulative Incidence Function CPB: cardio-pulmonary bypass

SC

CRT: cardiac resynchronization therapy

ECG: electrocardiogram ECV: electrical cardioversion

M AN U

CVVH: continuous veno-venous haemofiltration

EHRA: European Heart Rhythm Association GEE: generalized estimating equations

HSR: Heart Rhythm Society

TE D

HR: hazard ratio

ICD: implanted cardioverter device

EP

ILR: implantable loop recorder IQR: interquartile range

AC C

LA: left atrial L-S: long-standing

LVEDV: left ventricular end diastolic volume LVEDD: left ventricular end diastolic diameter LVEF: left ventricular ejection fraction NYHA: New York Heart Association OAC: oral anticoagulants RF: radiofrequency SPAP: systolic pulmonary artery pressure

19

ACCEPTED MANUSCRIPT SR: sinus rhythm TEE: transesophageal Doppler echocardiography TIA: transient ischemic attack

AC C

EP

TE D

M AN U

SC

RI PT

TTE: transthoracic echocardiography

20

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

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