Biatrial linear ablation in sustained nonpermanent AF: Results of the substrate modification with ablation and antiarrhythmic drugs in nonpermanent atrial fibrillation (SMAN-PAF) trial Gareth J. Wynn, MB ChB, MRCP, MD(Res),*†‡ Sandeep Panikker, MBBS, MRCP,*‡§¶ Maureen Morgan, RN,*† Mark Hall, MD, FRCP,*† Johan Waktare, MD, FRCP,*† Vias Markides, MD, FRCP,*‡§¶ Wajid Hussain, MB ChB, MRCP,*‡¶ Tushar Salukhe, MD(Res), MRCP,*‡§ Simon Modi, MBBS, MRCP,*† Julian Jarman, MA, MBBS, MRCP, MD(Res),*‡§ David G. Jones, MBBS, MD,*‡¶ Richard Snowdon, MD, MRCP,*† Derick Todd, MD, FRCP,*†‡ Tom Wong, MD, FRCP,*‡§¶ Dhiraj Gupta, MD, FRCP*†‡ From the *Institute of Cardiovascular Medicine and Science, Liverpool & London, United Kingdom, † Liverpool Heart and Chest Hospital, Liverpool, United Kingdom, ‡Imperial College London, London, United Kingdom, §Royal Brompton Hospital, London, United Kingdom, and ¶Harefield Hospital, London, United Kingdom. BACKGROUND More advanced atrial fibrillation (AF) is associated with lower success rates after pulmonary vein isolation (PVI), and the optimal ablation strategy is uncertain. OBJECTIVES To assess the impact of additional linear ablation (lines) compared to PVI alone. METHODS In this multicenter randomized controlled trial, 122 patients (mean age 61.9 ⫾ 10.5 years; left atrial diameter 43 ⫾ 6 mm) with persistent AF (PeAF) or sustained (412 hours) paroxysmal AF (SusPAF) with risk factors for atrial substrate were included and followed up for 12 months. Patients were randomized to PVI-only or PVI þ lines (left atrial roof line, mitral isthmus line, and tricuspid isthmus line) group. Holter monitoring was performed at 3, 6, and 12 months and according to symptoms. The primary outcome was atrial tachyarrhythmia recurrence lasting Z30 seconds. RESULTS Baseline characteristics were comparable between groups; 61% had PeAF and 39% SusPAF. Successful PVI was achieved for 98% of pulmonary veins, and bidirectional block was obtained in 90% of lines. The primary end point occurred in 38% of the PVI þ lines group and 32% of the PVI-only group (P ¼ .50), which was consistent in both PeAF (36% vs 28%; P ¼ .45) and SusPAF (42% vs 39%; P ¼ .86). Compared with the PVI-only group, the PVI þ lines group had higher procedure duration (209 ⫾ 52 minutes vs 172 ⫾ 44 minutes; P o .001), ablation time (4352 ⫾
1084 seconds vs 2503 ⫾ 1061 seconds; P o .001), and radiation exposure (Dose-area product 3992 ⫾ 6496 Gy cm2 vs 2106 ⫾ 1679 Gy cm2; P ¼ .03). Quality of life (disease-specific Atrial Fibrillation Effect on Quality of Life questionnaire and mental component scale of the Short Form 36 Health Survey) improved significantly during the study but did not differ between groups. CONCLUSION Adding lines to wide antral PVI in substrate-based AF requires significantly more ablation, increases procedure duration and radiation dose, but provides no additional clinical benefit. KEYWORDS Atrial Fibrillation; Ablation; Clinical trial; Persistent atrial fibrillation; Atrial substrate; Outcomes; Quality of life ABBREVIATIONS AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; AFEQT ¼ Atrial Fibrillation Effect on Quality of Life; AT ¼ atrial tachycardia; CI ¼ confidence interval; CTI ¼ cavotricuspid isthmus; ITT ¼ intention-to-treat; OR ¼ odds ratio; PAF ¼ paroxysmal atrial fibrillation; PeAF ¼ persistent atrial fibrillation; PV ¼ pulmonary vein; PVI ¼ pulmonary vein isolation; RCT ¼ randomized controlled trial; SusPAF ¼ sustained paroxysmal atrial fibrillation; WACA ¼ wide area circumferential ablation (Heart Rhythm 2016;13:399–406) I 2016 Heart Rhythm Society. All rights reserved.
Introduction Dr Panikker has received research grants from Boston Scientific. Dr Markides is on speakers bureau of Biosense Webster. Dr Gupta has received research grants and fellowship support from Biosense Webster. Address reprint requests and correspondence: Dr Dhiraj Gupta, Liverpool Heart and Chest Hospital, Thomas Dr, Liverpool L14 3PE, United Kingdom. E-mail address: [email protected].
1547-5271/$-see front matter B 2016 Heart Rhythm Society. All rights reserved.
Atrial fibrillation (AF) is a continuum of disease that ranges from a single paroxysm without accompanying comorbidity to continuous, permanent AF where sinus rhythm cannot be restored.1 Patients toward the latter end of this spectrum often have adversely remodeled left atria and may well have http://dx.doi.org/10.1016/j.hrthm.2015.10.006
400 additional comorbidities, known to increase AF susceptibility.2 The electrical, structural, and functional aspect of this remodeling is termed the AF substrate. Ablation techniques for AF have evolved from attempts to target individual triggers to modern encirclement of ipsilateral vein pairs (wide area circumferential ablation [WACA]) to achieve pulmonary vein isolation (PVI) where most ectopic triggers for AF reside.3,4 Further substrate modification can be achieved with antiarrhythmic drugs (AADs)5 by performing more extensive ablation6 or by combining both approaches, but it is still unclear whether this translates into net clinical benefit compared to PVI alone. In this multicenter randomized controlled trial (RCT), in a group of patients receiving periprocedural AADs we assessed whether substrate modification by addition of biatrial linear ablation lesions (lines) to a strategy of WACA alone provided greater freedom from AF recurrence. The study was prospectively registered at www.clinicaltrials.gov (Clinical Trial Registration No.: NCT01445925).
Heart Rhythm, Vol 13, No 2, February 2016 episode of atrial flutter occurred after randomization, patients were not excluded, but if they were randomized to the PVI-only group, patients also received linear ablation of the cavotricuspid isthmus (CTI).
Primary end point The primary end point was recurrence of documented AF or other atrial tachyarrhythmia (AF/AT), lasting Z30 seconds, after a single procedure within the 12-month follow-up period. Episodes of AF/AT occurring entirely and solely within 3 months of the ablation were blanked for the purpose of analyzing primary and secondary end points.11,12
Secondary end points Prespecified secondary end points were as follows:
adverse events (death, stroke, procedural complications, and cardiovascular hospitalization);
effect of ablation on quality of life according to the
Methods This was a prospective, multicenter, single-blinded RCT performed at 3 tertiary AF referral centers in the United Kingdom. Eligible consenting patients were randomized (in 1:1 ratio) to either
generic Short Form 36 Health Survey and the AF-specific Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire; analysis of the primary end point according to AF type; and recurrence of AF/AT after multiple procedures.
PVI-only group, or PVI and linear ablation (PVI þ lines) group. AAD regime All patients received periprocedural AADs as described below. Randomization was performed using freely available software (Minim, www.sghms.ac.uk/depts/phs/guide/randser. htm) incorporating partial minimization to balance for AF type and was stratified according to institution.
All patients were prescribed an AAD for a minimum of 6 weeks preprocedure and exactly 6 weeks postprocedure. Deviation from this was permitted only if mandated by clinical need. Amiodarone was the first choice AAD unless contraindicated, in which case flecainide was used. In addition, patients established on flecainide at enrollment were maintained on the drug.
Inclusion and exclusion criteria
Ablation procedure
Enrolled patients had to meet the following criteria: (1) age Z18 years, (2) ongoing symptoms (European Heart Rhythm Association class Z2) despite drug treatment, and (3) possible substrate-based AF defined as either: (a) persistent AF (PeAF)—continuous AF for 47 days1; or (b) sustained (412 hours but o7 days) episodes of paroxysmal AF (SusPAF), which was possibly substrate based because of Z1 other risk factor that might suggest an underlying substrate—(age 465 years,7 hypertension with left ventricular hypertrophy,8 left atrial dilatation of 445 mm, obesity (body mass index 430 kg/m2), or confirmed diagnosis of sleep apnea,9 and diabetes mellitus requiring medication).10 Exclusion criteria were as follows: (1) long-standing (412 months) PeAF, (2) previous AF ablation, (3) prosthetic mitral valve, (4) hypertrophic/infiltrative cardiomyopathy, (4) contraindication to both amiodarone and flecainide, (5) inability/unwillingness to take oral anticoagulation, and (e) documented typical atrial flutter. If the first documented
Patients continued oral anticoagulation periprocedurally, with an international normalized ratio of 2.0–3.5 on the day of the procedure considered acceptable for those taking warfarin.13,14 Periprocedural use of dabigatran was allowed according to local guidelines. Transesophageal echocardiography was performed preprocedurally to exclude left atrial thrombus at the discretion of the operator according to normal practice. AF ablation was performed under conscious sedation or general anesthesia using NaivStar or SmartTouch catheters (Biosense Webster Inc, Diamond Bar, CA).15 Transseptal punctures were made using fluoroscopic and pressure monitoring. After transseptal puncture, patients received intravenous unfractionated heparin to maintain an activated clotting time of 4300 seconds. If patients were in AF at that point, they underwent electrical cardioversion to allow ablation to be performed in sinus rhythm. An electroanatomic map of the left atrium was created and, whenever possible,
Wynn et al Table 1
SMAN-PAF Trial
401
Baseline characteristics of patients enrolled in the SMAN-PAF randomized controlled trial
Characteristic
Total(N ¼ 130)
PVI(n ¼ 64)
PVI þ lines(n ¼ 66)
P
Sex: male Age (y) BMI (kg/m2) Persistent AF Duration PeAF (mo)* Hypertension Previous MI Diabetes EHRA class CHA2DS2-VASc score LV ejection fraction (%) LA diameter (mm) Amiodarone
88 (68) 61.9 ⫾ 10.5 28.9 ⫾ 8.7 79 (61) 5.5þ4.0 75 (58) 12 (9) 8 (6) 2.8 ⫾ 0.6 1.7 ⫾ 1.3 61.1 ⫾ 11.8 43 ⫾ 6 100 (77)
47 (73) 61.8 ⫾ 9.7 29.2 ⫾ 9.3 39 (61) 5.5þ4.2 33 (52) 5 (8) 6 (9) 2.8 ⫾ 0.6 1.4 ⫾ 1.2 60.5 ⫾ 11.0 43 ⫾ 6 49 (77)
41 (62) 61.9 ⫾ 11.4 28.6 ⫾ 8.0 40 (61) 5.5þ3.9 42 (64) 7 (11) 2 (3) 2.8 ⫾ 0.7 1.9 ⫾ 1.4 61.5 ⫾ 12.6 43 ⫾ 6 51 (77)
.17 .98 .71 .97 .98 .16 .58 .13 .74 .054 .65 .81 4.99
Values are presented as mean ⫾ SD or as n (%). AF ¼ atrial fibrillation; BMI ¼ body mass index; EHRA ¼ European Heart Rhythm Association; LA ¼ left atrial; LV ¼ left ventricular; MI ¼ myocardial infarction; PeAF ¼ persistent atrial fibrillation; PVI ¼ pulmonary vein isolation. * Duration of the current episode at the time of randomization for patients in PeAF.
integrated with a magnetic resonance imaging or computed tomography reconstruction (CartoMerge, Biosense Webster).16,17 Patients randomized to the PVI-only group received a series of radiofrequency (RF) ablation lesions 42 mm outside pulmonary vein (PV) ostia to encircle and electrically isolate the PVs in 2 ipsilateral pairs (WACA).18 A 20-pole PV mapping catheter was used to confirm electrical isolation (entrance block). Patients randomized to the PVI þ lines group received a prespecified linear ablation lesion set in addition to PVI, as described above. This consisted of a left atrial roof line, mitral isthmus line (including ablation inside the coronary sinus, if necessary), and CTI line, with the end point of bidirectional conduction block across each line.12 In both groups, a minimum waiting time of 30 minutes was observed between complete isolation of the PVs and verification of PVI. Conduction block across lines was checked at the end of the procedure. Mapping of complex fractionated electrograms was not performed.
Follow-up Study follow-up visits were performed at 3, 6, and 12 months postablation. Additional clinical visits were permitted as required. A 12-lead resting electrocardiogram and 24-hour ambulatory Holter monitoring was performed at all study visits unless AF/AT had already been documented. Ad hoc Holter monitoring was also performed as required for intercurrent tachyarrhythmia symptoms. Prolonged (7- to 14-day) symptom-activated monitoring was performed for patients with ongoing symptoms where other monitoring was nondiagnostic. Anticoagulation was prescribed for at least 3 months postablation and then according to the current guidelines.19
Sample size calculation We assumed single procedure success rates of 55% (PVI only) and 80% (PVI þ lines). This was based on the results
of 3 studies that had previously trialed a PVI technique against one involving additional linear ablation in patients with PeAF.6,20,21 Of these, the mean difference between treatment arms was 33%. Therefore, although large, our expected effect size of 25% was in keeping with the available literature. Allowing for an α error of 0.05 and a β error of 20% (80% power), the number of patients required was calculated as 124. An anticipated 5% attrition rate gave a target sample size of 130.
Statistical analysis Statistical analyses were performed using SPSS Statistics version 21 (IBM Corp, Armonk, NY). All end points were examined by means of a modified intention-to-treat (ITT) analysis in which all patients who underwent a study procedure were eligible for the analysis. In this, patients who underwent ablation were analyzed according to the allocated treatment arm, irrespective of the actual lesion set delivered. Per-protocol and as-treated sensitivity analyses were also performed. Categorical variables were compared using the Fisher exact test or χ2 test. Continuous variables were expressed as means ⫾ SD and compared using the Student t test. Univariate and multivariate predictors of AF/ AT were examined using logistic regression analysis. Variables with a univariate P value of r.1 were included in the multivariate model. All reported P values were 2sided, and a P value of o.05 was considered significant.
Results Of 130 enrolled patients, 64 (49%) were randomized to the PVI-only group and 66 (51%) to the PVI þ lines group. Characteristics of the enrolled patients are listed in Table 1.
Follow-up The study CONSORT diagram is shown in Figure 1. All except 2 patients who underwent ablation completed 12-month follow-up. Neither of these 2 contributed any follow-up data. One reported freedom from symptomatic AF
402
Heart Rhythm, Vol 13, No 2, February 2016 Enrollment Assessed for eligibility (n=200)
Excluded (n=70) ♦ Inclusion/ exclusion criteria (n= 53) ♦ Declined to participate (n=12) ♦ Unable to comply with protocol (n=5)
Randomized (n= 130)
Allocated to PVI (n= 64) ♦ Received allocated intervention (n=61)
Allocation Allocated to PVI +lines (n= 66) ♦ Received allocated intervention (n=63)
♦ Did not receive allocated intervention (n=3) 1x Symptomatic improvement 2x Withdrew due to other medical problems
♦ Did not receive allocated intervention (n=3) 1x Symptomatic improvement 2x Underwent alternative intervention
Follow-Up Lost to follow-up (n= 2) 1 x Non-cardiovascular death 1 x Repeated non-attendance
Lost to follow-up (n=0) Discontinued intervention (n=0)
Discontinued intervention (n= 0)
Analysis Analysed (n=63) ♦ Excluded from analysis (n=0)
Analysed (n= 59) ♦ Excluded from analysis (n=0)
Figure 1
Study CONSORT diagram. PVI ¼ pulmonary vein isolation.
episodes but failed to attend any monitoring or review visits. A second patient with preexisting Crohn’s disease had a severe relapse shortly after his ablation, which directly led to his death 8 months later. Twenty-seven patients (14 in the PVI-only group and 23 in the PVI þ lines group) underwent additional or prolonged rhythm monitoring in addition to the prespecified study requirement. Six patients withdrew or were withdrawn from the study after randomization but before ablation had been performed. Two withdrew consent for ablation due to symptomatic improvement; 2 underwent alternative, nonstudy, procedures; and in 2 patients, a new diagnosis of hypertrophic cardiomyopathy, an exclusion criterion, was made using preprocedural imaging. These patients were not included in subsequent analyses.
Ablation procedures All patients were included in an ITT analysis according to their initial randomization. One protocol violation occurred when a patient randomized to the PVI þ lines group did not undergo the additional linear ablation procedure because of a clinical decision by the operating consultant. One more patient underwent no linear ablation because of technical
difficulties. In 8 patients allocated to the PVI-only group, an additional ablation procedure was performed on the CTI line because of sustained typical atrial flutter induced during the procedure. Details of the index procedure for all patients who underwent ablation, including the 2 lost to follow-up, are given in Table 2. Confirmed isolation of all 4 PVs was achieved in 121 patients (98%). Of the 496 PVs, 55 (11%) required additional ablation at the end of the waiting period because of early conduction recovery. Bidirectional block was achieved and proved in 90% of lines performed. In terms of individual linear lesions, bidirectional block was achieved in 90% (55 of 61) of roof lines, 83% (49 of 59) of mitral isthmus lines, and 96% (65 of 68) of CTI lines. Further ablation after the waiting period was required for 10 (5%) lines for early conduction recovery.
Primary end point Over the 12-month follow-up period after the index procedure, recurrence of AF/AT occurred in 19 patients (32%) in the PVI-only group and 24 patients (38%) in the PVI þ lines
Wynn et al Table 2
SMAN-PAF Trial
403
Details of the index procedure
Variable
Total(n ¼ 124)
PVI(n ¼ 61)
PVI þ lines(n ¼ 63)
P
Procedure time (min) Ablation time (s) DAP (Gy cm2) Fluoroscopy time (s) Wait time after PVI (min) Use of contact force sensing catheter CT/MR merge Sinus rhythm at the start Incomplete lesions
191 ⫾ 51 3435 ⫾ 1415 3065 ⫾ 4853 1356 ⫾ 764 62 ⫾ 33 104 (83.9) 84 (68) 89 (72) 19 (15)
172 ⫾ 44 2503 ⫾ 1061 2106 ⫾ 1679 1079 ⫾ 527 43 ⫾ 16 48 (78.7) 39 (64) 43 (71) 2 (3)
209 ⫾ 52 4352 ⫾ 1084 3992 ⫾ 6496 1610 ⫾ 858 80 ⫾ 35 56 (88.9) 45 (71) 46 (73) 17 (27)
o.001 o.001 .03 o.001 o.001 .12 .37 .75 o.001
Values are presented as mean ⫾ SD or as n (%). CT ¼ computed tomography; DAP ¼ dose-area product; MR ¼ magnetic resonance; PVI ¼ pulmonary vein isolation.
group after a single ablation procedure. The difference between the groups was not statistically significant (P ¼ .50). All patients successfully discontinued AADs postprocedure. In 3 patients (2 in the PVI-only group and 1 in the PVI þ lines group), AADs were later readministered on clinical grounds because of ongoing symptoms without documented AF/AT. Freedom from the primary end point without AADs occurred in 64% (38 of 59) of the PVI-only group and 62% (39 of 63) of the PVI þ lines group (P ¼ .78). Mechanism of recurrence Of the 43 patients with recurrence of atrial tachyarrhythmia, 34 (17 in each group) presented with AF and 9 (2 in the PVI-only group and 7 in the PVI þ lines group) with AT or atrial flutter. This difference in recurrence mechanism did not meet statistical significance (P ¼ .26). There was no significant association between the presence of an incomplete ablation lesion and AF/AT recurrence (8 of 43 [19%] with recurrence vs 11 of 79 [14%] without; P ¼ .5). This remained true for subgroup analysis according to treatment arm. Although none of these comparisons reached statistical significance, it should be noted that the size of the study did not have sufficient power to adequately investigate the differences seen. Predictors of AF recurrence Univariate and multivariable predictors of the primary end point were sought using logistic regression analysis. Details of the analysis are given in Table 3. Only female sex and procedural duration met the prespecified inclusion criteria for inclusion in the multivariable model. However, only procedure duration remained significant in multivariable analysis (odds ratio [OR] (per minute) 1.01; 95% confidence interval [CI] 1.01–1.02; P ¼ .03). Per-protocol and as-treated analyses The per-protocol analysis for the primary end point showed no significant difference between the treatment groups (31.4% [PVI-only group] vs 37.3% [PVI þ lines group]; P ¼ .52), suggesting that protocol deviations had a negligible effect on the findings by ITT analysis. Furthermore, as 2 patients randomized to lines received PVI alone, we performed the as-treated analysis of PVI alone against both PVI
þ complete linear lesion set (32.1% [PVI alone] vs 43.6% [PVI þ complete linear lesion set] P ¼ .61) and PVI þ any linear ablation (32.1% [PVI alone] vs 37.7% [PVI þ any linear ablation]; P ¼ .52). The results of both these additional sensitivity analyses were in concordance with the main ITT analysis.
Secondary end points Comparison of PeAF and SusPAF Of the 122 patients who completed follow-up, the primary end point was observed in 24 of 75 patients with PeAF (32.0%) and 19 of 47 with SusPAF (40.4%) (P ¼ .34). The mean duration of PeAF was 5.5 ⫾ 4.2 months in the PVI-only group and 5.5 ⫾ 3.9 months in the PVI þ lines group (P ¼ .98). Although not powered for subgroup analysis, there was no signal that the occurrence of the primary end point differed between treatment arms according to AF type (PeAF [PVI 27.8%; PVI þ lines 35.9%; P ¼ .45] and SusPAF [PVI 39.1%; PVI þ lines 41.7%; P ¼ .86]). Outcomes after multiple procedures Sixteen patients (8 in each group) had repeat ablation procedures performed, and 10 of these remained free of AF/AT after their second procedure, although it should be borne in mind that the follow-up period after a second ablation procedure is considerably shorter (median 110 days; interquartile range 43–207 days) than that after the index procedure. After their last procedure, recurrence of AF/AT occurred in 14 patients (23.7%) in the PVI-only group and 14 patients (30.2%) in the PVI þ lines group (P ¼ .42). Quality of life The overall AFEQT score for the cohort at baseline was 50.9 ⫾ 22.6, which improved significantly to 76.5 ⫾ 23.4 at the end of the study (P o .001). The improvement after ablation was seen in both treatment groups, with no significant difference between the study groups, either at baseline (50.5 ⫾ 23.3 vs 51.3 ⫾ 22.0; P ¼ .86) or at the final follow-up visit (76.9 ⫾ 23.0 vs 76.1 ⫾ 24.1; P ¼ .62). Also, the individual AFEQT domains of symptoms, activities, and concerns all followed the same pattern, with each improving significantly between baseline and the final follow-up visit as an overall cohort and when analyzed according to treatment
404 Table 3
Heart Rhythm, Vol 13, No 2, February 2016 Details of the logistic regression analysis Univariate analysis
Multivariable analysis
Variable
Odds ratio
95% confidence interval
P
Ablation time (per minute) CHA2DS2-VASc score Diabetes Ejection fraction (%) Sex: female General anesthetic Hypertension Incomplete lesions Left atrial diameter (per millimeter) Myocardial infarction Persistent AF Procedure time (per minute) Treatment allocation Wait time (min) Contact force sensing catheter
1.01 1.21 0.50 1.00 1.99 0.83 0.90 1.41 1.01 0.34 0.69 1.01 1.30 1.00 1.00
0.99–1.03 0.91–1.561 0.17–1.44 0.97–1.04 0.91–4.36 0.39–1.77 0.42–1.91 0.52–3.83 0.94–1.07 0.07–1.61 0.33–1.48 1.00–1.02 0.61–2.73 0.99–1.01 0.27–3.63
.29 .19 .20 .97 .09 .62 .78 .50 .89 .17 .34 .02 .50 .54 4.99
Odds ratio
95% confidence interval
P
1.01
1.01–1.02
.03
AF ¼ atrial fibrillation.
group (P r .001 for all analyses), but all between-group analyses were nonsignificant. The mental component score of the Short Form 36 Health Survey improved significantly over the course of the study (from 45.7 ⫾ 12.1 to 52.0 ⫾ 9.5; P o .001), but the physical component score did not (from 44.7 ⫾ 10.8 to 47.9 ⫾ 10.5; P ¼ .07). Treatment groups did not differ significantly for either component score either at baseline (physical component score: P ¼ .39; mental component score: P ¼ .72) or at 12 months (physical component score: P ¼ .09; mental component score: P ¼ .73).
Safety end point One patient (PVI-only group) developed a pericardial effusion postprocedure, successfully drained percutaneously without sequalae. Two patients developed femoral pseudoaneurysms, both successfully treated with direct thrombin injection. The rate of major complications was 2.4% (3 of 124), with no difference between groups (P ¼ .62). There were no periprocedural deaths, and no thromboembolic events occurred in the periprocedural period or during follow-up. Five patients developed femoral hematomas, which were managed conservatively but which either delayed discharge or prompted readmission. Two patients (both of the PVI þ lines group) were admitted with heart failure after their procedure, both of whom were successfully managed medically. Including these, the combined incidence of major complications, all-cause death, and minor complications was 9.7%, with no difference between the treatment groups (PVI 8.2%; PVI þ lines 9.5%; P 4 .99).
Discussion AF represents a spectrum of disease ranging from lone occasional PAF at one end to long-standing PeAF in the presence of multiple comorbidities at the other. It is believed that while the former is largely caused by ectopic triggers in
the PVs, patients with more advanced disease suffer from an increasing contribution from abnormal structural and electrical atrial “substrate” that contributes to the perpetuation of AF. As such, it is important to evaluate interventions that can modify this atrial substrate favorably. Our group’s previous meta-analysis found that the addition of lines was the only adjunctive ablation lesion to significantly reduce the risk of AF recurrence in patients with PeAF (OR 0.22; 95% CI 0.10–0.49; P o .001).22 Two of the studies that contributed to that analysis also included patients with PAF and found a benefit of lines in both. However, we found no such difference in the RCT we present here. There may be several reasons why our results differ from those of the aforementioned studies. Unlike them, our protocol specified PVI by the WACA technique that involves ablation of a significant amount of antral atrial, rather than venous, tissue.23 WACA may well have an additional substrate modification effect over and above pure venous isolation by creating physical barriers to reentry, interrupting potential sites of rotor activation and by modification of autonomic innervation due to indirect ablation of ganglionated plexi, typically concentrated antrally. We previously found WACA to be associated with a nonsignificant trend toward a lower incidence of AF recurrence compared to segmental PVI (OR 0.41; 95% CI 0.15–1.10; P ¼ .08).22 In addition, our study had a high use of contact force sensing ablation catheters, which have recently been shown to improve the durability of PVI.24,25 The widespread adoption of such technology may necessitate reevaluation of much of the evidence base derived from the era before it was available. Our acute success rates (isolation of 98% of PVs and bidirectional block of 90% of lines) compare favorably with those in the previous studies in which the rates of bidirectional linear block ranged from 31% to 80%. However, all ablation lesions have the potential for subacute recovery, leading to zones of slow conduction that may be proarrhythmic and explain the slightly worse results seen in our study with more extensive ablation. It may well be that
Wynn et al
SMAN-PAF Trial
after high-quality durable WACA PVI, “less is more” in terms of additional lesions. Our results are concordant with the recent Substrate and Trigger Ablation for Reduction of Atrial Fibrillation 2 trial, which showed no incremental benefit of lines or complex electrogram ablation over PVI alone, with both groups performing nonsignificantly worse, as in our trial, than PVI alone.26 Taken together, these 2 trials would suggest that given the shorter procedure times, ablation times, and lower radiation doses associated with a PVI-only strategy, clinicians should avoid the empirical use of additional linear lesions. In this study, we included patients with PAF if they had additional risk factor(s) for poor outcome after ablation and, importantly, only if their paroxysms lasted 412 hours, as we felt this was suggestive of a role of left atrial substrate in maintaining these prolonged attacks. For convenience, we used the nonstandard term SusPAF. Several clinical risk factors such as systemic hypertension, diabetes mellitus, obesity, and sleep apnea have been associated with altered atrial substrate,7–10 and recent magnetic resonance imagingbased research has shown that advanced atrial substrate can be present even in patients with PAF and is associated with poor outcomes with PVI.27 The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation trial similarly included both patients with PeAF and “advanced” PAF.28 Our subanalyses by AF type suggests that the inclusion of the SusPAF group did not alter the overall primary finding of our trial, and the similarity of results between the SusPAF and PeAF groups would seem to back our assertion that patients with SusPAF have a similar disease process to those with PeAF. In our trial, we mandated universal use of AADs in the periprocedural period, whereas previous studies have usually discontinued AADs at or before the time of ablation. The benefit of continued AAD has been suggested by a number of observational studies.5,29 Although the recently published AMIOdarone after CATheter ablation for atrial fibrillation (AMIO-CAT) RCT found no benefit of 8 weeks of amiodarone in 212 patients with either PAF or PeAF,30 we cannot exclude the possibility that our use of this strategy reduced the benefit that would have been seen in one study group or the other in this trial. Our study excluded patients with long-standing PeAF as well as patients with paroxysmal AF (PAF) without other possible risk factors for substrate abnormalities, and therefore our results cannot be extrapolated to these groups. Brooks et al31 performed a comprehensive review of studies in long-standing PeAF. They found low success rates in, mainly nonrandomized, studies using a PVI-only strategy. A prospective RCT in this group, using modern WACA techniques, may now be warranted.
Study limitations Our follow-up period of 12 months will not have identified late AF recurrences, but this would not be expected to affect the comparison between the 2 study groups. Equally, our use of intermittent monitoring for AF/AT may have underestimated
405 the true recurrence rate, especially if patients suffered asymptomatic recurrences, but this potential underestimate would not be expected to differ between groups. Our sample size calculation allowed for 5% attrition rate, whereas our eventual rate was 6%. However, our results show no trend to suggest that a slightly larger sample would have produced a different result. Although we tested for entrance block into the PVs, our protocol did not mandate testing of exit block, nor the use of adenosine. It is possible that these additional techniques would have improved the durability of PVI. Finally, some patients in the PVI þ lines group received incomplete lesion sets while a few randomized to the PVI-only group received additional ablation of the CTI. With this in mind, we performed per-protocol and as-treated sensitivity analyses which showed no evidence that there was any confounding of the primary outcome.
Conclusion For patients with possible substrate-based AF, the addition of linear ablation lesions to PVI with WACA prolongs procedure duration and significantly increases radiation dose, but provides no additional clinical benefit in terms of freedom from arrhythmia or improvement in quality of life.
References 1. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–2429. 2. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. JAMA 1994;271:840–844. 3. Marchlinski FE, Callans D, Dixit S, et al. Efficacy and safety of targeted focal ablation versus PV isolation assisted by magnetic electroanatomic mapping. J Cardiovasc Electrophysiol 2003;14:358–365. 4. Mansour M, Ruskin J, Keane D. Efficacy and safety of segmental ostial versus circumferential extra-ostial pulmonary vein isolation for atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:532–537. 5. Khan A, Mittal S, Kamath GS, Garikipati NV, Marrero D, Steinberg JS. Pulmonary vein isolation alone in patients with persistent atrial fibrillation: an ablation strategy facilitated by antiarrhythmic drug induced reverse remodeling. J Cardiovasc Electrophysiol 2011;22:142–148. 6. Willems S, Klemm H, Rostock T, et al. Substrate modification combined with pulmonary vein isolation improves outcome of catheter ablation in patients with persistent atrial fibrillation: a prospective randomized comparison. Eur Heart J 2006;27:2871–2878. 7. Tuan TC, Chang SL, Tsao HM, et al. The impact of age on the electroanatomical characteristics and outcome of catheter ablation in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:966–972. 8. Medi C, Kalman JM, Spence SJ, et al. Atrial electrical and structural changes associated with longstanding hypertension in humans: implications for the substrate for atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:1317–1324. 9. Chilukuri K, Dalal D, Gadrey S, et al. A prospective study evaluating the role of obesity and obstructive sleep apnea for outcomes after catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:521–525. 10. Chao TF, Suenari K, Chang SL, et al. Atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation associated with diabetes mellitus or impaired fasting glucose. Am J Cardiol 2010;106: 1615–1620. 11. Kirchhof P, Auricchio A, Bax J, et al. Outcome parameters for trials in atrial fibrillation: executive summary. Eur Heart J 2007;28:2803–2817. 12. Calkins H, Kuck KH, Cappato R, 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. Heart Rhythm 2012;9:632–696.
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13. Finlay M, Sawhney V, Schilling R, et al. Uninterrupted warfarin for periprocedural anticoagulation in catheter ablation of typical atrial flutter: a safe and costeffective strategy. J Cardiovasc Electrophysiol 2010;21:150–154. 14. Page SP, Siddiqui MS, Finlay M, et al. Catheter ablation for atrial fibrillation on uninterrupted warfarin: can it be done without echo guidance? J Cardiovasc Electrophysiol 2011;22:265–270. 15. Earley MJ, Abrams DJ, Staniforth AD, Sporton SC, Schilling RJ. Catheter ablation of permanent atrial fibrillation: medium term results. Heart 2006;92:233–238. 16. Kistler PM, Rajappan K, Jahngir M, et al. The impact of CT image integration into an electroanatomic mapping system on clinical outcomes of catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:1093–1101. 17. Caponi D, Corleto A, Scaglione M, et al. Ablation of atrial fibrillation: does the addition of three-dimensional magnetic resonance imaging of the left atrium to electroanatomic mapping improve the clinical outcome? A randomized comparison of Carto-Merge vs. Carto-XP three-dimensional mapping ablation in patients with paroxysmal and persistent atrial fibrillation. Europace 2010;12:1098–1104. 18. Oral H, Scharf C, Chugh A, et al. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. Circulation 2003;108:2355–2360. 19. Camm AJ, Lip GY, De CR, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation: developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–2747. 20. Gaita F, Caponi D, Scaglione M, et al. Long-term clinical results of 2 different ablation strategies in patients with paroxysmal and persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2008;1:269–275. 21. Fassini G, Riva S, Chiodelli R, et al. Left mitral isthmus ablation associated with PV Isolation: long-term results of a prospective randomized study. J Cardiovasc Electrophysiol 2005;16:1150–1156. 22. Wynn GJ, Das M, Bonnett LJ, Panikker S, Wong T, Gupta D. Efficacy of catheter ablation for persistent atrial fibrillation: a systematic review and meta-analysis of
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evidence from randomised and non-randomised controlled trials. Circ Arrhythm Electrophysiol 2014;7:841–852. Nilsson B, Chen X, Pehrson S, Kober L, Hilden J, Svendsen JH. Recurrence of pulmonary vein conduction and atrial fibrillation after pulmonary vein isolation for atrial fibrillation: a randomized trial of the ostial versus the extraostial ablation strategy. Am Heart J 2006;152:537–538. Haldar S, Jarman JW, Panikker S, et al. Contact force sensing technology identifies sites of inadequate contact and reduces acute pulmonary vein reconnection: a prospective case control study. Int J Cardiol 2013;168: 1160–1166. Jarman JW, Panikker S, Das M, et al. Relationship between contact force sensing technology and medium-term outcome of atrial fibrillation ablation: a multicenter study of 600 patients. J Cardiovasc Electrophysiol 2015;26:378–384. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–1822. Mahnkopf C, Badger TJ, Burgon NS, et al. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm 2010;7: 1475–1481. Verma A, Mantovan R, Macle L, et al. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial. Eur Heart J 2010;31:1344–1356. Rivard L, Hocini M, Rostock T, et al. Improved outcome following restoration of sinus rhythm prior to catheter ablation of persistent atrial fibrillation: a comparative multicenter study. Heart Rhythm 2012;9:1025–1030. Darkner S, Chen X, Hansen J, et al. Recurrence of arrhythmia following shortterm oral AMIOdarone after CATheter ablation for atrial fibrillation: a doubleblind, randomized, placebo-controlled study (AMIO-CAT trial). Eur Heart J 2014;35:3356–3364. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835–846.
CLINICAL PERSPECTIVES More advanced forms of atrial fibrillation (AF) are associated with lower success rates after pulmonary vein isolation (PVI), and more extensive lesion sets are often advocated, although recent data have questioned the validity of this approach. In this multicenter randomized controlled trial of 122 patients, we evaluated the impact of additional biatrial linear ablation compared with a strategy of wide antral PVI alone. We enrolled patients with persistent AF or sustained (412 hours) episodes of paroxysmal AF with Z1 other risk factor that might suggest an underlying substrate. High acute procedural success rates were achieved in both treatment arms. Over the 12-month follow-up period, recurrence of atrial tachyarrhythmia occurred in 38% of the PVI þ linear ablation group and 32% of the PVI-only group, a difference that was not statistically different. This pattern was consistent for both patients with persistent AF and those with sustained paroxysmal AF. Compared with the PVI-only group, the linear ablation group had significantly longer procedure duration and higher radiation exposure. Quality of life improved from baseline to the final follow-up visit, but did not differ between the treatment arms. Given that the more extensive ablation strategy (PVI þ linear ablation) provided no additional benefit for patients in terms of clinical outcome and quality of life, the ancillary benefits of shorter procedure times and lower radiation doses associated with a PVI-only strategy should make this the strategy of choice for clinicians.
1084 seconds vs 2503 ⫾ 1061 seconds; P o .001), and radiation exposure (Dose-area product 3992 ⫾ 6496 Gy cm2 vs 2106 ⫾ 1679 Gy cm2; P ¼ .03). Quality of life (disease-specific Atrial Fibrillation Effect on Quality of Life questionnaire and mental component scale of the Short Form 36 Health Survey) improved significantly during the study but did not differ between groups. CONCLUSION Adding lines to wide antral PVI in substrate-based AF requires significantly more ablation, increases procedure duration and radiation dose, but provides no additional clinical benefit. KEYWORDS Atrial Fibrillation; Ablation; Clinical trial; Persistent atrial fibrillation; Atrial substrate; Outcomes; Quality of life ABBREVIATIONS AAD ¼ antiarrhythmic drug; AF ¼ atrial fibrillation; AFEQT ¼ Atrial Fibrillation Effect on Quality of Life; AT ¼ atrial tachycardia; CI ¼ confidence interval; CTI ¼ cavotricuspid isthmus; ITT ¼ intention-to-treat; OR ¼ odds ratio; PAF ¼ paroxysmal atrial fibrillation; PeAF ¼ persistent atrial fibrillation; PV ¼ pulmonary vein; PVI ¼ pulmonary vein isolation; RCT ¼ randomized controlled trial; SusPAF ¼ sustained paroxysmal atrial fibrillation; WACA ¼ wide area circumferential ablation (Heart Rhythm 2016;13:399–406) I 2016 Heart Rhythm Society. All rights reserved.
Introduction Dr Panikker has received research grants from Boston Scientific. Dr Markides is on speakers bureau of Biosense Webster. Dr Gupta has received research grants and fellowship support from Biosense Webster. Address reprint requests and correspondence: Dr Dhiraj Gupta, Liverpool Heart and Chest Hospital, Thomas Dr, Liverpool L14 3PE, United Kingdom. E-mail address: [email protected].
1547-5271/$-see front matter B 2016 Heart Rhythm Society. All rights reserved.
Atrial fibrillation (AF) is a continuum of disease that ranges from a single paroxysm without accompanying comorbidity to continuous, permanent AF where sinus rhythm cannot be restored.1 Patients toward the latter end of this spectrum often have adversely remodeled left atria and may well have http://dx.doi.org/10.1016/j.hrthm.2015.10.006
400 additional comorbidities, known to increase AF susceptibility.2 The electrical, structural, and functional aspect of this remodeling is termed the AF substrate. Ablation techniques for AF have evolved from attempts to target individual triggers to modern encirclement of ipsilateral vein pairs (wide area circumferential ablation [WACA]) to achieve pulmonary vein isolation (PVI) where most ectopic triggers for AF reside.3,4 Further substrate modification can be achieved with antiarrhythmic drugs (AADs)5 by performing more extensive ablation6 or by combining both approaches, but it is still unclear whether this translates into net clinical benefit compared to PVI alone. In this multicenter randomized controlled trial (RCT), in a group of patients receiving periprocedural AADs we assessed whether substrate modification by addition of biatrial linear ablation lesions (lines) to a strategy of WACA alone provided greater freedom from AF recurrence. The study was prospectively registered at www.clinicaltrials.gov (Clinical Trial Registration No.: NCT01445925).
Heart Rhythm, Vol 13, No 2, February 2016 episode of atrial flutter occurred after randomization, patients were not excluded, but if they were randomized to the PVI-only group, patients also received linear ablation of the cavotricuspid isthmus (CTI).
Primary end point The primary end point was recurrence of documented AF or other atrial tachyarrhythmia (AF/AT), lasting Z30 seconds, after a single procedure within the 12-month follow-up period. Episodes of AF/AT occurring entirely and solely within 3 months of the ablation were blanked for the purpose of analyzing primary and secondary end points.11,12
Secondary end points Prespecified secondary end points were as follows:
adverse events (death, stroke, procedural complications, and cardiovascular hospitalization);
effect of ablation on quality of life according to the
Methods This was a prospective, multicenter, single-blinded RCT performed at 3 tertiary AF referral centers in the United Kingdom. Eligible consenting patients were randomized (in 1:1 ratio) to either
generic Short Form 36 Health Survey and the AF-specific Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire; analysis of the primary end point according to AF type; and recurrence of AF/AT after multiple procedures.
PVI-only group, or PVI and linear ablation (PVI þ lines) group. AAD regime All patients received periprocedural AADs as described below. Randomization was performed using freely available software (Minim, www.sghms.ac.uk/depts/phs/guide/randser. htm) incorporating partial minimization to balance for AF type and was stratified according to institution.
All patients were prescribed an AAD for a minimum of 6 weeks preprocedure and exactly 6 weeks postprocedure. Deviation from this was permitted only if mandated by clinical need. Amiodarone was the first choice AAD unless contraindicated, in which case flecainide was used. In addition, patients established on flecainide at enrollment were maintained on the drug.
Inclusion and exclusion criteria
Ablation procedure
Enrolled patients had to meet the following criteria: (1) age Z18 years, (2) ongoing symptoms (European Heart Rhythm Association class Z2) despite drug treatment, and (3) possible substrate-based AF defined as either: (a) persistent AF (PeAF)—continuous AF for 47 days1; or (b) sustained (412 hours but o7 days) episodes of paroxysmal AF (SusPAF), which was possibly substrate based because of Z1 other risk factor that might suggest an underlying substrate—(age 465 years,7 hypertension with left ventricular hypertrophy,8 left atrial dilatation of 445 mm, obesity (body mass index 430 kg/m2), or confirmed diagnosis of sleep apnea,9 and diabetes mellitus requiring medication).10 Exclusion criteria were as follows: (1) long-standing (412 months) PeAF, (2) previous AF ablation, (3) prosthetic mitral valve, (4) hypertrophic/infiltrative cardiomyopathy, (4) contraindication to both amiodarone and flecainide, (5) inability/unwillingness to take oral anticoagulation, and (e) documented typical atrial flutter. If the first documented
Patients continued oral anticoagulation periprocedurally, with an international normalized ratio of 2.0–3.5 on the day of the procedure considered acceptable for those taking warfarin.13,14 Periprocedural use of dabigatran was allowed according to local guidelines. Transesophageal echocardiography was performed preprocedurally to exclude left atrial thrombus at the discretion of the operator according to normal practice. AF ablation was performed under conscious sedation or general anesthesia using NaivStar or SmartTouch catheters (Biosense Webster Inc, Diamond Bar, CA).15 Transseptal punctures were made using fluoroscopic and pressure monitoring. After transseptal puncture, patients received intravenous unfractionated heparin to maintain an activated clotting time of 4300 seconds. If patients were in AF at that point, they underwent electrical cardioversion to allow ablation to be performed in sinus rhythm. An electroanatomic map of the left atrium was created and, whenever possible,
Wynn et al Table 1
SMAN-PAF Trial
401
Baseline characteristics of patients enrolled in the SMAN-PAF randomized controlled trial
Characteristic
Total(N ¼ 130)
PVI(n ¼ 64)
PVI þ lines(n ¼ 66)
P
Sex: male Age (y) BMI (kg/m2) Persistent AF Duration PeAF (mo)* Hypertension Previous MI Diabetes EHRA class CHA2DS2-VASc score LV ejection fraction (%) LA diameter (mm) Amiodarone
88 (68) 61.9 ⫾ 10.5 28.9 ⫾ 8.7 79 (61) 5.5þ4.0 75 (58) 12 (9) 8 (6) 2.8 ⫾ 0.6 1.7 ⫾ 1.3 61.1 ⫾ 11.8 43 ⫾ 6 100 (77)
47 (73) 61.8 ⫾ 9.7 29.2 ⫾ 9.3 39 (61) 5.5þ4.2 33 (52) 5 (8) 6 (9) 2.8 ⫾ 0.6 1.4 ⫾ 1.2 60.5 ⫾ 11.0 43 ⫾ 6 49 (77)
41 (62) 61.9 ⫾ 11.4 28.6 ⫾ 8.0 40 (61) 5.5þ3.9 42 (64) 7 (11) 2 (3) 2.8 ⫾ 0.7 1.9 ⫾ 1.4 61.5 ⫾ 12.6 43 ⫾ 6 51 (77)
.17 .98 .71 .97 .98 .16 .58 .13 .74 .054 .65 .81 4.99
Values are presented as mean ⫾ SD or as n (%). AF ¼ atrial fibrillation; BMI ¼ body mass index; EHRA ¼ European Heart Rhythm Association; LA ¼ left atrial; LV ¼ left ventricular; MI ¼ myocardial infarction; PeAF ¼ persistent atrial fibrillation; PVI ¼ pulmonary vein isolation. * Duration of the current episode at the time of randomization for patients in PeAF.
integrated with a magnetic resonance imaging or computed tomography reconstruction (CartoMerge, Biosense Webster).16,17 Patients randomized to the PVI-only group received a series of radiofrequency (RF) ablation lesions 42 mm outside pulmonary vein (PV) ostia to encircle and electrically isolate the PVs in 2 ipsilateral pairs (WACA).18 A 20-pole PV mapping catheter was used to confirm electrical isolation (entrance block). Patients randomized to the PVI þ lines group received a prespecified linear ablation lesion set in addition to PVI, as described above. This consisted of a left atrial roof line, mitral isthmus line (including ablation inside the coronary sinus, if necessary), and CTI line, with the end point of bidirectional conduction block across each line.12 In both groups, a minimum waiting time of 30 minutes was observed between complete isolation of the PVs and verification of PVI. Conduction block across lines was checked at the end of the procedure. Mapping of complex fractionated electrograms was not performed.
Follow-up Study follow-up visits were performed at 3, 6, and 12 months postablation. Additional clinical visits were permitted as required. A 12-lead resting electrocardiogram and 24-hour ambulatory Holter monitoring was performed at all study visits unless AF/AT had already been documented. Ad hoc Holter monitoring was also performed as required for intercurrent tachyarrhythmia symptoms. Prolonged (7- to 14-day) symptom-activated monitoring was performed for patients with ongoing symptoms where other monitoring was nondiagnostic. Anticoagulation was prescribed for at least 3 months postablation and then according to the current guidelines.19
Sample size calculation We assumed single procedure success rates of 55% (PVI only) and 80% (PVI þ lines). This was based on the results
of 3 studies that had previously trialed a PVI technique against one involving additional linear ablation in patients with PeAF.6,20,21 Of these, the mean difference between treatment arms was 33%. Therefore, although large, our expected effect size of 25% was in keeping with the available literature. Allowing for an α error of 0.05 and a β error of 20% (80% power), the number of patients required was calculated as 124. An anticipated 5% attrition rate gave a target sample size of 130.
Statistical analysis Statistical analyses were performed using SPSS Statistics version 21 (IBM Corp, Armonk, NY). All end points were examined by means of a modified intention-to-treat (ITT) analysis in which all patients who underwent a study procedure were eligible for the analysis. In this, patients who underwent ablation were analyzed according to the allocated treatment arm, irrespective of the actual lesion set delivered. Per-protocol and as-treated sensitivity analyses were also performed. Categorical variables were compared using the Fisher exact test or χ2 test. Continuous variables were expressed as means ⫾ SD and compared using the Student t test. Univariate and multivariate predictors of AF/ AT were examined using logistic regression analysis. Variables with a univariate P value of r.1 were included in the multivariate model. All reported P values were 2sided, and a P value of o.05 was considered significant.
Results Of 130 enrolled patients, 64 (49%) were randomized to the PVI-only group and 66 (51%) to the PVI þ lines group. Characteristics of the enrolled patients are listed in Table 1.
Follow-up The study CONSORT diagram is shown in Figure 1. All except 2 patients who underwent ablation completed 12-month follow-up. Neither of these 2 contributed any follow-up data. One reported freedom from symptomatic AF
402
Heart Rhythm, Vol 13, No 2, February 2016 Enrollment Assessed for eligibility (n=200)
Excluded (n=70) ♦ Inclusion/ exclusion criteria (n= 53) ♦ Declined to participate (n=12) ♦ Unable to comply with protocol (n=5)
Randomized (n= 130)
Allocated to PVI (n= 64) ♦ Received allocated intervention (n=61)
Allocation Allocated to PVI +lines (n= 66) ♦ Received allocated intervention (n=63)
♦ Did not receive allocated intervention (n=3) 1x Symptomatic improvement 2x Withdrew due to other medical problems
♦ Did not receive allocated intervention (n=3) 1x Symptomatic improvement 2x Underwent alternative intervention
Follow-Up Lost to follow-up (n= 2) 1 x Non-cardiovascular death 1 x Repeated non-attendance
Lost to follow-up (n=0) Discontinued intervention (n=0)
Discontinued intervention (n= 0)
Analysis Analysed (n=63) ♦ Excluded from analysis (n=0)
Analysed (n= 59) ♦ Excluded from analysis (n=0)
Figure 1
Study CONSORT diagram. PVI ¼ pulmonary vein isolation.
episodes but failed to attend any monitoring or review visits. A second patient with preexisting Crohn’s disease had a severe relapse shortly after his ablation, which directly led to his death 8 months later. Twenty-seven patients (14 in the PVI-only group and 23 in the PVI þ lines group) underwent additional or prolonged rhythm monitoring in addition to the prespecified study requirement. Six patients withdrew or were withdrawn from the study after randomization but before ablation had been performed. Two withdrew consent for ablation due to symptomatic improvement; 2 underwent alternative, nonstudy, procedures; and in 2 patients, a new diagnosis of hypertrophic cardiomyopathy, an exclusion criterion, was made using preprocedural imaging. These patients were not included in subsequent analyses.
Ablation procedures All patients were included in an ITT analysis according to their initial randomization. One protocol violation occurred when a patient randomized to the PVI þ lines group did not undergo the additional linear ablation procedure because of a clinical decision by the operating consultant. One more patient underwent no linear ablation because of technical
difficulties. In 8 patients allocated to the PVI-only group, an additional ablation procedure was performed on the CTI line because of sustained typical atrial flutter induced during the procedure. Details of the index procedure for all patients who underwent ablation, including the 2 lost to follow-up, are given in Table 2. Confirmed isolation of all 4 PVs was achieved in 121 patients (98%). Of the 496 PVs, 55 (11%) required additional ablation at the end of the waiting period because of early conduction recovery. Bidirectional block was achieved and proved in 90% of lines performed. In terms of individual linear lesions, bidirectional block was achieved in 90% (55 of 61) of roof lines, 83% (49 of 59) of mitral isthmus lines, and 96% (65 of 68) of CTI lines. Further ablation after the waiting period was required for 10 (5%) lines for early conduction recovery.
Primary end point Over the 12-month follow-up period after the index procedure, recurrence of AF/AT occurred in 19 patients (32%) in the PVI-only group and 24 patients (38%) in the PVI þ lines
Wynn et al Table 2
SMAN-PAF Trial
403
Details of the index procedure
Variable
Total(n ¼ 124)
PVI(n ¼ 61)
PVI þ lines(n ¼ 63)
P
Procedure time (min) Ablation time (s) DAP (Gy cm2) Fluoroscopy time (s) Wait time after PVI (min) Use of contact force sensing catheter CT/MR merge Sinus rhythm at the start Incomplete lesions
191 ⫾ 51 3435 ⫾ 1415 3065 ⫾ 4853 1356 ⫾ 764 62 ⫾ 33 104 (83.9) 84 (68) 89 (72) 19 (15)
172 ⫾ 44 2503 ⫾ 1061 2106 ⫾ 1679 1079 ⫾ 527 43 ⫾ 16 48 (78.7) 39 (64) 43 (71) 2 (3)
209 ⫾ 52 4352 ⫾ 1084 3992 ⫾ 6496 1610 ⫾ 858 80 ⫾ 35 56 (88.9) 45 (71) 46 (73) 17 (27)
o.001 o.001 .03 o.001 o.001 .12 .37 .75 o.001
Values are presented as mean ⫾ SD or as n (%). CT ¼ computed tomography; DAP ¼ dose-area product; MR ¼ magnetic resonance; PVI ¼ pulmonary vein isolation.
group after a single ablation procedure. The difference between the groups was not statistically significant (P ¼ .50). All patients successfully discontinued AADs postprocedure. In 3 patients (2 in the PVI-only group and 1 in the PVI þ lines group), AADs were later readministered on clinical grounds because of ongoing symptoms without documented AF/AT. Freedom from the primary end point without AADs occurred in 64% (38 of 59) of the PVI-only group and 62% (39 of 63) of the PVI þ lines group (P ¼ .78). Mechanism of recurrence Of the 43 patients with recurrence of atrial tachyarrhythmia, 34 (17 in each group) presented with AF and 9 (2 in the PVI-only group and 7 in the PVI þ lines group) with AT or atrial flutter. This difference in recurrence mechanism did not meet statistical significance (P ¼ .26). There was no significant association between the presence of an incomplete ablation lesion and AF/AT recurrence (8 of 43 [19%] with recurrence vs 11 of 79 [14%] without; P ¼ .5). This remained true for subgroup analysis according to treatment arm. Although none of these comparisons reached statistical significance, it should be noted that the size of the study did not have sufficient power to adequately investigate the differences seen. Predictors of AF recurrence Univariate and multivariable predictors of the primary end point were sought using logistic regression analysis. Details of the analysis are given in Table 3. Only female sex and procedural duration met the prespecified inclusion criteria for inclusion in the multivariable model. However, only procedure duration remained significant in multivariable analysis (odds ratio [OR] (per minute) 1.01; 95% confidence interval [CI] 1.01–1.02; P ¼ .03). Per-protocol and as-treated analyses The per-protocol analysis for the primary end point showed no significant difference between the treatment groups (31.4% [PVI-only group] vs 37.3% [PVI þ lines group]; P ¼ .52), suggesting that protocol deviations had a negligible effect on the findings by ITT analysis. Furthermore, as 2 patients randomized to lines received PVI alone, we performed the as-treated analysis of PVI alone against both PVI
þ complete linear lesion set (32.1% [PVI alone] vs 43.6% [PVI þ complete linear lesion set] P ¼ .61) and PVI þ any linear ablation (32.1% [PVI alone] vs 37.7% [PVI þ any linear ablation]; P ¼ .52). The results of both these additional sensitivity analyses were in concordance with the main ITT analysis.
Secondary end points Comparison of PeAF and SusPAF Of the 122 patients who completed follow-up, the primary end point was observed in 24 of 75 patients with PeAF (32.0%) and 19 of 47 with SusPAF (40.4%) (P ¼ .34). The mean duration of PeAF was 5.5 ⫾ 4.2 months in the PVI-only group and 5.5 ⫾ 3.9 months in the PVI þ lines group (P ¼ .98). Although not powered for subgroup analysis, there was no signal that the occurrence of the primary end point differed between treatment arms according to AF type (PeAF [PVI 27.8%; PVI þ lines 35.9%; P ¼ .45] and SusPAF [PVI 39.1%; PVI þ lines 41.7%; P ¼ .86]). Outcomes after multiple procedures Sixteen patients (8 in each group) had repeat ablation procedures performed, and 10 of these remained free of AF/AT after their second procedure, although it should be borne in mind that the follow-up period after a second ablation procedure is considerably shorter (median 110 days; interquartile range 43–207 days) than that after the index procedure. After their last procedure, recurrence of AF/AT occurred in 14 patients (23.7%) in the PVI-only group and 14 patients (30.2%) in the PVI þ lines group (P ¼ .42). Quality of life The overall AFEQT score for the cohort at baseline was 50.9 ⫾ 22.6, which improved significantly to 76.5 ⫾ 23.4 at the end of the study (P o .001). The improvement after ablation was seen in both treatment groups, with no significant difference between the study groups, either at baseline (50.5 ⫾ 23.3 vs 51.3 ⫾ 22.0; P ¼ .86) or at the final follow-up visit (76.9 ⫾ 23.0 vs 76.1 ⫾ 24.1; P ¼ .62). Also, the individual AFEQT domains of symptoms, activities, and concerns all followed the same pattern, with each improving significantly between baseline and the final follow-up visit as an overall cohort and when analyzed according to treatment
404 Table 3
Heart Rhythm, Vol 13, No 2, February 2016 Details of the logistic regression analysis Univariate analysis
Multivariable analysis
Variable
Odds ratio
95% confidence interval
P
Ablation time (per minute) CHA2DS2-VASc score Diabetes Ejection fraction (%) Sex: female General anesthetic Hypertension Incomplete lesions Left atrial diameter (per millimeter) Myocardial infarction Persistent AF Procedure time (per minute) Treatment allocation Wait time (min) Contact force sensing catheter
1.01 1.21 0.50 1.00 1.99 0.83 0.90 1.41 1.01 0.34 0.69 1.01 1.30 1.00 1.00
0.99–1.03 0.91–1.561 0.17–1.44 0.97–1.04 0.91–4.36 0.39–1.77 0.42–1.91 0.52–3.83 0.94–1.07 0.07–1.61 0.33–1.48 1.00–1.02 0.61–2.73 0.99–1.01 0.27–3.63
.29 .19 .20 .97 .09 .62 .78 .50 .89 .17 .34 .02 .50 .54 4.99
Odds ratio
95% confidence interval
P
1.01
1.01–1.02
.03
AF ¼ atrial fibrillation.
group (P r .001 for all analyses), but all between-group analyses were nonsignificant. The mental component score of the Short Form 36 Health Survey improved significantly over the course of the study (from 45.7 ⫾ 12.1 to 52.0 ⫾ 9.5; P o .001), but the physical component score did not (from 44.7 ⫾ 10.8 to 47.9 ⫾ 10.5; P ¼ .07). Treatment groups did not differ significantly for either component score either at baseline (physical component score: P ¼ .39; mental component score: P ¼ .72) or at 12 months (physical component score: P ¼ .09; mental component score: P ¼ .73).
Safety end point One patient (PVI-only group) developed a pericardial effusion postprocedure, successfully drained percutaneously without sequalae. Two patients developed femoral pseudoaneurysms, both successfully treated with direct thrombin injection. The rate of major complications was 2.4% (3 of 124), with no difference between groups (P ¼ .62). There were no periprocedural deaths, and no thromboembolic events occurred in the periprocedural period or during follow-up. Five patients developed femoral hematomas, which were managed conservatively but which either delayed discharge or prompted readmission. Two patients (both of the PVI þ lines group) were admitted with heart failure after their procedure, both of whom were successfully managed medically. Including these, the combined incidence of major complications, all-cause death, and minor complications was 9.7%, with no difference between the treatment groups (PVI 8.2%; PVI þ lines 9.5%; P 4 .99).
Discussion AF represents a spectrum of disease ranging from lone occasional PAF at one end to long-standing PeAF in the presence of multiple comorbidities at the other. It is believed that while the former is largely caused by ectopic triggers in
the PVs, patients with more advanced disease suffer from an increasing contribution from abnormal structural and electrical atrial “substrate” that contributes to the perpetuation of AF. As such, it is important to evaluate interventions that can modify this atrial substrate favorably. Our group’s previous meta-analysis found that the addition of lines was the only adjunctive ablation lesion to significantly reduce the risk of AF recurrence in patients with PeAF (OR 0.22; 95% CI 0.10–0.49; P o .001).22 Two of the studies that contributed to that analysis also included patients with PAF and found a benefit of lines in both. However, we found no such difference in the RCT we present here. There may be several reasons why our results differ from those of the aforementioned studies. Unlike them, our protocol specified PVI by the WACA technique that involves ablation of a significant amount of antral atrial, rather than venous, tissue.23 WACA may well have an additional substrate modification effect over and above pure venous isolation by creating physical barriers to reentry, interrupting potential sites of rotor activation and by modification of autonomic innervation due to indirect ablation of ganglionated plexi, typically concentrated antrally. We previously found WACA to be associated with a nonsignificant trend toward a lower incidence of AF recurrence compared to segmental PVI (OR 0.41; 95% CI 0.15–1.10; P ¼ .08).22 In addition, our study had a high use of contact force sensing ablation catheters, which have recently been shown to improve the durability of PVI.24,25 The widespread adoption of such technology may necessitate reevaluation of much of the evidence base derived from the era before it was available. Our acute success rates (isolation of 98% of PVs and bidirectional block of 90% of lines) compare favorably with those in the previous studies in which the rates of bidirectional linear block ranged from 31% to 80%. However, all ablation lesions have the potential for subacute recovery, leading to zones of slow conduction that may be proarrhythmic and explain the slightly worse results seen in our study with more extensive ablation. It may well be that
Wynn et al
SMAN-PAF Trial
after high-quality durable WACA PVI, “less is more” in terms of additional lesions. Our results are concordant with the recent Substrate and Trigger Ablation for Reduction of Atrial Fibrillation 2 trial, which showed no incremental benefit of lines or complex electrogram ablation over PVI alone, with both groups performing nonsignificantly worse, as in our trial, than PVI alone.26 Taken together, these 2 trials would suggest that given the shorter procedure times, ablation times, and lower radiation doses associated with a PVI-only strategy, clinicians should avoid the empirical use of additional linear lesions. In this study, we included patients with PAF if they had additional risk factor(s) for poor outcome after ablation and, importantly, only if their paroxysms lasted 412 hours, as we felt this was suggestive of a role of left atrial substrate in maintaining these prolonged attacks. For convenience, we used the nonstandard term SusPAF. Several clinical risk factors such as systemic hypertension, diabetes mellitus, obesity, and sleep apnea have been associated with altered atrial substrate,7–10 and recent magnetic resonance imagingbased research has shown that advanced atrial substrate can be present even in patients with PAF and is associated with poor outcomes with PVI.27 The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation trial similarly included both patients with PeAF and “advanced” PAF.28 Our subanalyses by AF type suggests that the inclusion of the SusPAF group did not alter the overall primary finding of our trial, and the similarity of results between the SusPAF and PeAF groups would seem to back our assertion that patients with SusPAF have a similar disease process to those with PeAF. In our trial, we mandated universal use of AADs in the periprocedural period, whereas previous studies have usually discontinued AADs at or before the time of ablation. The benefit of continued AAD has been suggested by a number of observational studies.5,29 Although the recently published AMIOdarone after CATheter ablation for atrial fibrillation (AMIO-CAT) RCT found no benefit of 8 weeks of amiodarone in 212 patients with either PAF or PeAF,30 we cannot exclude the possibility that our use of this strategy reduced the benefit that would have been seen in one study group or the other in this trial. Our study excluded patients with long-standing PeAF as well as patients with paroxysmal AF (PAF) without other possible risk factors for substrate abnormalities, and therefore our results cannot be extrapolated to these groups. Brooks et al31 performed a comprehensive review of studies in long-standing PeAF. They found low success rates in, mainly nonrandomized, studies using a PVI-only strategy. A prospective RCT in this group, using modern WACA techniques, may now be warranted.
Study limitations Our follow-up period of 12 months will not have identified late AF recurrences, but this would not be expected to affect the comparison between the 2 study groups. Equally, our use of intermittent monitoring for AF/AT may have underestimated
405 the true recurrence rate, especially if patients suffered asymptomatic recurrences, but this potential underestimate would not be expected to differ between groups. Our sample size calculation allowed for 5% attrition rate, whereas our eventual rate was 6%. However, our results show no trend to suggest that a slightly larger sample would have produced a different result. Although we tested for entrance block into the PVs, our protocol did not mandate testing of exit block, nor the use of adenosine. It is possible that these additional techniques would have improved the durability of PVI. Finally, some patients in the PVI þ lines group received incomplete lesion sets while a few randomized to the PVI-only group received additional ablation of the CTI. With this in mind, we performed per-protocol and as-treated sensitivity analyses which showed no evidence that there was any confounding of the primary outcome.
Conclusion For patients with possible substrate-based AF, the addition of linear ablation lesions to PVI with WACA prolongs procedure duration and significantly increases radiation dose, but provides no additional clinical benefit in terms of freedom from arrhythmia or improvement in quality of life.
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CLINICAL PERSPECTIVES More advanced forms of atrial fibrillation (AF) are associated with lower success rates after pulmonary vein isolation (PVI), and more extensive lesion sets are often advocated, although recent data have questioned the validity of this approach. In this multicenter randomized controlled trial of 122 patients, we evaluated the impact of additional biatrial linear ablation compared with a strategy of wide antral PVI alone. We enrolled patients with persistent AF or sustained (412 hours) episodes of paroxysmal AF with Z1 other risk factor that might suggest an underlying substrate. High acute procedural success rates were achieved in both treatment arms. Over the 12-month follow-up period, recurrence of atrial tachyarrhythmia occurred in 38% of the PVI þ linear ablation group and 32% of the PVI-only group, a difference that was not statistically different. This pattern was consistent for both patients with persistent AF and those with sustained paroxysmal AF. Compared with the PVI-only group, the linear ablation group had significantly longer procedure duration and higher radiation exposure. Quality of life improved from baseline to the final follow-up visit, but did not differ between the treatment arms. Given that the more extensive ablation strategy (PVI þ linear ablation) provided no additional benefit for patients in terms of clinical outcome and quality of life, the ancillary benefits of shorter procedure times and lower radiation doses associated with a PVI-only strategy should make this the strategy of choice for clinicians.
